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Sample records for splicing factor polymorphisms

  1. Single nucleotide polymorphisms at erythropoietin, superoxide dismutase 1, splicing factor, arginine/serin-rich 15 and plasmacytoma variant translocation genes association with diabetic nephropathy

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    Maisaa Alwohhaib

    2014-01-01

    Full Text Available A number of genes have been identified in diabetic nephropathy. Association between diabetes-associated nephropathy and polymorphisms in the erythropoietin (EPO gene, variants in the superoxide dismutase 1 (SOD1 gene and plasmacytoma variant translocation 1 (PVT1 gene have been identified. The EPO, SOD1:SFRS15 and PVT1 genes were genotyped using the single nucleotide polymorphism (SNP technique in 38 diabetic nephropathy patients (Group 1 compared with 64 diabetic type 2 subjects without nephropathy (Group 2 at the Mubarak Alkabeer Hospital, Kuwait. The frequency of the risk allele T of the EPO (rs1617640 gene was high in both groups (0.96 in Group 1 and 0.92 in Group 2. Similarly, SNPs of the PVT1 (rs2720709 gene showed a higher frequency of the risk allele G in both groups (0.70 in the Group 1 and 0.68 in Group 2. Although the frequency of the risk allele A was higher than the frequency of the non-risk allele C of the SOD1:SFRS15 gene in both groups, the lowest probability value was observed in those gene SNPs (P = 0.05. We observed that the A allele of the SOD1:SFRS15 gene (rs17880135 was more frequently present in Group 1 (0.75 compared with Group 2 (0.62. Susceptibility to diabetes-associated nephropathy is partially mediated by genetic predisposition, and screening tests may open the gate for new therapeutic approaches.

  2. The Human Splicing Factor ASF/SF2 can Specifically Recognize Pre-mRNA 5' Splice Sites

    Science.gov (United States)

    Zuo, Ping; Manley, James L.

    1994-04-01

    ASF/SF2 is a human protein previously shown to function in in vitro pre-mRNA splicing as an essential factor necessary for all splices and also as an alternative splicing factor, capable of switching selection of 5' splice sites. To begin to study the protein's mechanism of action, we have investigated the RNA binding properties of purified recombinant ASF/SF2. Using UV crosslinking and gel shift assays, we demonstrate that the RNA binding region of ASF/SF2 can interact with RNA in a sequence-specific manner, recognizing the 5' splice site in each of two different pre-mRNAs. Point mutations in the 5' splice site consensus can reduce binding by as much as a factor of 100, with the largest effects observed in competition assays. These findings support a model in which ASF/SF2 aids in the recognition of pre-mRNA 5' splice sites.

  3. A synonymous polymorphic variation in ACADM exon 11 affects splicing efficiency and may affect fatty acid oxidation

    DEFF Research Database (Denmark)

    Bruun, Gitte Hoffmann; Doktor, Thomas Koed; Andresen, Brage Storstein

    2013-01-01

    beta-oxidation of medium-chain fatty acids. We examined the functional basis for this association and identified linkage between rs211718 and the intragenic synonymous polymorphic variant c.1161A>G in ACADM exon 11 (rs1061337). Employing minigene studies we show that the c.1161A allele is associated......, perhaps due to improved splicing. This study is a proof of principle that synonymous SNPs are not neutral. By changing the binding sites for splicing regulatory proteins they can have significant effects on pre-mRNA splicing and thus protein function. In addition, this study shows that for a sequence...

  4. Functions for fission yeast splicing factors SpSlu7 and SpPrp18 in alternative splice-site choice and stress-specific regulated splicing.

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    Geetha Melangath

    Full Text Available Budding yeast spliceosomal factors ScSlu7 and ScPrp18 interact and mediate intron 3'ss choice during second step pre-mRNA splicing. The fission yeast genome with abundant multi-intronic transcripts, degenerate splice signals and SR proteins is an apt unicellular fungal model to deduce roles for core spliceosomal factors in alternative splice-site choice, intron retention and to study the cellular implications of regulated splicing. From our custom microarray data we deduce a stringent reproducible subset of S. pombe alternative events. We examined the role of factors SpSlu7 or SpPrp18 for these splice events and investigated the relationship to growth phase and stress. Wild-type log and stationary phase cells showed ats1+ exon 3 skipped and intron 3 retained transcripts. Interestingly the non-consensus 5'ss in ats1+ intron 3 caused SpSlu7 and SpPrp18 dependent intron retention. We validated the use of an alternative 5'ss in dtd1+ intron 1 and of an upstream alternative 3'ss in DUF3074 intron 1. The dtd1+ intron 1 non-canonical 5'ss yielded an alternative mRNA whose levels increased in stationary phase. Utilization of dtd1+ intron 1 sub-optimal 5' ss required functional SpPrp18 and SpSlu7 while compromise in SpSlu7 function alone hampered the selection of the DUF3074 intron 1 non canonical 3'ss. We analysed the relative abundance of these splice isoforms during mild thermal, oxidative and heavy metal stress and found stress-specific splice patterns for ats1+ and DUF3074 intron 1 some of which were SpSlu7 and SpPrp18 dependent. By studying ats1+ splice isoforms during compromised transcription elongation rates in wild-type, spslu7-2 and spprp18-5 mutant cells we found dynamic and intron context-specific effects in splice-site choice. Our work thus shows the combinatorial effects of splice site strength, core splicing factor functions and transcription elongation kinetics to dictate alternative splice patterns which in turn serve as an additional

  5. Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

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    Michael Seiler

    2018-04-01

    Full Text Available Summary: Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA, and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like, or hotspot mutation profile (oncogene-like. Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis. : Seiler et al. report that 119 splicing factor genes carry putative driver mutations over 33 tumor types in TCGA. The most common mutations appear to be mutually exclusive and are associated with lineage-independent altered splicing. Samples with these mutations show deregulation of cell-autonomous pathways and immune infiltration. Keywords: splicing, SF3B1, U2AF1, SRSF2, RBM10, FUBP1, cancer, mutation

  6. Genome-wide data-mining of candidate human splice translational efficiency polymorphisms (STEPs and an online database.

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    Christopher A Raistrick

    2010-10-01

    Full Text Available Variation in pre-mRNA splicing is common and in some cases caused by genetic variants in intronic splicing motifs. Recent studies into the insulin gene (INS discovered a polymorphism in a 5' non-coding intron that influences the likelihood of intron retention in the final mRNA, extending the 5' untranslated region and maintaining protein quality. Retention was also associated with increased insulin levels, suggesting that such variants--splice translational efficiency polymorphisms (STEPs--may relate to disease phenotypes through differential protein expression. We set out to explore the prevalence of STEPs in the human genome and validate this new category of protein quantitative trait loci (pQTL using publicly available data.Gene transcript and variant data were collected and mined for candidate STEPs in motif regions. Sequences from transcripts containing potential STEPs were analysed for evidence of splice site recognition and an effect in expressed sequence tags (ESTs. 16 publicly released genome-wide association data sets of common diseases were searched for association to candidate polymorphisms with HapMap frequency data. Our study found 3324 candidate STEPs lying in motif sequences of 5' non-coding introns and further mining revealed 170 with transcript evidence of intron retention. 21 potential STEPs had EST evidence of intron retention or exon extension, as well as population frequency data for comparison.Results suggest that the insulin STEP was not a unique example and that many STEPs may occur genome-wide with potentially causal effects in complex disease. An online database of STEPs is freely accessible at http://dbstep.genes.org.uk/.

  7. The conserved splicing factor SUA controls alternative splicing of the developmental regulator ABI3 in Arabidopsis.

    NARCIS (Netherlands)

    Sugliani, M.; Brambilla, V.; Clerkx, E.J.M.; Koornneef, M.; Soppe, W.J.J.

    2010-01-01

    ABSCISIC ACID INSENSITIVE3 (ABI3) is a major regulator of seed maturation in Arabidopsis thaliana. We detected two ABI3 transcripts, ABI3- and ABI3-ß, which encode full-length and truncated proteins, respectively. Alternative splicing of ABI3 is developmentally regulated, and the ABI3-ß transcript

  8. Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing

    Science.gov (United States)

    Shinde, Mansi Y.; Sidoli, Simone; Kulej, Katarzyna; Mallory, Michael J.; Radens, Caleb M.; Reicherter, Amanda L.; Myers, Rebecca L.; Barash, Yoseph; Lynch, Kristen W.; Garcia, Benjamin A.; Klein, Peter S.

    2017-01-01

    Glycogen synthase kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed protein kinase that regulates multiple signaling pathways. In vitro kinase assays and genetic and pharmacological manipulations of GSK-3 have identified more than 100 putative GSK-3 substrates in diverse cell types. Many more have been predicted on the basis of a recurrent GSK-3 consensus motif ((pS/pT)XXX(S/T)), but this prediction has not been tested by analyzing the GSK-3 phosphoproteome. Using stable isotope labeling of amino acids in culture (SILAC) and MS techniques to analyze the repertoire of GSK-3–dependent phosphorylation in mouse embryonic stem cells (ESCs), we found that ∼2.4% of (pS/pT)XXX(S/T) sites are phosphorylated in a GSK-3–dependent manner. A comparison of WT and Gsk3a;Gsk3b knock-out (Gsk3 DKO) ESCs revealed prominent GSK-3–dependent phosphorylation of multiple splicing factors and regulators of RNA biosynthesis as well as proteins that regulate transcription, translation, and cell division. Gsk3 DKO reduced phosphorylation of the splicing factors RBM8A, SRSF9, and PSF as well as the nucleolar proteins NPM1 and PHF6, and recombinant GSK-3β phosphorylated these proteins in vitro. RNA-Seq of WT and Gsk3 DKO ESCs identified ∼190 genes that are alternatively spliced in a GSK-3–dependent manner, supporting a broad role for GSK-3 in regulating alternative splicing. The MS data also identified posttranscriptional regulation of protein abundance by GSK-3, with ∼47 proteins (1.4%) whose levels increased and ∼78 (2.4%) whose levels decreased in the absence of GSK-3. This study provides the first unbiased analysis of the GSK-3 phosphoproteome and strong evidence that GSK-3 broadly regulates alternative splicing. PMID:28916722

  9. The Associations between RNA Splicing Complex Gene SF3A1 Polymorphisms and Colorectal Cancer Risk in a Chinese Population.

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    Xiaohua Chen

    Full Text Available Aberrant alternative splicing included alterations in components of the mRNA splicing machinery often occurred in colon cancer. However, the role of SF3A1, one key component of the mRNA splicing machinery, on colorectal cancer (CRC risk was still not elucidated.We performed a hospital-based case-control study containing 801 CRC patients and 817 cancer-free controls to examine the association between SF3A1 polymorphisms and CRC risk in a Chinese population. Four candidate SNPs (rs10376, rs5753073, rs2839998 and rs2074733 were selected based on bioinformatics analysis and previous findings. The results showed no significant associations between these SNPs and CRC risk (P > 0.05. Besides, the stratified analysis based on the smoking and alcohol use status obtained no statistically significant results.Our study was the first one to investigate the association between SF3A1 polymorphisms and CRC risk. The results suggested these four SNPs in SF3A1 were not associated with CRC risk in a Chinese population, however, further more studies are needed to confirm our findings.

  10. The RNA splicing factor ASF/SF2 inhibits human topoisomerase I mediated DNA relaxation

    DEFF Research Database (Denmark)

    Andersen, Félicie Faucon; Tange, Thomas Ø.; Sinnathamby, Thayaline

    2002-01-01

    Human topoisomerase I interacts with and phosphorylates the SR-family of RNA splicing factors, including ASF/SF2, and has been suggested to play an important role in the regulation of RNA splicing. Here we present evidence to support the theory that the regulation can go the other way around...

  11. RRM domain of Arabidopsis splicing factor SF1 is important for pre-mRNA splicing of a specific set of genes

    KAUST Repository

    Lee, Keh Chien

    2017-04-11

    The RNA recognition motif of Arabidopsis splicing factor SF1 affects the alternative splicing of FLOWERING LOCUS M pre-mRNA and a heat shock transcription factor HsfA2 pre-mRNA. Splicing factor 1 (SF1) plays a crucial role in 3\\' splice site recognition by binding directly to the intron branch point. Although plant SF1 proteins possess an RNA recognition motif (RRM) domain that is absent in its fungal and metazoan counterparts, the role of the RRM domain in SF1 function has not been characterized. Here, we show that the RRM domain differentially affects the full function of the Arabidopsis thaliana AtSF1 protein under different experimental conditions. For example, the deletion of RRM domain influences AtSF1-mediated control of flowering time, but not the abscisic acid sensitivity response during seed germination. The alternative splicing of FLOWERING LOCUS M (FLM) pre-mRNA is involved in flowering time control. We found that the RRM domain of AtSF1 protein alters the production of alternatively spliced FLM-β transcripts. We also found that the RRM domain affects the alternative splicing of a heat shock transcription factor HsfA2 pre-mRNA, thereby mediating the heat stress response. Taken together, our results suggest the importance of RRM domain for AtSF1-mediated alternative splicing of a subset of genes involved in the regulation of flowering and adaptation to heat stress.

  12. Splicing regulatory factors, ageing and age-related disease.

    Science.gov (United States)

    Latorre, Eva; Harries, Lorna W

    2017-07-01

    Alternative splicing is a co-transcriptional process, which allows for the production of multiple transcripts from a single gene and is emerging as an important control point for gene expression. Alternatively expressed isoforms often have antagonistic function and differential temporal or spatial expression patterns, yielding enormous plasticity and adaptability to cells and increasing their ability to respond to environmental challenge. The regulation of alternative splicing is critical for numerous cellular functions in both pathological and physiological conditions, and deregulated alternative splicing is a key feature of common chronic diseases. Isoform choice is controlled by a battery of splicing regulatory proteins, which include the serine arginine rich (SRSF) proteins and the heterogeneous ribonucleoprotein (hnRNP) classes of genes. These important splicing regulators have been implicated in age-related disease, and in the ageing process itself. This review will outline the important contribution of splicing regulator proteins to ageing and age-related disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

    DEFF Research Database (Denmark)

    Heintz, Caroline; Doktor, Thomas K; Lanjuin, Anne

    2017-01-01

    via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also...... homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction...

  14. Rhythmic Behavior Is Controlled by the SRm160 Splicing Factor in Drosophila melanogaster.

    Science.gov (United States)

    Beckwith, Esteban J; Hernando, Carlos E; Polcowñuk, Sofía; Bertolin, Agustina P; Mancini, Estefania; Ceriani, M Fernanda; Yanovsky, Marcelo J

    2017-10-01

    Circadian clocks organize the metabolism, physiology, and behavior of organisms throughout the day-night cycle by controlling daily rhythms in gene expression at the transcriptional and post-transcriptional levels. While many transcription factors underlying circadian oscillations are known, the splicing factors that modulate these rhythms remain largely unexplored. A genome-wide assessment of the alterations of gene expression in a null mutant of the alternative splicing regulator SR-related matrix protein of 160 kDa (SRm160) revealed the extent to which alternative splicing impacts on behavior-related genes. We show that SRm160 affects gene expression in pacemaker neurons of the Drosophila brain to ensure proper oscillations of the molecular clock. A reduced level of SRm160 in adult pacemaker neurons impairs circadian rhythms in locomotor behavior, and this phenotype is caused, at least in part, by a marked reduction in period ( per ) levels. Moreover, rhythmic accumulation of the neuropeptide PIGMENT DISPERSING FACTOR in the dorsal projections of these neurons is abolished after SRm160 depletion. The lack of rhythmicity in SRm160-downregulated flies is reversed by a fully spliced per construct, but not by an extra copy of the endogenous locus, showing that SRm160 positively regulates per levels in a splicing-dependent manner. Our findings highlight the significant effect of alternative splicing on the nervous system and particularly on brain function in an in vivo model. Copyright © 2017 by the Genetics Society of America.

  15. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations

    DEFF Research Database (Denmark)

    Nielsen, Karsten Bork; Sørensen, Suzette; Cartegni, Luca

    2007-01-01

    assays to show that a missense mutation in exon 5 of the medium-chain acyl-CoA dehydrogenase (MCAD) gene primarily causes exon skipping by inactivating a crucial exonic splicing enhancer (ESE), thus leading to loss of a functional protein and to MCAD deficiency. This ESE functions by antagonizing...

  16. The group II intron maturase: a reverse transcriptase and splicing factor go hand in hand.

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    Zhao, Chen; Pyle, Anna Marie

    2017-12-01

    The splicing of group II introns in vivo requires the assistance of a multifunctional intron encoded protein (IEP, or maturase). Each IEP is also a reverse-transcriptase enzyme that enables group II introns to behave as mobile genetic elements. During splicing or retro-transposition, each group II intron forms a tight, specific complex with its own encoded IEP, resulting in a highly reactive holoenzyme. This review focuses on the structural basis for IEP function, as revealed by recent crystal structures of an IEP reverse transcriptase domain and cryo-EM structures of an IEP-intron complex. These structures explain how the same IEP scaffold is utilized for intron recognition, splicing and reverse transcription, while providing a physical basis for understanding the evolutionary transformation of the IEP into the eukaryotic splicing factor Prp8. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Molecular effects of autoimmune-risk promoter polymorphisms on expression, exon choice, and translational efficiency of interferon regulatory factor 5.

    Science.gov (United States)

    Clark, Daniel N; Lambert, Jared P; Till, Rodney E; Argueta, Lissenya B; Greenhalgh, Kathryn E; Henrie, Brandon; Bills, Trieste; Hawkley, Tyson F; Roznik, Marinya G; Sloan, Jason M; Mayhew, Vera; Woodland, Loc; Nelson, Eric P; Tsai, Meng-Hsuan; Poole, Brian D

    2014-05-01

    The rs2004640 single nucleotide polymorphism and the CGGGG copy-number variant (rs77571059) are promoter polymorphisms within interferon regulatory factor 5 (IRF5). They have been implicated as susceptibility factors for several autoimmune diseases. IRF5 uses alternative promoter splicing, where any of 4 first exons begin the mRNA. The CGGGG indel is in exon 1A's promoter; the rs2004640 allele creates a splicing recognition site, enabling usage of exon 1B. This study aimed at characterizing alterations in IRF5 mRNA due to these polymorphisms. Cells with risk polymorphisms exhibited ~2-fold higher levels of IRF5 mRNA and protein, but demonstrated no change in mRNA stability. Quantitative PCR demonstrated decreased usage of exons 1C and 1D in cell lines with the risk polymorphisms. RNA folding analysis revealed a hairpin in exon 1B; mutational analysis showed that the hairpin shape decreased translation 5-fold. Although translation of mRNA that uses exon 1B is low due to a hairpin, increased IRF5 mRNA levels in individuals with the rs2004640 risk allele lead to higher overall protein expression. In addition, several new splice variants of IRF5 were sequenced. IRF5's promoter polymorphisms alter first exon usage and increase transcription levels. High levels of IRF5 may bias the immune system toward autoimmunity.

  18. Characterization of an apparently synonymous F5 mutation causing aberrant splicing and factor V deficiency.

    Science.gov (United States)

    Nuzzo, F; Bulato, C; Nielsen, B I; Lee, K; Wielders, S J; Simioni, P; Key, N S; Castoldi, E

    2015-03-01

    Coagulation factor V (FV) deficiency is a rare autosomal recessive bleeding disorder. We investigated a patient with severe FV deficiency (FV:C mutation in exon 4 (c.578G>C, p.Cys193Ser), predicting the abolition of a conserved disulphide bridge, and an apparently synonymous variant in exon 8 (c.1281C>G). The observation that half of the patient's F5 mRNA lacked the last 18 nucleotides of exon 8 prompted us to re-evaluate the c.1281C>G variant for its possible effects on splicing. Bioinformatics sequence analysis predicted that this transversion would activate a cryptic donor splice site and abolish an exonic splicing enhancer. Characterization in a F5 minigene model confirmed that the c.1281C>G variant was responsible for the patient's splicing defect, which could be partially corrected by a mutation-specific morpholino antisense oligonucleotide. The aberrantly spliced F5 mRNA, whose stability was similar to that of the normal mRNA, encoded a putative FV mutant lacking amino acids 427-432. Expression in COS-1 cells indicated that the mutant protein is poorly secreted and not functional. In conclusion, the c.1281C>G mutation, which was predicted to be translationally silent and hence neutral, causes FV deficiency by impairing pre-mRNA splicing. This finding underscores the importance of cDNA analysis for the correct assessment of exonic mutations. © 2014 John Wiley & Sons Ltd.

  19. Effect of splice-site polymorphisms of the TMPRSS4, NPHP4 and ...

    Indian Academy of Sciences (India)

    Unknown

    Genetic polymorphisms associated with structural changes of their gene product are important in terms of their poten- tial relation with .... PCR conditions are available on request. ... lyze (ver 3.2) software (Dynacom, Yokohama, Japan).

  20. Targeting Splicing in Prostate Cancer

    OpenAIRE

    Effrosyni Antonopoulou; Michael Ladomery

    2018-01-01

    Over 95% of human genes are alternatively spliced, expressing splice isoforms that often exhibit antagonistic functions. We describe genes whose alternative splicing has been linked to prostate cancer; namely VEGFA, KLF6, BCL2L2, ERG, and AR. We discuss opportunities to develop novel therapies that target specific splice isoforms, or that target the machinery of splicing. Therapeutic approaches include the development of small molecule inhibitors of splice factor kinases, splice isoform speci...

  1. The role of polymorphisms in the spliced leader addition domain in determining promoter activity in Brugia malayi.

    Science.gov (United States)

    Bailey, Michelle; Chauhan, Chitra; Liu, Canhui; Unnasch, Thomas R

    2011-03-01

    Previous studies of Brugia malayi promoters have suggested that they are unusual in that they lack the CAAT or TATAA boxes that are often emblematic of eucaryotic core promoter domains. Instead, the region surrounding the spliced leader (SL) addition site appears to function as the core promoter domain in B. malayi. To test the hypothesis that polymorphisms in this SL addition domain are important determinants of promoter activity, a series of domain swap mutants were prepared replacing the SL addition domain of the B. malayi 13kDa large subunit ribosomal protein (BmRPL13) with those of other ribosomal protein (RP) promoters exhibiting a wide range of activities. These constructs were then tested for promoter activity in a homologous transient transfection system. On average, polymorphisms in the SL addition domain were found to be responsible for 80% of the variation in promoter activity exhibited by the RP promoters tested. Essentially all of this effect could be attributable to polymorphisms in the 10nt located directly upstream of the SL addition site. A comparison of the sequence of this domain to the promoter activity exhibited by the domain swap mutants suggested that promoter activity was related to the number of T residues present in the coding strand of the upstream domain. Confirming this, mutation of the upstream domain of the promoter of the BmRPS4 gene to a homogeneous stretch of 10 T residues resulted in a significant increase in promoter activity. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. The splicing factor SRSF6 is amplified and is an oncoprotein in lung and colon cancers

    DEFF Research Database (Denmark)

    Cohen-Eliav, Michal; Golan-Gerstl, Regina; Siegfried, Zahava

    2013-01-01

    and lung tumors and found that the gene encoding for the splicing factor SRSF6 is amplified and overexpressed in these cancers. Moreover, overexpression of SRSF6 in immortal lung epithelial cells enhanced proliferation, protected them from chemotherapy-induced cell death and converted them...

  3. Poliovirus 2A protease triggers a selective nucleo-cytoplasmic redistribution of splicing factors to regulate alternative pre-mRNA splicing.

    Directory of Open Access Journals (Sweden)

    Enrique Álvarez

    Full Text Available Poliovirus protease 2A (2A(pro obstructs host gene expression by reprogramming transcriptional and post-transcriptional regulatory events during infection. Here we demonstrate that expression of 2A(pro induces a selective nucleo-cytoplasm translocation of several important RNA binding proteins and splicing factors. Subcellular fractionation studies, together with immunofluorescence microscopy revealed an asymmetric distribution of HuR and TIA1/TIAR in 2A(pro expressing cells, which modulates splicing of the human Fas exon 6. Consistent with this result, knockdown of HuR or overexpression of TIA1/TIAR, leads to Fas exon 6 inclusion in 2A(pro-expressing cells. Therefore, poliovirus 2A(pro can target alternative pre-mRNA splicing by regulating protein shuttling between the nucleus and the cytoplasm.

  4. The Splicing Factor SRSF1 as a Marker for Endothelial Senescence

    Science.gov (United States)

    Blanco, Francisco Javier; Bernabéu, Carmelo

    2012-01-01

    Aging is the major risk factor per se for the development of cardiovascular diseases. The senescence of the endothelial cells (ECs) that line the lumen of blood vessels is the cellular basis for these age-dependent vascular pathologies, including atherosclerosis and hypertension. During their lifespan, ECs may reach a stage of senescence by two different pathways; a replicative one derived from their preprogrammed finite number of cell divisions; and one induced by stress stimuli. Also, certain physiological stimuli, such as transforming growth factor-β, are able to modulate cellular senescence. Currently, the cellular aging process is being widely studied to identify novel molecular markers whose changes correlate with senescence. This review focuses on the regulation of alternative splicing mediated by the serine–arginine splicing factor 1 (SRSF1, or ASF/SF2) during endothelial senescence, a process that is associated with a differential subcellular localization of SRSF1, which typically exhibits a scattered distribution throughout the cytoplasm. Based on its senescence-dependent involvement in alternative splicing, we postulate that SRSF1 is a key marker of EC senescence, regulating the expression of alternative isoforms of target genes such as endoglin (ENG), vascular endothelial growth factor A (VEGFA), tissue factor (T3), or lamin A (LMNA) that integrate in a common molecular senescence program. PMID:22470345

  5. PAP-1, the mutated gene underlying the RP9 form of dominant retinitis pigmentosa, is a splicing factor

    International Nuclear Information System (INIS)

    Maita, Hiroshi; Kitaura, Hirotake; Keen, T. Jeffrey; Inglehearn, Chris F.; Ariga, Hiroyoshi; Iguchi-Ariga, Sanae M.M.

    2004-01-01

    PAP-1 is an in vitro phosphorylation target of the Pim-1 oncogene. Although PAP-1 binds to Pim-1, it is not a substrate for phosphorylation by Pim-1 in vivo. PAP-1 has recently been implicated as the defective gene in RP9, one type of autosomal dominant retinitis pigmentosa (adRP). However, RP9 is a rare disease and only two missense mutations have been described, so the report of a link between PAP-1 and RP9 was tentative. The precise cellular role of PAP-1 was also unknown at that time. We now report that PAP-1 localizes in nuclear speckles containing the splicing factor SC35 and interacts directly with another splicing factor, U2AF35. Furthermore, we used in vitro and in vivo splicing assays to show that PAP-1 has an activity, which alters the pattern of pre-mRNA splicing and that this activity is dependent on the phosphorylation state of PAP-1. We used the same splicing assay to examine the activities of two mutant forms of PAP-1 found in RP9 patients. The results showed that while one of the mutations, H137L, had no effect on splicing activity compared with that of wild-type PAP-1, the other, D170G, resulted in both a defect in splicing activity and a decreased proportion of phosphorylated PAP-1. The D170G mutation may therefore cause RP by altering splicing of retinal genes through a decrease in PAP-1 phosphorylation. These results demonstrate that PAP-1 has a role in pre-mRNA splicing and, given that three other splicing factors have been implicated in adRP, this finding provides compelling further evidence that PAP-1 is indeed the RP9 gene

  6. Novel splice mutation in microthalmia-associated transcription factor in Waardenburg Syndrome.

    Science.gov (United States)

    Brenner, Laura; Burke, Kelly; Leduc, Charles A; Guha, Saurav; Guo, Jiancheng; Chung, Wendy K

    2011-01-01

    Waardenburg Syndrome (WS) is a syndromic form of hearing loss associated with mutations in six different genes. We identified a large family with WS that had previously undergone clinical testing, with no reported pathogenic mutation. Using linkage analysis, a region on 3p14.1 with an LOD score of 6.6 was identified. Microthalmia-Associated Transcription Factor, a gene known to cause WS, is located within this region of linkage. Sequencing of Microthalmia-Associated Transcription Factor demonstrated a c.1212 G>A synonymous variant that segregated with the WS in the family and was predicted to cause a novel splicing site that was confirmed with expression analysis of the mRNA. This case illustrates the need to computationally analyze novel synonymous sequence variants for possible effects on splicing to maximize the clinical sensitivity of sequence-based genetic testing.

  7. Loss of Pnn expression attenuates expression levels of SR family splicing factors and modulates alternative pre-mRNA splicing in vivo

    International Nuclear Information System (INIS)

    Chiu Yali; Ouyang Pin

    2006-01-01

    SR and SR-related proteins have been implicated as trans-acting factors that play an important role in splice selection and are involved at specific stages of spliceosome formation. A well-established property of SR protein splicing factors is their ability to influence selection of alternative splice sites in a concentration-dependent manner. Identification of molecules that regulate SR family protein expression is therefore of vital importance in RNA biology. Here we report that depletion of Pnn expression, a SR-related protein with functions involved in pre-mRNA splicing and mRNA export, induces reduced expression of a subset of cellular proteins, especially that of SR family proteins, including SC35, SRm300, SRp55, and SRp40, but not that of other nuclear proteins, such as p53, Mdm2, and ki67. Knocking down Pnn expression was achieved in vitro by siRNA transfection. Expression levels of SR and SR-related proteins in Pnn-depleted cells as compared to those in control cells were evaluated by immunofluorescent staining and Western blot with specific antibodies. In addition, we also demonstrate that loss of Pnn expression could modulate splice site selection of model reporter gene in vivo. Our finding is significant in terms of regulation of SR protein cellular concentration because it reveals that Pnn may play a general role in the control of the cellular amount of family SR proteins through down-regulation of its own expression, thereby providing us with a better understanding of the cellular mechanism by which Pnn fulfills its biological function

  8. The candidate splicing factor Sfswap regulates growth and patterning of inner ear sensory organs.

    Directory of Open Access Journals (Sweden)

    Yalda Moayedi

    2014-01-01

    Full Text Available The Notch signaling pathway is thought to regulate multiple stages of inner ear development. Mutations in the Notch signaling pathway cause disruptions in the number and arrangement of hair cells and supporting cells in sensory regions of the ear. In this study we identify an insertional mutation in the mouse Sfswap gene, a putative splicing factor, that results in mice with vestibular and cochlear defects that are consistent with disrupted Notch signaling. Homozygous Sfswap mutants display hyperactivity and circling behavior consistent with vestibular defects, and significantly impaired hearing. The cochlea of newborn Sfswap mutant mice shows a significant reduction in outer hair cells and supporting cells and ectopic inner hair cells. This phenotype most closely resembles that seen in hypomorphic alleles of the Notch ligand Jagged1 (Jag1. We show that Jag1; Sfswap compound mutants have inner ear defects that are more severe than expected from simple additive effects of the single mutants, indicating a genetic interaction between Sfswap and Jag1. In addition, expression of genes involved in Notch signaling in the inner ear are reduced in Sfswap mutants. There is increased interest in how splicing affects inner ear development and function. Our work is one of the first studies to suggest that a putative splicing factor has specific effects on Notch signaling pathway members and inner ear development.

  9. A 5' splice site enhances the recruitment of basal transcription initiation factors in vivo

    DEFF Research Database (Denmark)

    Damgaard, Christian Kroun; Kahns, Søren; Lykke-Andersen, Søren

    2008-01-01

    RNAs, harboring wild-type or various 5′ splice site mutations, we demonstrate a strong positive correlation between splicing efficiency and transcription activity. Interestingly, a 5′ splice site can stimulate transcription even in the absence of splicing. Chromatin immunoprecipitation experiments show enhanced...... a promoter-proximal 5′ splice site via its U1 snRNA interaction can feed back to stimulate transcription initiation by enhancing preinitiation complex assembly....

  10. Alternative splicing of a single transcription factor drives selfish reproductive behavior in honeybee workers (Apis mellifera).

    Science.gov (United States)

    Jarosch, Antje; Stolle, Eckart; Crewe, Robin M; Moritz, Robin F A

    2011-09-13

    In eusocial insects the production of daughters is generally restricted to mated queens, and unmated workers are functionally sterile. The evolution of this worker sterility has been plausibly explained by kin selection theory [Hamilton W (1964) J Theor Biol 7:1-52], and many traits have evolved to prevent conflict over reproduction among the females in an insect colony. In honeybees (Apis mellifera), worker reproduction is regulated by the queen, brood pheromones, and worker policing. However, workers of the Cape honeybee, Apis mellifera capensis, can evade this control and establish themselves as social parasites by activating their ovaries, parthenogenetically producing diploid female offspring (thelytoky) and producing queen-like amounts of queen pheromones. All these traits have been shown to be strongly influenced by a single locus on chromosome 13 [Lattorff HMG, et al. (2007) Biol Lett 3:292-295]. We screened this region for candidate genes and found that alternative splicing of a gene homologous to the gemini transcription factor of Drosophila controls worker sterility. Knocking out the critical exon in a series of RNAi experiments resulted in rapid worker ovary activation-one of the traits characteristic of the social parasites. This genetic switch may be controlled by a short intronic splice enhancer motif of nine nucleotides attached to the alternative splice site. The lack of this motif in parasitic Cape honeybee clones suggests that the removal of nine nucleotides from the altruistic worker genome may be sufficient to turn a honeybee from an altruistic worker into a parasite.

  11. New polymorphic variants of human blood clotting factor IX

    Energy Technology Data Exchange (ETDEWEB)

    Surin, V.L.; Luk`yanenko, A.V.; Tagiev, A.F.; Smirnova, O.V. [Hematological Research Center, Moscow (Russian Federation); Plutalov, O.V.; Berlin, Yu.A. [Shemyakin Institute of Bioorganic Chemistry, Moscow (Russian Federation)

    1995-04-01

    The polymorphism of Alu-repeats, which are located in the introns of the human factor IX gene (copies 1-3), was studied. To identify polymorphic variants, direct sequencing of PCR products that contained appropriate repeats was used. In each case, 20 unrelated X chromosomes were studied. A polymorphic Dra I site was found near the 3{prime}-end of Alu copy 3 within the region of the polyA tract. A PCR-based testing system with internal control of restriction hydrolysis was suggested. Testing 81 unrelated X chromosomes revealed that the frequency of the polymorphic Dra I site is 0.23. Taq I polymorphism, which was revealed in Alu copy 4 of factor IX gene in our previous work, was found to be closely linked to Dra I polymorphism. Studies in linkage between different types of polymorphisms of the factor IX gene revealed the presence of a rare polymorphism in intron a that was located within the same minisatellite region as the known polymorphic insertion 50 bp/Dde I. However, the size of the insertion in our case was 26 bp. Only one polymorphic variant was found among over 150 unrelated X chromosomes derived from humans from Moscow and its vicinity. 10 refs., 4 figs., 1 tab.

  12. Structure, dynamics and RNA binding of the multi-domain splicing factor TIA-1

    Science.gov (United States)

    Wang, Iren; Hennig, Janosch; Jagtap, Pravin Kumar Ankush; Sonntag, Miriam; Valcárcel, Juan; Sattler, Michael

    2014-01-01

    Alternative pre-messenger ribonucleic acid (pre-mRNA) splicing is an essential process in eukaryotic gene regulation. The T-cell intracellular antigen-1 (TIA-1) is an apoptosis-promoting factor that modulates alternative splicing of transcripts, including the pre-mRNA encoding the membrane receptor Fas. TIA-1 is a multi-domain ribonucleic acid (RNA) binding protein that recognizes poly-uridine tract RNA sequences to facilitate 5′ splice site recognition by the U1 small nuclear ribonucleoprotein (snRNP). Here, we characterize the RNA interaction and conformational dynamics of TIA-1 by nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC) and small angle X-ray scattering (SAXS). Our NMR-derived solution structure of TIA-1 RRM2–RRM3 (RRM2,3) reveals that RRM2 adopts a canonical RNA recognition motif (RRM) fold, while RRM3 is preceded by an non-canonical helix α0. NMR and SAXS data show that all three RRMs are largely independent structural modules in the absence of RNA, while RNA binding induces a compact arrangement. RRM2,3 binds to pyrimidine-rich FAS pre-mRNA or poly-uridine (U9) RNA with nanomolar affinities. RRM1 has little intrinsic RNA binding affinity and does not strongly contribute to RNA binding in the context of RRM1,2,3. Our data unravel the role of binding avidity and the contributions of the TIA-1 RRMs for recognition of pyrimidine-rich RNAs. PMID:24682828

  13. Fanconi anemia FANCD2 and FANCI proteins regulate the nuclear dynamics of splicing factors.

    Science.gov (United States)

    Moriel-Carretero, María; Ovejero, Sara; Gérus-Durand, Marie; Vryzas, Dimos; Constantinou, Angelos

    2017-12-04

    Proteins disabled in the cancer-prone disorder Fanconi anemia (FA) ensure the maintenance of chromosomal stability during DNA replication. FA proteins regulate replication dynamics, coordinate replication-coupled repair of interstrand DNA cross-links, and mitigate conflicts between replication and transcription. Here we show that FANCI and FANCD2 associate with splicing factor 3B1 (SF3B1), a key spliceosomal protein of the U2 small nuclear ribonucleoprotein (U2 snRNP). FANCI is in close proximity to SF3B1 in the nucleoplasm of interphase and mitotic cells. Furthermore, we find that DNA replication stress induces the release of SF3B1 from nuclear speckles in a manner that depends on FANCI and on the activity of the checkpoint kinase ATR. In chromatin, both FANCD2 and FANCI associate with SF3B1, prevent accumulation of postcatalytic intron lariats, and contribute to the timely eviction of splicing factors. We propose that FANCD2 and FANCI contribute to the organization of functional domains in chromatin, ensuring the coordination of DNA replication and cotranscriptional processes. © 2017 Moriel-Carretero et al.

  14. pPKCδ activates SC35 splicing factor during H9c2 myoblastic differentiation.

    Science.gov (United States)

    Zara, Susi; Falconi, Mirella; Rapino, Monica; Zago, Michela; Orsini, Giovanna; Mazzotti, Giovanni; Cataldi, Amelia; Teti, Gabriella

    2011-01-01

    Although Protein Kinase C (PKC) isoforms' role in the neonatal and adult cardiac tissue development and ageing has been widely described "in vivo", the interaction of such enzymes with specific nuclear substrates needs to be investigated. The aim of our research has been the study of the expression, localization and interaction with the splicing factor SC35 of PKC isoforms (α, δ, ε, ζ) and their potential role in modulating the transcription machinery. H9c2 cells induced to myoblast differentiation in the presence of 1% Horse Serum (HS) have represented our experimental model. The expression of PKC isoforms, their distribution and interaction with SC35 have been evaluated by western blotting, co-immunoprecipitation and double gold immunolabeling for transmission and scanning electron microscopy. Our results show PKCδ as the most expressed isoform in differentiated cells. Surprisingly, the distribution of PKCδ and SC35 does not show any significant modification between 10%FBS and 1%HS treated samples and no co-localization is observed. Moreover the interaction between the phosphorylated form of PKCδ (pPKCδ) and SC35 increases, is distributed and co-localizes within the nucleus of differentiated H9c2. These data represent reasonable evidence of pPKCδ mediated SC35 splicing factor activation, suggesting its direct effect on transcription via interaction with the transcription machinery. Furthermore, this co-localization represents a crucial event resulting in downstream changes in transcription of components which determine the morphological modifications related to cardiomyoblast differentiated phenotype.

  15. HIV-1 infection induces changes in expression of cellular splicing factors that regulate alternative viral splicing and virus production in macrophages

    Directory of Open Access Journals (Sweden)

    Purcell Damian FJ

    2008-02-01

    Full Text Available Abstract Background Macrophages are important targets and long-lived reservoirs of HIV-1, which are not cleared of infection by currently available treatments. In the primary monocyte-derived macrophage model of infection, replication is initially productive followed by a decline in virion output over ensuing weeks, coincident with a decrease in the levels of the essential viral transactivator protein Tat. We investigated two possible mechanisms in macrophages for regulation of viral replication, which appears to be primarily regulated at the level of tat mRNA: 1 differential mRNA stability, used by cells and some viruses for the rapid regulation of gene expression and 2 control of HIV-1 alternative splicing, which is essential for optimal viral replication. Results Following termination of transcription at increasing times after infection in macrophages, we found that tat mRNA did indeed decay more rapidly than rev or nef mRNA, but with similar kinetics throughout infection. In addition, tat mRNA decayed at least as rapidly in peripheral blood lymphocytes. Expression of cellular splicing factors in uninfected and infected macrophage cultures from the same donor showed an inverse pattern over time between enhancing factors (members of the SR family of RNA binding proteins and inhibitory factors (members of the hnRNP family. While levels of the SR protein SC35 were greatly up-regulated in the first week or two after infection, hnRNPs of the A/B and H groups were down-regulated. Around the peak of virus production in each culture, SC35 expression declined to levels in uninfected cells or lower, while the hnRNPs increased to control levels or above. We also found evidence for increased cytoplasmic expression of SC35 following long-term infection. Conclusion While no evidence of differential regulation of tat mRNA decay was found in macrophages following HIV-1 infection, changes in the balance of cellular splicing factors which regulate alternative

  16. Differential splicing of oncogenes and tumor suppressor genes in African and Caucasian American populations: contributing factor in prostate cancer disparities

    Science.gov (United States)

    2017-12-01

    populations: contributing factor in prostate cancer disparities? PRINCIPAL INVESTIGATOR: Norman H Lee, PhD CONTRACTING ORGANIZATION: George Washington...splicing of oncogenes and tumor suppressor genes in African and Caucasian American populations: contributing factor in prostate cancer disparities? 5b...American (AA) versus Caucasian American (CA) prostate cancer (PCa). We focused our efforts on two oncogenes, phosphatidylinositol-4,5-bisphosphate 3

  17. Resveratrol, by modulating RNA processing factor levels, can influence the alternative splicing of pre-mRNAs.

    Directory of Open Access Journals (Sweden)

    M Andrea Markus

    Full Text Available Alternative pre-mRNA splicing defects can contribute to, or result from, various diseases, including cancer. Aberrant mRNAs, splicing factors and other RNA processing factors have therefore become targets for new therapeutic interventions. Here we report that the natural polyphenol resveratrol can modulate alternative splicing in a target-specific manner. We transfected minigenes of several alternatively spliceable primary mRNAs into HEK293 cells in the presence or absence of 1, 5, 20 and 50 µM resveratrol and measured exon levels by semi-quantitative PCR after separation by agarose gel electrophoresis. We found that 20 µg/ml and 50 µg/ml of resveratrol affected exon inclusion of SRp20 and SMN2 pre-mRNAs, but not CD44v5 or tau pre-mRNAs. By Western blotting and immunofluorescence we showed that this effect may be due to the ability of resveratrol to change the protein level but not the localization of several RNA processing factors. The processing factors that increased significantly were ASF/SF2, hnRNPA1 and HuR, but resveratrol did not change the levels of RBM4, PTBP1 and U2AF35. By means of siRNA-mediated knockdown we depleted cells of SIRT1, regarded as a major target of resveratrol, and showed that the effect on splicing was not dependent on SIRT1. Our results suggest that resveratrol might be an attractive small molecule to treat diseases in which aberrant splicing has been implicated, and justify more extensive research on the effects of resveratrol on the splicing machinery.

  18. Resveratrol, by modulating RNA processing factor levels, can influence the alternative splicing of pre-mRNAs.

    Science.gov (United States)

    Markus, M Andrea; Marques, Francine Z; Morris, Brian J

    2011-01-01

    Alternative pre-mRNA splicing defects can contribute to, or result from, various diseases, including cancer. Aberrant mRNAs, splicing factors and other RNA processing factors have therefore become targets for new therapeutic interventions. Here we report that the natural polyphenol resveratrol can modulate alternative splicing in a target-specific manner. We transfected minigenes of several alternatively spliceable primary mRNAs into HEK293 cells in the presence or absence of 1, 5, 20 and 50 µM resveratrol and measured exon levels by semi-quantitative PCR after separation by agarose gel electrophoresis. We found that 20 µg/ml and 50 µg/ml of resveratrol affected exon inclusion of SRp20 and SMN2 pre-mRNAs, but not CD44v5 or tau pre-mRNAs. By Western blotting and immunofluorescence we showed that this effect may be due to the ability of resveratrol to change the protein level but not the localization of several RNA processing factors. The processing factors that increased significantly were ASF/SF2, hnRNPA1 and HuR, but resveratrol did not change the levels of RBM4, PTBP1 and U2AF35. By means of siRNA-mediated knockdown we depleted cells of SIRT1, regarded as a major target of resveratrol, and showed that the effect on splicing was not dependent on SIRT1. Our results suggest that resveratrol might be an attractive small molecule to treat diseases in which aberrant splicing has been implicated, and justify more extensive research on the effects of resveratrol on the splicing machinery.

  19. Cellular organization of pre-mRNA splicing factors in several tissues. Changes in the uterus by hormone action.

    Science.gov (United States)

    George-Téllez, R; Segura-Valdez, M L; González-Santos, L; Jiménez-García, L F

    2002-05-01

    In the mammalian cell nucleus, splicing factors are distributed in nuclear domains known as speckles or splicing factor compartments (SFCs). In cultured cells, these domains are dynamic and reflect transcriptional and splicing activities. We used immunofluorescence and confocal microscopy to monitor whether splicing factors in differentiated cells display similar features. Speckled patterns are observed in rat hepatocytes, beta-cells, bronchial and intestine epithelia and also in three cell types of the uterus. Moreover, the number, distribution and sizes of the speckles vary among them. In addition, we studied variations in the circular form (shape) of speckles in uterine cells that are transcriptionally modified by a hormone action. During proestrus of the estral cycle, speckles are irregular in shape while in diestrus I they are circular. Experimentally, in castrated rats luminal epithelial cells show a pattern where speckles are dramatically rounded, but they recover their irregular shape rapidly after an injection of estradiol. The same results were observed in muscle and gland epithelial cells of the uterus. We concluded that different speckled patterns are present in various cells types in differentiated tissues and that these patterns change in the uterus depending upon the presence or absence of hormones such as estradiol.

  20. RRM domain of Arabidopsis splicing factor SF1 is important for pre-mRNA splicing of a specific set of genes

    KAUST Repository

    Lee, Keh Chien; Jang, Yun Hee; Kim, SoonKap; Park, Hyo-Young; Thu, May Phyo; Lee, Jeong Hwan; Kim, Jeong-Kook

    2017-01-01

    , but not the abscisic acid sensitivity response during seed germination. The alternative splicing of FLOWERING LOCUS M (FLM) pre-mRNA is involved in flowering time control. We found that the RRM domain of AtSF1 protein alters the production of alternatively spliced FLM

  1. Alternative RNA splicing and gastric cancer.

    Science.gov (United States)

    Li, Ying; Yuan, Yuan

    2017-07-01

    Alternative splicing (AS) linked to diseases, especially to tumors. Recently, more and more studies focused on the relationship between AS and gastric cancer (GC). This review surveyed the hot topic from four aspects: First, the common types of AS in cancer, including exon skipping, intron retention, mutually exclusive exon, alternative 5 ' or 3' splice site, alternative first or last exon and alternative 3' untranslated regions. Second, basic mechanisms of AS and its relationship with cancer. RNA splicing in eukaryotes follows the GT-AG rule by both cis-elements and trans-acting factors regulatory. Through RNA splicing, different proteins with different forms and functions can be produced and may be associated with carcinogenesis. Third, AS types of GC-related genes and their splicing variants. In this paper, we listed 10 common genes with AS and illustrated its possible molecular mechanisms owing to genetic variation (mutation and /or polymorphism). Fourth, the splicing variants of GC-associated genes and gastric carcinogenesis, invasion and metastasis. Many studies have found that the different splicing variants of the same gene are differentially expressed in GC and its precancerous diseases, suggesting AS has important implications in GC development. Taking together, this review highlighted the role of AS and splicing variants in the process of GC. We hope that this is not only beneficial to advances in the study field of GC, but also can provide valuable information to other similar tumor research.Although we already know some gene splicing and splicing variants play an important role in the development of GC, but many phenomena and mechanisms are still unknown. For example, how the tumor microenvironment and signal transduction pathway effect the forming and function of AS? Unfortunately, this review did not cover the contents because the current study is limited. It is no doubt that clarifying the phenomena and mechanisms of these unknown may help to reveal

  2. Proteomic analysis of polyribosomes identifies splicing factors as potential regulators of translation during mitosis.

    Science.gov (United States)

    Aviner, Ranen; Hofmann, Sarah; Elman, Tamar; Shenoy, Anjana; Geiger, Tamar; Elkon, Ran; Ehrlich, Marcelo; Elroy-Stein, Orna

    2017-06-02

    Precise regulation of mRNA translation is critical for proper cell division, but little is known about the factors that mediate it. To identify mRNA-binding proteins that regulate translation during mitosis, we analyzed the composition of polysomes from interphase and mitotic cells using unbiased quantitative mass-spectrometry (LC-MS/MS). We found that mitotic polysomes are enriched with a subset of proteins involved in RNA processing, including alternative splicing and RNA export. To demonstrate that these may indeed be regulators of translation, we focused on heterogeneous nuclear ribonucleoprotein C (hnRNP C) as a test case and confirmed that it is recruited to elongating ribosomes during mitosis. Then, using a combination of pulsed SILAC, metabolic labeling and ribosome profiling, we showed that knockdown of hnRNP C affects both global and transcript-specific translation rates and found that hnRNP C is specifically important for translation of mRNAs that encode ribosomal proteins and translation factors. Taken together, our results demonstrate how proteomic analysis of polysomes can provide insight into translation regulation under various cellular conditions of interest and suggest that hnRNP C facilitates production of translation machinery components during mitosis to provide daughter cells with the ability to efficiently synthesize proteins as they enter G1 phase. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  3. Aberrant alternative splicing is another hallmark of cancer.

    Science.gov (United States)

    Ladomery, Michael

    2013-01-01

    The vast majority of human genes are alternatively spliced. Not surprisingly, aberrant alternative splicing is increasingly linked to cancer. Splice isoforms often encode proteins that have distinct and even antagonistic properties. The abnormal expression of splice factors and splice factor kinases in cancer changes the alternative splicing of critically important pre-mRNAs. Aberrant alternative splicing should be added to the growing list of cancer hallmarks.

  4. Aberrant Alternative Splicing Is Another Hallmark of Cancer

    OpenAIRE

    Ladomery, Michael

    2013-01-01

    The vast majority of human genes are alternatively spliced. Not surprisingly, aberrant alternative splicing is increasingly linked to cancer. Splice isoforms often encode proteins that have distinct and even antagonistic properties. The abnormal expression of splice factors and splice factor kinases in cancer changes the alternative splicing of critically important pre-mRNAs. Aberrant alternative splicing should be added to the growing list of cancer hallmarks.

  5. Identification of Splice Variants, Targeted MicroRNAs and Functional Single Nucleotide Polymorphisms of the BOLA-DQA2 Gene in Dairy Cattle

    Science.gov (United States)

    Hou, Qinlei; Huang, Jinming; Ju, Zhihua; Li, Qiuling; Li, Liming; Wang, Changfa; Sun, Tao; Wang, Lingling; Hou, Minghai

    2012-01-01

    Major histocompatibility complex, class II, DQ alpha 2, also named BOLA-DQA2, belongs to the Bovine Leukocyte Antigen (BOLA) class II genes which are involved in the immune response. To explore the variability of the BOLA-DQA2 gene and resistance to mastitis in cows, the splice variants (SV), targeted microRNAs (miRNAs), and single nucleotide polymorphisms (SNPs) were identified in this study. A new SV (BOLA-DQA2-SV1) lacking part of exon 3 (195 bp) and two 3′-untranslated regions (UTR) (52 bp+167 bp) of the BOLA-DQA2 gene was found in the healthy and mastitis-infected mammary gland tissues. Four of 13 new SNPs and multiple nucleotide polymorphisms resulted in amino acid changes in the protein and SNP (c. +1283 C>T) may affect the binding to the seed sequence of bta-miR-2318. Further, we detected the relative expressions of two BOLA-DQA2 transcripts and five candidated microRNAs binding to the 3′-UTR of two transcripts in the mammary gland tissues in dairy cattle by using the quantitative real-time polymerase chain reaction. The result showed that expression of the BOLA-DQA2-SV1 mRNA was significantly upregulated 2.67-fold (pmastitis-infected mammary tissues (n=5) compared with the healthy mammary gland mammary tissues (n=5). Except for bta-miR-1777a, miRNA expression (bta-miR-296, miR-2430, and miR-671) was upregulated 1.75 to 2.59-fold (pmastitis cows. Our findings reveal that BOLA-DQA2-SV1 may play an important role in the mastitis resistance in dairy cattle. Whether the SNPs affect the structure of the BOLA-DQA2 gene or association with mastitis resistance is unknown and warrants further investigation. PMID:22084936

  6. Splicing factor SR34b mutation reduces cadmium tolerance in Arabidopsis by regulating iron-regulated transporter 1 gene

    International Nuclear Information System (INIS)

    Zhang, Wentao; Du, Bojing; Liu, Di; Qi, Xiaoting

    2014-01-01

    Highlights: • Arabidopsis splicing factor SR34b gene is cadmium-inducible. • SR34b T-DNA insertion mutant is sensitive to cadmium due to high cadmium uptake. • SR34b is a regulator of cadmium transporter IRT1 at the posttranscription level. • These results highlight the roles of splicing factors in cadmium tolerance of plant. - Abstract: Serine/arginine-rich (SR) proteins are important splicing factors. However, the biological functions of plant SR proteins remain unclear especially in abiotic stresses. Cadmium (Cd) is a non-essential element that negatively affects plant growth and development. In this study, we provided clear evidence for SR gene involved in Cd tolerance in planta. Systemic expression analysis of 17 Arabidopsis SR genes revealed that SR34b is the only SR gene upregulated by Cd, suggesting its potential roles in Arabidopsis Cd tolerance. Consistent with this, a SR34b T-DNA insertion mutant (sr34b) was moderately sensitive to Cd, which had higher Cd 2+ uptake rate and accumulated Cd in greater amounts than wild-type. This was due to the altered expression of iron-regulated transporter 1 (IRT1) gene in sr34b mutant. Under normal growth conditions, IRT1 mRNAs highly accumulated in sr34b mutant, which was a result of increased stability of IRT1 mRNA. Under Cd stress, however, sr34b mutant plants had a splicing defect in IRT1 gene, thus reducing the IRT1 mRNA accumulation. Despite of this, sr34b mutant plants still constitutively expressed IRT1 proteins under Cd stress, thereby resulting in Cd stress-sensitive phenotype. We therefore propose the essential roles of SR34b in posttranscriptional regulation of IRT1 expression and identify it as a regulator of Arabidopsis Cd tolerance

  7. Splicing factor SR34b mutation reduces cadmium tolerance in Arabidopsis by regulating iron-regulated transporter 1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Wentao; Du, Bojing; Liu, Di; Qi, Xiaoting, E-mail: qixiaoting@cnu.edu.cn

    2014-12-12

    Highlights: • Arabidopsis splicing factor SR34b gene is cadmium-inducible. • SR34b T-DNA insertion mutant is sensitive to cadmium due to high cadmium uptake. • SR34b is a regulator of cadmium transporter IRT1 at the posttranscription level. • These results highlight the roles of splicing factors in cadmium tolerance of plant. - Abstract: Serine/arginine-rich (SR) proteins are important splicing factors. However, the biological functions of plant SR proteins remain unclear especially in abiotic stresses. Cadmium (Cd) is a non-essential element that negatively affects plant growth and development. In this study, we provided clear evidence for SR gene involved in Cd tolerance in planta. Systemic expression analysis of 17 Arabidopsis SR genes revealed that SR34b is the only SR gene upregulated by Cd, suggesting its potential roles in Arabidopsis Cd tolerance. Consistent with this, a SR34b T-DNA insertion mutant (sr34b) was moderately sensitive to Cd, which had higher Cd{sup 2+} uptake rate and accumulated Cd in greater amounts than wild-type. This was due to the altered expression of iron-regulated transporter 1 (IRT1) gene in sr34b mutant. Under normal growth conditions, IRT1 mRNAs highly accumulated in sr34b mutant, which was a result of increased stability of IRT1 mRNA. Under Cd stress, however, sr34b mutant plants had a splicing defect in IRT1 gene, thus reducing the IRT1 mRNA accumulation. Despite of this, sr34b mutant plants still constitutively expressed IRT1 proteins under Cd stress, thereby resulting in Cd stress-sensitive phenotype. We therefore propose the essential roles of SR34b in posttranscriptional regulation of IRT1 expression and identify it as a regulator of Arabidopsis Cd tolerance.

  8. A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR.

    Directory of Open Access Journals (Sweden)

    Kelly Broen

    Full Text Available Nonmyeloablative allogeneic stem cell transplantation (SCT can induce remission in patients with renal cell carcinoma (RCC, but this graft-versus-tumor (GVT effect is often accompanied by graft-versus-host disease (GVHD. Here, we evaluated minor histocompatibility antigen (MiHA-specific T cell responses in two patients with metastatic RCC who were treated with reduced-intensity conditioning SCT followed by donor lymphocyte infusion (DLI. One patient had stable disease and emergence of SMCY.A2-specific CD8+ T cells was observed after DLI with the potential of targeting SMCY-expressing RCC tumor cells. The second patient experienced partial regression of lung metastases from whom we isolated a MiHA-specific CTL clone with the capability of targeting RCC cell lines. Whole genome association scanning revealed that this CTL recognizes a novel HLA-B7-restricted MiHA, designated ZAPHIR, resulting from a polymorphism in the splice donor site of the ZNF419 gene. Tetramer analysis showed that emergence of ZAPHIR-specific CD8+ T cells in peripheral blood occurred in the absence of GVHD. Furthermore, the expression of ZAPHIR in solid tumor cell lines indicates the involvement of ZAPHIR-specific CD8+ T cell responses in selective GVT immunity. These findings illustrate that the ZNF419-encoded MiHA ZAPHIR is an attractive target for specific immunotherapy after allogeneic SCT.

  9. An intron splice acceptor polymorphism in hMSH2 and risk of leukemia after treatment with chemotherapeutic alkylating agents.

    Science.gov (United States)

    Worrillow, Lisa J; Travis, Lois B; Smith, Alexandra G; Rollinson, Sara; Smith, Andrew J; Wild, Christopher P; Holowaty, Eric J; Kohler, Betsy A; Wiklund, Tom; Pukkala, Eero; Roman, Eve; Morgan, Gareth J; Allan, James M

    2003-08-01

    We sought to determine whether the -6 exon 13 T>C polymorphism in the DNA mismatch repair gene hMSH2 modulates susceptibility to acute myeloid leukemia after therapy and particularly after O(6)-guanine alkylating chemotherapy. We also determined the extent of microsatellite instability (MSI) in therapy-related acute myeloid leukemia (t-AML) as a marker of dysfunctional DNA mismatch repair. Using a novel restriction fragment length polymorphism, verified by direct sequencing, we have genotyped 91 t-AML cases, 420 de novo acute myeloid leukemia cases, and 837 controls for the hMSH2 -6 exon 13 polymorphism. MSI was evaluated in presentation bone marrow from 34 cases using the mononucleotide microsatellite markers BAT16, BAT25, and BAT26. Distribution of the hMSH2 -6 exon 13 polymorphism was not significantly different between de novo acute myeloid leukemia cases and controls, with heterozygotes and homozygotes for the variant (C) allele representing 12.2 and 1.6%, respectively, of the control population. However, the variant (C) hMSH2 allele was significantly overrepresented in t-AML cases that had previously been treated with O(6)-guanine alkylating agents, including cyclophosphamide and procarbazine, compared with controls (odds ratio, 4.02; 95% confidence interval, 1.40-11.37). Thirteen of 34 (38%) t-AML cases were MSI positive, and 2 of these 13 cases were homozygous for the variant (C) allele, a frequency substantially higher than in the control population. Association of the hMSH2 -6 exon 13 variant (C) allele with leukemia after O(6)-guanine alkylating agents implicates this allele in conferring a nondisabling DNA mismatch repair defect with concomitant moderate alkylation tolerance, which predisposes to the development of t-AML via the induction of DNA mismatch repair-disabling mutations and high-grade MSI. Homozygosity for the hMSH2 variant in 2 of 13 MSI-positive t-AML cases provides some support for this model.

  10. Expression analysis of an evolutionarily conserved alternative splicing factor, Sfrs10, in age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Devi Krishna Priya Karunakaran

    Full Text Available Age-related macular degeneration (AMD is the most common cause of blindness in the elderly population. Hypoxic stress created in the micro-environment of the photoreceptors is thought to be the underlying cause that results in the pathophysiology of AMD. However, association of AMD with alternative splicing mediated gene regulation is not well explored. Alternative Splicing is one of the primary mechanisms in humans by which fewer protein coding genes are able to generate a vast proteome. Here, we investigated the expression of a known stress response gene and an alternative splicing factor called Serine-Arginine rich splicing factor 10 (Sfrs10. Sfrs10 is a member of the serine-arginine (SR rich protein family and is 100% identical at the amino acid level in most mammals. Immunoblot analysis on retinal extracts from mouse, rat, and chicken showed a single immunoreactive band. Further, immunohistochemistry on adult mouse, rat and chicken retinae showed pan-retinal expression. However, SFRS10 was not detected in normal human retina but was observed as distinct nuclear speckles in AMD retinae. This is in agreement with previous reports that show Sfrs10 to be a stress response gene, which is upregulated under hypoxia. The difference in the expression of Sfrs10 between humans and lower mammals and the upregulation of SFRS10 in AMD is further reflected in the divergence of the promoter sequence between these species. Finally, SFRS10+ speckles were independent of the SC35+ SR protein speckles or the HSF1+ stress granules. In all, our data suggests that SFRS10 is upregulated and forms distinct stress-induced speckles and might be involved in AS of stress response genes in AMD.

  11. Self-hydroxylation of the splicing factor lysyl hydroxylase, JMJD6

    DEFF Research Database (Denmark)

    Mantri, M.; Webby, C.J.; Loik, N.D.

    2012-01-01

    The lysyl 5S-hydroxylase, JMJD6 acts on proteins involved in RNA splicing. We find that in the absence of substrate JMJD6 catalyses turnover of 2OG to succinate. H-NMR analyses demonstrate that consumption of 2OG is coupled to succinate formation. MS analyses reveal that JMJD6 undergoes self......-hydroxylation in the presence of Fe(ii) and 2OG resulting in production of 5S-hydroxylysine residues. JMJD6 in human cells is also found to be hydroxylated. Self-hydroxylation of JMJD6 may play a regulatory role in modulating the hydroxylation status of proteins involved in RNA splicing. This journal is...

  12. Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma.

    Directory of Open Access Journals (Sweden)

    Justina McEvoy

    Full Text Available Retinoblastoma is a childhood cancer of the developing retina that begins in utero and is diagnosed in the first years of life. Biallelic RB1 gene inactivation is the initiating genetic lesion in retinoblastoma. The p53 gene is intact in human retinoblastoma but the pathway is believed to be suppressed by increased expression of MDM4 (MDMX and MDM2. Here we quantify the expression of MDM4 and MDM2 mRNA and protein in human fetal retinae, primary retinoblastomas, retinoblastoma cell lines and several independent orthotopic retinoblastoma xenografts. We found that MDM4 is the major p53 antagonist expressed in retinoblastoma and in the developing human retina. We also discovered that MDM4 protein steady state levels are much higher in retinoblastoma than in human fetal retinae. This increase would not have been predicted based on the mRNA levels. We explored several possible post-transcriptional mechanisms that may contribute to the elevated levels of MDM4 protein. A proportion of MDM4 transcripts are alternatively spliced to produce protein products that are reported to be more stable and oncogenic. We also discovered that a microRNA predicted to target MDM4 (miR191 was downregulated in retinoblastoma relative to human fetal retinae and a subset of samples had somatic mutations that eliminated the miR-191 binding site in the MDM4 mRNA. Taken together, these data suggest that post-transcriptional mechanisms may contribute to stabilization of the MDM4 protein in retinoblastoma.

  13. Mechano growth factor, a splice variant of IGF-1, promotes neurogenesis in the aging mouse brain.

    Science.gov (United States)

    Tang, Jason J; Podratz, Jewel L; Lange, Miranda; Scrable, Heidi J; Jang, Mi-Hyeon; Windebank, Anthony J

    2017-07-07

    Mechano growth factor (MGF) is a splice variant of IGF-1 first described in skeletal muscle. MGF induces muscle cell proliferation in response to muscle stress and injury. In control mice we found endogenous expression of MGF in neurogenic areas of the brain and these levels declined with age. To better understand the role of MGF in the brain, we used transgenic mice that constitutively overexpressed MGF from birth. MGF overexpression significantly increased the number of BrdU+ proliferative cells in the dentate gyrus (DG) of the hippocampus and subventricular zone (SVG). Although MGF overexpression increased the overall rate of adult hippocampal neurogenesis at the proliferation stage it did not alter the distribution of neurons at post-mitotic maturation stages. We then used the lac-operon system to conditionally overexpress MGF in the mouse brain beginning at 1, 3 and 12 months with histological and behavioral observation at 24 months of age. With conditional overexpression there was an increase of BrdU+ proliferating cells and BrdU+ differentiated mature neurons in the olfactory bulbs at 24 months when overexpression was induced from 1 and 3 months of age but not when started at 12 months. This was associated with preserved olfactory function. In vitro, MGF increased the size and number of neurospheres harvested from SVZ-derived neural stem cells (NSCs). These findings indicate that MGF overexpression increases the number of neural progenitor cells and promotes neurogenesis but does not alter the distribution of adult newborn neurons at post-mitotic stages. Maintaining youthful levels of MGF may be important in reversing age-related neuronal loss and brain dysfunction.

  14. Arabidopsis IRE1 catalyses unconventional splicing of bZIP60 mRNA to produce the active transcription factor

    KAUST Repository

    Nagashima, Yukihiro

    2011-07-01

    IRE1 plays an essential role in the endoplasmic reticulum (ER) stress response in yeast and mammals. We found that a double mutant of Arabidopsis IRE1A and IRE1B (ire1a/ire1b) is more sensitive to the ER stress inducer tunicamycin than the wild-type. Transcriptome analysis revealed that genes whose induction was reduced in ire1a/ire1b largely overlapped those in the bzip60 mutant. We observed that the active form of bZIP60 protein detected in the wild-type was missing in ire1a/ire1b. We further demonstrated that bZIP60 mRNA is spliced by ER stress, removing 23 ribonucleotides and therefore causing a frameshift that replaces the C-terminal region of bZIP60 including the transmembrane domain (TMD) with a shorter region without a TMD. This splicing was detected in ire1a and ire1b single mutants, but not in the ire1a/ire1b double mutant. We conclude that IRE1A and IRE1B catalyse unconventional splicing of bZIP60 mRNA to produce the active transcription factor.

  15. Structural Basis for Polypyrimidine Tract Recognition by the Essential Pre-mRNA Splicing Factor U2AF65

    International Nuclear Information System (INIS)

    Sickmier, E.; Frato, K.; Shen, H.; Paranawithana, S.; Green, M.; Kielkopf, C.

    2006-01-01

    The essential pre-mRNA splicing factor, U2AF 65 , guides the early stages of splice site choice by recognizing a polypyrimidine (Py)-tract consensus sequence near the 3'-splice site. Since Py-tracts are relatively poorly conserved in higher eukaryotes, U2AF 65 is faced with the problem of specifying uridine-rich sequences, yet tolerating a variety of nucleotide substitutions found in natural Py-tracts. To better understand these apparently contradictory RNA binding characteristics, the X-ray structure of the U2AF 65 RNA binding domain bound to a Py-tract composed of seven uridines has been determined at 2.5Angstroms resolution. Specific hydrogen bonds between U2AF 65 and the uracil bases provide an explanation for polyuridine recognition. Flexible sidechains and bound water molecules form the majority of the base contacts, and potentially could rearrange when the U2AF 65 structure adapts to different Py-tract sequences. The energetic importance of conserved residues for Py-tract binding is established by analysis of site-directed mutant U2AF 65 proteins using surface plasmon resonance

  16. Activation-induced cytidine deaminase (AID) is localized to subnuclear domains enriched in splicing factors

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Yi, E-mail: yihooyi@gmail.com; Ericsson, Ida, E-mail: ida.ericsson@ntnu.no; Doseth, Berit, E-mail: berit.doseth@ntnu.no; Liabakk, Nina B., E-mail: nina.beate.liabakk@ntnu.no; Krokan, Hans E., E-mail: hans.krokan@ntnu.no; Kavli, Bodil, E-mail: bodil.kavli@ntnu.no

    2014-03-10

    Activation-induced cytidine deaminase (AID) is the mutator enzyme in adaptive immunity. AID initiates the antibody diversification processes in activated B cells by deaminating cytosine to uracil in immunoglobulin genes. To some extent other genes are also targeted, which may lead to genome instability and B cell malignancy. Thus, it is crucial to understand its targeting and regulation mechanisms. AID is regulated at several levels including subcellular compartmentalization. However, the complex nuclear distribution and trafficking of AID has not been studied in detail previously. In this work, we examined the subnuclear localization of AID and its interaction partner CTNNBL1 and found that they associate with spliceosome-associated structures including Cajal bodies and nuclear speckles. Moreover, protein kinase A (PKA), which activates AID by phosphorylation at Ser38, is present together with AID in nuclear speckles. Importantly, we demonstrate that AID physically associates with the major spliceosome subunits (small nuclear ribonucleoproteins, snRNPs), as well as other essential splicing components, in addition to the transcription machinery. Based on our findings and the literature, we suggest a transcription-coupled splicing-associated model for AID targeting and activation. - Highlights: • AID and its interaction partner CTNNBL1 localize to Cajal bodies and nuclear speckles. • AID associates with its activating kinase PKA in nuclear speckles. • AID is linked to the splicing machinery in switching B-cells. • Our findings suggest a transcription-coupled splicing associated mechanism for AID targeting and activation.

  17. Fox-2 Splicing Factor Binds to a Conserved Intron Motif to PromoteInclusion of Protein 4.1R Alternative Exon 16

    Energy Technology Data Exchange (ETDEWEB)

    Ponthier, Julie L.; Schluepen, Christina; Chen, Weiguo; Lersch,Robert A.; Gee, Sherry L.; Hou, Victor C.; Lo, Annie J.; Short, Sarah A.; Chasis, Joel A.; Winkelmann, John C.; Conboy, John G.

    2006-03-01

    Activation of protein 4.1R exon 16 (E16) inclusion during erythropoiesis represents a physiologically important splicing switch that increases 4.1R affinity for spectrin and actin. Previous studies showed that negative regulation of E16 splicing is mediated by the binding of hnRNP A/B proteins to silencer elements in the exon and that downregulation of hnRNP A/B proteins in erythroblasts leads to activation of E16 inclusion. This paper demonstrates that positive regulation of E16 splicing can be mediated by Fox-2 or Fox-1, two closely related splicing factors that possess identical RNA recognition motifs. SELEX experiments with human Fox-1 revealed highly selective binding to the hexamer UGCAUG. Both Fox-1 and Fox-2 were able to bind the conserved UGCAUG elements in the proximal intron downstream of E16, and both could activate E16 splicing in HeLa cell co-transfection assays in a UGCAUG-dependent manner. Conversely, knockdown of Fox-2 expression, achieved with two different siRNA sequences resulted in decreased E16 splicing. Moreover, immunoblot experiments demonstrate mouse erythroblasts express Fox-2, but not Fox-1. These findings suggest that Fox-2 is a physiological activator of E16 splicing in differentiating erythroid cells in vivo. Recent experiments show that UGCAUG is present in the proximal intron sequence of many tissue-specific alternative exons, and we propose that the Fox family of splicing enhancers plays an important role in alternative splicing switches during differentiation in metazoan organisms.

  18. Transforming growth factor-β1 regulates fibronectin isoform expression and splicing factor SRp40 expression during ATDC5 chondrogenic maturation

    International Nuclear Information System (INIS)

    Han Fei; Gilbert, James R.; Harrison, Gerald; Adams, Christopher S.; Freeman, Theresa; Tao Zhuliang; Zaka, Raihana; Liang Hongyan; Williams, Charlene; Tuan, Rocky S.; Norton, Pamela A.; Hickok, Noreen J.

    2007-01-01

    Fibronectin (FN) isoform expression is altered during chondrocyte commitment and maturation, with cartilage favoring expression of FN isoforms that includes the type II repeat extra domain B (EDB) but excludes extra domain A (EDA). We and others have hypothesized that the regulated splicing of FN mRNAs is necessary for the progression of chondrogenesis. To test this, we treated the pre-chondrogenic cell line ATDC5 with transforming growth factor-β1, which has been shown to modulate expression of the EDA and EDB exons, as well as the late markers of chondrocyte maturation; it also slightly accelerates the early acquisition of a sulfated proteoglycan matrix without affecting cell proliferation. When chondrocytes are treated with TGF-β1, the EDA exon is preferentially excluded at all times whereas the EDB exon is relatively depleted at early times. This regulated alternative splicing of FN correlates with the regulation of alternative splicing of SRp40, a splicing factor facilitating inclusion of the EDA exon. To determine if overexpression of the SRp40 isoforms altered FN and FN EDA organization, cDNAs encoding these isoforms were overexpressed in ATDC5 cells. Overexpression of the long-form of SRp40 yielded an FN organization similar to TGF-β1 treatment; whereas overexpression of the short form of SRp40 (which facilitates EDA inclusion) increased formation of long-thick FN fibrils. Therefore, we conclude that the effects of TGF-β1 on FN splicing during chondrogenesis may be largely dependent on its effect on SRp40 isoform expression

  19. Porcine ubiquitin-like 5 (UBL5) gene: genomic organization, polymorphisms, mRNA cloning, splicing variants and association study

    Czech Academy of Sciences Publication Activity Database

    Masopust, Martin; Weisz, Filip; Bartenschlager, H.; Knoll, A.; Vykoukalová, Z.; Geldermann, H.; Čepica, Stanislav

    2014-01-01

    Roč. 41, č. 4 (2014), s. 2353-2362 ISSN 0301-4851 R&D Projects: GA ČR GAP502/10/1216 Institutional support: RVO:67985904 Keywords : pig * UBL5 * PCR cloning Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.024, year: 2014

  20. Tumour necrosis factorpolymorphism as one of the complex inherited factors in pemphigus

    Directory of Open Access Journals (Sweden)

    Jolanta Dorota Torzecka

    2003-01-01

    Full Text Available The aim of our study was to analyse a significance of tumour necrosis factor (TNF-α promoter gene polymorphisms in relation to the HLA-DR locus in genetic predisposition to pemphigus. TNF-α gene polymorphisms in position -238 and -308 were identified using a modified polymerase chain reaction-restriction fragment length polymorphism method in 53 patients with pemphigus (38 with pemphigus vulgaris, 15 with pemphigus foliaceus and 87 healthy controls. The HLA-DRB1 locus was typed using the polymerase chain reaction SSO method in all the patients and 152 population controls.

  1. Variation in antiviral 2',5'-oligoadenylate synthetase (2'5'AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene

    DEFF Research Database (Denmark)

    Bonnevie-Nielsen, Vagn; Field, L Leigh; Lu, Shao

    2005-01-01

    It is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2',5'-oligoadenylate synthetase (2'5'AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine......=.0044), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism...... at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20; P=3 x 10(-11)). Enzyme activity varied in a dose-dependent manner across the GG, GA...

  2. The splicing regulator PTBP1 controls the activity of the transcription factor Pbx1 during neuronal differentiation.

    Science.gov (United States)

    Linares, Anthony J; Lin, Chia-Ho; Damianov, Andrey; Adams, Katrina L; Novitch, Bennett G; Black, Douglas L

    2015-12-24

    The RNA-binding proteins PTBP1 and PTBP2 control programs of alternative splicing during neuronal development. PTBP2 was found to maintain embryonic splicing patterns of many synaptic and cytoskeletal proteins during differentiation of neuronal progenitor cells (NPCs) into early neurons. However, the role of the earlier PTBP1 program in embryonic stem cells (ESCs) and NPCs was not clear. We show that PTBP1 controls a program of neuronal gene expression that includes the transcription factor Pbx1. We identify exons specifically regulated by PTBP1 and not PTBP2 as mouse ESCs differentiate into NPCs. We find that PTBP1 represses Pbx1 exon 7 and the expression of the neuronal Pbx1a isoform in ESCs. Using CRISPR-Cas9 to delete regulatory elements for exon 7, we induce Pbx1a expression in ESCs, finding that this activates transcription of neuronal genes. Thus, PTBP1 controls the activity of Pbx1 to suppress its neuronal transcriptional program prior to induction of NPC development.

  3. Co-localisation studies of Arabidopsis SR splicing factors reveal different types of speckles in plant cell nuclei

    International Nuclear Information System (INIS)

    Lorkovic, Zdravko J.; Hilscher, Julia; Barta, Andrea

    2008-01-01

    SR proteins are multidomain splicing factors which are important for spliceosome assembly and for regulation of alternative splicing. In mammalian nuclei these proteins localise to speckles from where they are recruited to transcription sites. By using fluorescent protein fusion technology and different experimental approaches it has been shown that Arabidopsis SR proteins, in addition to diffuse nucleoplasmic staining, localise into an irregular nucleoplasmic network resembling speckles in mammalian cells. As Arabidopsis SR proteins fall into seven conserved sub-families we investigated co-localisation of members of the different sub-families in transiently transformed tobacco protoplast. Here we demonstrate the new finding that members of different SR protein sub-families localise into distinct populations of nuclear speckles with no, partial or complete co-localisation. This is particularly interesting as we also show that these proteins do interact in a yeast two-hybrid assay as well as in pull-down and in co-immunopreciptiation assays. Our data raise the interesting possibility that SR proteins are partitioned into distinct populations of nuclear speckles to allow a more specific recruitment to the transcription/pre-mRNA processing sites of particular genes depending on cell type and developmental stage

  4. Intron-Mediated Alternative Splicing of WOOD-ASSOCIATED NAC TRANSCRIPTION FACTOR1B Regulates Cell Wall Thickening during Fiber Development in Populus Species1[W

    Science.gov (United States)

    Zhao, Yunjun; Sun, Jiayan; Xu, Peng; Zhang, Rui; Li, Laigeng

    2014-01-01

    Alternative splicing is an important mechanism involved in regulating the development of multicellular organisms. Although many genes in plants undergo alternative splicing, little is understood of its significance in regulating plant growth and development. In this study, alternative splicing of black cottonwood (Populus trichocarpa) wood-associated NAC domain transcription factor (PtrWNDs), PtrWND1B, is shown to occur exclusively in secondary xylem fiber cells. PtrWND1B is expressed with a normal short-transcript PtrWND1B-s as well as its alternative long-transcript PtrWND1B-l. The intron 2 structure of the PtrWND1B gene was identified as a critical sequence that causes PtrWND1B alternative splicing. Suppression of PtrWND1B expression specifically inhibited fiber cell wall thickening. The two PtrWND1B isoforms play antagonistic roles in regulating cell wall thickening during fiber cell differentiation in Populus spp. PtrWND1B-s overexpression enhanced fiber cell wall thickening, while overexpression of PtrWND1B-l repressed fiber cell wall thickening. Alternative splicing may enable more specific regulation of processes such as fiber cell wall thickening during wood formation. PMID:24394777

  5. Intron-mediated alternative splicing of WOOD-ASSOCIATED NAC TRANSCRIPTION FACTOR1B regulates cell wall thickening during fiber development in Populus species.

    Science.gov (United States)

    Zhao, Yunjun; Sun, Jiayan; Xu, Peng; Zhang, Rui; Li, Laigeng

    2014-02-01

    Alternative splicing is an important mechanism involved in regulating the development of multicellular organisms. Although many genes in plants undergo alternative splicing, little is understood of its significance in regulating plant growth and development. In this study, alternative splicing of black cottonwood (Populus trichocarpa) wood-associated NAC domain transcription factor (PtrWNDs), PtrWND1B, is shown to occur exclusively in secondary xylem fiber cells. PtrWND1B is expressed with a normal short-transcript PtrWND1B-s as well as its alternative long-transcript PtrWND1B-l. The intron 2 structure of the PtrWND1B gene was identified as a critical sequence that causes PtrWND1B alternative splicing. Suppression of PtrWND1B expression specifically inhibited fiber cell wall thickening. The two PtrWND1B isoforms play antagonistic roles in regulating cell wall thickening during fiber cell differentiation in Populus spp. PtrWND1B-s overexpression enhanced fiber cell wall thickening, while overexpression of PtrWND1B-l repressed fiber cell wall thickening. Alternative splicing may enable more specific regulation of processes such as fiber cell wall thickening during wood formation.

  6. Temporal and tissue specific regulation of RP-associated splicing factor genes PRPF3, PRPF31 and PRPC8--implications in the pathogenesis of RP.

    Directory of Open Access Journals (Sweden)

    Huibi Cao

    2011-01-01

    Full Text Available Genetic mutations in several ubiquitously expressed RNA splicing genes such as PRPF3, PRP31 and PRPC8, have been found to cause retina-specific diseases in humans. To understand this intriguing phenomenon, most studies have been focused on testing two major hypotheses. One hypothesis assumes that these mutations interrupt retina-specific interactions that are important for RNA splicing, implying that there are specific components in the retina interacting with these splicing factors. The second hypothesis suggests that these mutations have only a mild effect on the protein function and thus affect only the metabolically highly active cells such as retinal photoreceptors.We examined the second hypothesis using the PRPF3 gene as an example. We analyzed the spatial and temporal expression of the PRPF3 gene in mice and found that it is highly expressed in retinal cells relative to other tissues and its expression is developmentally regulated. In addition, we also found that PRP31 and PRPC8 as well as snRNAs are highly expressed in retinal cells.Our data suggest that the retina requires a relatively high level of RNA splicing activity for optimal tissue-specific physiological function. Because the RP18 mutation has neither a debilitating nor acute effect on protein function, we suggest that retinal degeneration is the accumulative effect of decades of suboptimal RNA splicing due to the mildly impaired protein.

  7. Expression of a splice variant of the platelet-activating factor receptor transcript 2 in various human cancer cell lines

    Directory of Open Access Journals (Sweden)

    Ibtissam Youlyouz

    2002-01-01

    Full Text Available Platelet-activating factor receptor (PAF-R transcripts were analysed by reverse transcriptase-polymerase chain reaction in five human cancer cell lines derived from the breast (BT20, SKBR3 and T47D cells, the pancreas (Miapaca cells and the bladder (5637 cells in order to confirm the existence of a splice variant of the PAF-R transcript 2. After cloning and sequencing, we confirmed its existence in all cell lines. It consisted of the PAF-R transcript 2 lengthening with 82 nucleotides from the 3' end of exon 1 of the PAF-R gene. The role of this elongated form of the tissue-type PAF-R transcript in cell physiology remains to be elucidated.

  8. Complement Factor H-Related Protein 4A Is the Dominant Circulating Splice Variant of CFHR4

    Directory of Open Access Journals (Sweden)

    Richard B. Pouw

    2018-04-01

    Full Text Available Recent research has elucidated circulating levels of almost all factor H-related (FHR proteins. Some of these proteins are hypothesized to act as antagonists of the important complement regulator factor H (FH, fine-tuning complement regulation on human surfaces. For the CFHR4 splice variants FHR-4A and FHR-4B, the individual circulating levels are unknown, with only total levels being described. Specific reagents for FHR-4A or FHR-4B are lacking due to the fact that the unique domains in FHR-4A show high sequence similarity with FHR-4B, making it challenging to distinguish them. We developed an assay that specifically measures FHR-4A using novel, well-characterized monoclonal antibodies (mAbs that target unique domains in FHR-4A only. Using various FHR-4A/FHR-4B-specific mAbs, no FHR-4B was identified in any of the serum samples tested. The results demonstrate that FHR-4A is the dominant splice variant of CFHR4 in the circulation, while casting doubt on the presence of FHR-4B. FHR-4A levels (avg. 2.55 ± 1.46 µg/mL were within the range of most of the previously reported levels for all other FHRs. FHR-4A was found to be highly variable among the population, suggesting a strong genetic regulation. These results shed light on the physiological relevance of the previously proposed role of FHR-4A and FHR-4B as antagonists of FH in the circulation.

  9. PTB-associated splicing factor (PSF) functions as a repressor of STAT6-mediated IG{epsilon} gene transcription by recruitment of HDAC1

    DEFF Research Database (Denmark)

    Dong, Lijie; Zhang, Xinyu; Fu, Xiao

    2010-01-01

    understood. Here we identified by proteomic approach that PTB-associated splicing factor (PSF) interacts with STAT6. In cells the interaction required IL-4 stimulation and was observed both with endogenous and ectopically expressed proteins. The ligand dependency of the interaction suggested involvement...

  10. The Arabidopsis splicing factors, AtU2AF65, AtU2AF35, and AtSF1 shuttle between nuclei and cytoplasms

    KAUST Repository

    Park, Hyo-Young

    2017-04-21

    The Arabidopsis splicing factors, AtU2AF65, AtU2AF35, and AtSF1 shuttle between nuclei and cytoplasms. These proteins also move rapidly and continuously in the nuclei, and their movements are affected by ATP depletion. The U2AF65 proteins are splicing factors that interact with SF1 and U2AF35 proteins to promote U2snRNP for the recognition of the pre-mRNA 3\\' splice site during early spliceosome assembly. We have determined the subcellular localization and movement of these proteins\\' Arabidopsis homologs. It was found that Arabidopsis U2AF65 homologs, AtU2AF65a, and AtU2AF65b proteins interact with AtU2AF35a and AtU2AF35b, which are Arabidopsis U2AF35 homologs. We have examined the mobility of these proteins including AtSF1 using fluorescence recovery after photobleaching and fluorescence loss in photobleaching analyses. These proteins displayed dynamic movements in nuclei and their movements were affected by ATP depletion. We have also demonstrated that these proteins shuttle between nuclei and cytoplasms, suggesting that they may also function in cytoplasm. These results indicate that such splicing factors show very similar characteristics to their human counterparts, suggesting evolutionary conservation.

  11. The Arabidopsis splicing factors, AtU2AF65, AtU2AF35, and AtSF1 shuttle between nuclei and cytoplasms

    KAUST Repository

    Park, Hyo-Young; Lee, Keh Chien; Jang, Yun Hee; Kim, SoonKap; Thu, May Phyo; Lee, Jeong Hwan; Kim, Jeong-Kook

    2017-01-01

    The Arabidopsis splicing factors, AtU2AF65, AtU2AF35, and AtSF1 shuttle between nuclei and cytoplasms. These proteins also move rapidly and continuously in the nuclei, and their movements are affected by ATP depletion. The U2AF65 proteins are splicing factors that interact with SF1 and U2AF35 proteins to promote U2snRNP for the recognition of the pre-mRNA 3' splice site during early spliceosome assembly. We have determined the subcellular localization and movement of these proteins' Arabidopsis homologs. It was found that Arabidopsis U2AF65 homologs, AtU2AF65a, and AtU2AF65b proteins interact with AtU2AF35a and AtU2AF35b, which are Arabidopsis U2AF35 homologs. We have examined the mobility of these proteins including AtSF1 using fluorescence recovery after photobleaching and fluorescence loss in photobleaching analyses. These proteins displayed dynamic movements in nuclei and their movements were affected by ATP depletion. We have also demonstrated that these proteins shuttle between nuclei and cytoplasms, suggesting that they may also function in cytoplasm. These results indicate that such splicing factors show very similar characteristics to their human counterparts, suggesting evolutionary conservation.

  12. Functional analysis of the isoforms of an ABI3-like factor of Pisum sativum generated by alternative splicing.

    Science.gov (United States)

    Gagete, Andrés P; Riera, Marta; Franco, Luis; Rodrigo, M Isabel

    2009-01-01

    At least seven isoforms (PsABI3-1 to PsABI3-7) of a putative, pea ABI3-like factor, originated by alternative splicing, have been identified after cDNA cloning. A similar variability had previously only been described for monocot genes. The full-length isoform, PsABI3-1, contains the typical N-terminal acidic domains and C-terminal basic subdomains, B1 to B3. Reverse transcriptase-PCR analysis revealed that the gene is expressed just in seeds, starting at middle embryogenesis; no gene products are observed in embryo axes after 18 h post-imbibition although they are more persistent in cotyledons. The activity of the isoforms was studied by yeast one-hybrid assays. When yeast was transformed with the isoforms fused to the DNA binding domain of Gal4p, only the polypeptides PsABI3-2 and PsABI3-7 failed to complement the activity of Gal4p. Acidic domains A1 and A2 exhibit transactivating activity, but the former requires a small C-terminal extension to be active. Yeast two-hybrid analysis showed that PsABI3 is able to heterodimerize with Arabidopsis thaliana ABI5, thus proving that PsABI3 is functionally active. The minimum requirement for the interaction PsABI3-AtABI5 is the presence of the subdomain B1 with an extension, 81 amino acids long, at their C-terminal side. Finally, a transient onion transformation assay showed that both the active PsABI3-1 and the inactive PsABI3-2 isoforms are localized to nuclei. Considering that the major isoforms remain approximately constant in developing seeds although their relative proportion varied, the possible role of splicing in the regulatory network of ABA signalling is discussed.

  13. Novel splice site mutation in the growth hormone receptor gene in Turkish patients with Laron-type dwarfism.

    Science.gov (United States)

    Arman, Ahmet; Ozon, Alev; Isguven, Pinar S; Coker, Ajda; Peker, Ismail; Yordam, Nursen

    2008-01-01

    Growth hormone (GH) is involved in growth, and fat and carbohydrate metabolism. Interaction of GH with the GH receptor (GHR) is necessary for systemic and local production of insulin-like growth factor-I (IGF-I) which mediates GH actions. Mutations in the GHR cause severe postnatal growth failure; the disorder is an autosomal recessive genetic disease resulting in GH insensitivity, called Laron syndrome. It is characterized by dwarfism with elevated serum GH and low levels of IGF-I. We analyzed the GHR gene for mutations and polymorphisms in eight patients with Laron-type dwarfism from six families. We found three missense mutations (S40L, V125A, I526L), one nonsense mutation (W157X), and one splice site mutation in the extracellular domain of GHR. Furthermore, G168G and exon 3 deletion polymorphisms were detected in patients with Laron syndrome. The splice site mutation, which is a novel mutation, was located at the donor splice site of exon 2/ intron 2 within GHR. Although this mutation changed the highly conserved donor splice site consensus sequence GT to GGT by insertion of a G residue, the intron splicing between exon 2 and exon 3 was detected in the patient. These results imply that the splicing occurs arthe GT site in intron 2, leaving the extra inserted G residue at the end of exon 2, thus changing the open reading frame of GHR resulting in a premature termination codon in exon 3.

  14. An alternatively spliced heat shock transcription factor, OsHSFA2dI, functions in the heat stress-induced unfolded protein response in rice.

    Science.gov (United States)

    Cheng, Q; Zhou, Y; Liu, Z; Zhang, L; Song, G; Guo, Z; Wang, W; Qu, X; Zhu, Y; Yang, D

    2015-03-01

    As sessile organisms, plants have evolved a wide range of defence pathways to cope with environmental stress such as heat shock. However, the molecular mechanism of these defence pathways remains unclear in rice. In this study, we found that OsHSFA2d, a heat shock transcriptional factor, encodes two main splice variant proteins, OsHSFA2dI and OsHSFA2dII in rice. Under normal conditions, OsHSFA2dII is the dominant but transcriptionally inactive spliced form. However, when the plant suffers heat stress, OsHSFA2d is alternatively spliced into a transcriptionally active form, OsHSFA2dI, which participates in the heat stress response (HSR). Further study found that this alternative splicing was induced by heat shock rather than photoperiod. We found that OsHSFA2dI is localised to the nucleus, whereas OsHSFA2dII is localised to the nucleus and cytoplasm. Moreover, expression of the unfolded protein response (UNFOLDED PROTEIN RESPONSE) sensors, OsIRE1, OsbZIP39/OsbZIP60 and the UNFOLDED PROTEIN RESPONSE marker OsBiP1, was up-regulated. Interestingly, OsbZIP50 was also alternatively spliced under heat stress, indicating that UNFOLDED PROTEIN RESPONSE signalling pathways were activated by heat stress to re-establish cellular protein homeostasis. We further demonstrated that OsHSFA2dI participated in the unfolded protein response by regulating expression of OsBiP1. © 2014 German Botanical Society and The Royal Botanical Society of the Netherlands.

  15. Association of transforming growth factor-ß3 gene polymorphism ...

    African Journals Online (AJOL)

    Genotyping for the TGF-β3 gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and BslI restriction endonuclease showed a mutation in 294-bp fragment located on the fourth intron of chromosome 5. Polymorphism in TGF-β3 gene was significantly (P < 0.1) associated with ...

  16. Alternative REST Splicing Underappreciated

    OpenAIRE

    Chen, Guo-Lin; Miller, Gregory

    2017-01-01

    As a major orchestrator of the cellular epigenome, the repressor element-1 silencing transcription factor (REST) can either repress or activate thousands of genes depending on cellular context, suggesting a highly context-dependent REST function tuned by environmental cues. While REST shows cell-type non-selective active transcription, an N-terminal REST4 isoform caused by alternative splicing - inclusion of an extra exon (N3c) which introduces a pre-mature stop codon - has been implicated in...

  17. Alternative splicing and expression of the insulin-like growth factor (IGF-1) gene in osteoblasts under mechanical stretch

    Institute of Scientific and Technical Information of China (English)

    XIAN Chengyu; WANG Yuanliang; ZHANG Bingbing; TANG Liling; PAN Jun; LUO Yanfeng; JIANG Peng; LI Dajun

    2006-01-01

    Insulin-like growth factor 1 (IGF-1) promotes osteoblasts differentiation and bone formation,and its expression is induced by mechanical stretch,thus IGF-1 has been considered an effector molecule that links mechanical stimulation and local tissue responses. In this study, a mechanical stretching device was designed to apply physiological level static or cyclic stretching stimulation to osteoblasts.Different isoforms of IGF-1 mRNA were amplified by RT-PCR from the cells using respective primers and these amplified products were sequenced. An isoform of IGF-1 splicing product was found to be selectively produced by osteoblasts under stretching stimulation. This IGF-1 isoform had identical sequence with the mechano growth factor (MGF) which was originally identified in muscle cells. Regulations of the expression of the liver-type IGF (L.IGF-1) and MGF in osteoblasts under stretch stimulation were further studied using semi-quantitative RT-PCR.Stretch stimulation was found to promot the expression of IGF-1 (L.IGF-1 and MGF), and for both isoforms expression was more effectively stimulated by cyclic stretch than static stretch. MGF was detected only in osteoblasts subjected to mechanical stretch,suggesting MGF was a stretch sensitive growth factor.Expression of MGF peaked earlier than that of L.IGF-1, which was similar to their regulation in muscie and suggested similar roles of MGF and L.IGF-1in bone as in muscle cells. The functions of MGF and L.IGF-1 in osteoblasts shall be established by further experimental studies.

  18. [RNA polymerase II and pre-mRNA splicing factors in diplotene oocyte nuclei of the giant African gastropod Achatina fulica].

    Science.gov (United States)

    Stepanova, I S; Bogoliubov, D S

    2003-01-01

    The nuclear distribution of pre-mRNA splicing factors (snRNPs and SR-protein SC35) and unphosphorylated from of RNA polymerase II (Pol II) was studied using fluorescent and immunoelectron cytochemistry in diplotene oocytes of the gastropod Achatina fulica. Association of Pol II and splicing factors with oocyte nuclear structures was analysed. The antibodies against splicing factors and Pol II were shown to label perichromatin fibrils at the periphery of condensed chromatin blocks as well as those in interchromatin regions of nucleoplasm. The revealed character of distribution of snRNPs, SC35 protein, and Pol II, together with the decondensed chromatin and absence of karyosphere, enable us to suggest that oocyte chromosomes maintain their transcriptional activity at the diplotene stage of oogenesis. In A. fulica oocytes, sparse nuclear bodies (NBs) of a complex morphological structure were revealed. These NBs contain snRNPs rather than SC35 protein. NBs are associated with a fibrogranular material (FGM), which contains SC35 protein. No snRNPs were revealed in this material. Homology of A. fulica oocyte nuclear structures to Cajal bodies and interchromatin granule clusters is discussed.

  19. Synergistic effect of factor VII gene polymorphisms causing mild factor VII deficiency in a case of severe factor X deficiency.

    Science.gov (United States)

    Deshpande, Rutuja; Ghosh, Kanjaksha; Shetty, Shrimati

    2017-01-01

    Congenital combined deficiency of coagulation factors VII and X are mainly attributed to large deletions involving both the genes in chromosome 13 or occasionally due to the coincidental occurrence of independently occurring mutations. We report the molecular basis of congenital combined deficiency of factors VII and X in a 6-year-old female child. Direct DNA sequencing of both factor VII (F7) and factor X (F10) genes showed a novel homozygous missense mutation p.Cys90Tyr (c.307G>A) in exon 4 of F10. No mutations were detected in F7; however, the patient was homozygous for three polymorphic alleles known to be associated with reduced factor VII levels. The present case illustrates the synergistic effect of multiple polymorphisms resulting in phenotypic factor VII deficiency in the absence of a pathogenic mutation.

  20. Splicing Factor Prp8 Interacts With NES(AR) and Regulates Androgen Receptor in Prostate Cancer Cells.

    Science.gov (United States)

    Wang, Dan; Nguyen, Minh M; Masoodi, Khalid Z; Singh, Prabhpreet; Jing, Yifeng; O'Malley, Katherine; Dar, Javid A; Dhir, Rajiv; Wang, Zhou

    2015-12-01

    Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES) (NES(AR)) in AR ligand-binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP)-tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated 7 yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor pre-mRNA processing factor 8 (Prp8). We further showed that Prp8 could regulate NES(AR) function using short hairpin RNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration-resistant LuCaP35 xenograft tumors as compared with androgen-sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 mRNA levels were decreased in human prostate cancer specimens with high Gleason scores. In prostate cancer cells, coimmunoprecipitation and deletion mutagenesis revealed a physical interaction between Prp8 and AR mainly mediated by NES(AR). Luciferase assay with prostate specific antigen promoter-driven reporter demonstrated that Prp8 regulated AR transcription activity in prostate cancer cells. Interestingly, Prp8 knockdown also increased polyubiquitination of endogenous AR. This may be 1 possible mechanism by which it modulates AR activity. These results show that Prp8 is a novel AR cofactor that interacts with NES(AR) and regulates AR function in prostate cancer cells.

  1. Formation of Nuclear Splicing Factor Compartments Is Independent of Lamins A/C

    Czech Academy of Sciences Publication Activity Database

    Večeřová, Jaromíra; Koberna, Karel; Malínský, Jan; Soutoglou, E.; Sullivan, T.; Stewart, C. L.; Raška, Ivan; Misteli, T.

    2004-01-01

    Roč. 15, č. 11 (2004), s. 4904-4910 ISSN 1059-1524 R&D Projects: GA AV ČR IAA5039103; GA ČR GA304/02/0342 Institutional research plan: CEZ:AV0Z5039906 Keywords : lamins A/C Subject RIV: EA - Cell Biology Impact factor: 7.517, year: 2004

  2. Selective expression of a splice variant of decay-accelerating factor in c-erbB-2-positive mammary carcinoma cells showing increased transendothelial invasiveness

    International Nuclear Information System (INIS)

    Brandt, Burkhard; Mikesch, Jan-Hendrik; Simon, Ronald; Roetger, Antje; Kemming, Dirk; Schier, Katrin; Sauter, Guido; Buerger, Horst

    2005-01-01

    By differential-display-PCR a subclone of the SK-BR-3 cell line with high in vitro transendothelial invasiveness was identified to express increased levels of a new alternative splice variant of decay-accelerating factor (DAF). DAF seems to play an important role in some malignant tumours since on the one hand the expression of complement inhibitors on the surface of tumour cells prevents the accumulation of complement factors and in consequence cell lysis. On the other hand, DAF has been identified as a ligand for the CD97 surface receptor which induces cell migration. Immunofluorescence procedures, Western blot analyses, and cDNA clone sequencing were employed to confirm the expression of DAF restricted to invasive tumour cells. Using a radioactive RNA-in situ hybridisation on freshly frozen tissue microarrays and RT-PCR on native tumour tissue, the expression of alternative spliced DAF mRNA was demonstrated in invasive breast cancer. Due to the fact that it could thereby not be detected in normal mammary tissues, it has to be confirmed in larger studies that the DAF splice variant might be a specific tumour marker for invasive breast cancer

  3. Role of an SNP in Alternative Splicing of Bovine NCF4 and Mastitis Susceptibility.

    Directory of Open Access Journals (Sweden)

    Zhihua Ju

    Full Text Available Neutrophil cytosolic factor 4 (NCF4 is component of the nicotinamide dinucleotide phosphate oxidase complex, a key factor in biochemical pathways and innate immune responses. In this study, splice variants and functional single-nucleotide polymorphism (SNP of NCF4 were identified to determine the variability and association of the gene with susceptibility to bovine mastitis characterized by inflammation. A novel splice variant, designated as NCF4-TV and characterized by the retention of a 48 bp sequence in intron 9, was detected in the mammary gland tissues of infected cows. The expression of the NCF4-reference main transcript in the mastitic mammary tissues was higher than that in normal tissues. A novel SNP, g.18174 A>G, was also found in the retained 48 bp region of intron 9. To determine whether NCF4-TV could be due to the g.18174 A>G mutation, we constructed two mini-gene expression vectors with the wild-type or mutant NCF4 g.18174 A>G fragment. The vectors were then transiently transfected into 293T cells, and alternative splicing of NCF4 was analyzed by reverse transcription-PCR and sequencing. Mini-gene splicing assay demonstrated that the aberrantly spliced NCF4-TV with 48 bp retained fragment in intron 9 could be due to g.18174 A>G, which was associated with milk somatic count score and increased risk of mastitis infection in cows. NCF4 expression was also regulated by alternative splicing. This study proposes that NCF4 splice variants generated by functional SNP are important risk factors for mastitis susceptibility in dairy cows.

  4. Nuclear pre-mRNA compartmentalization: Trafficking of released transcripts to splicing factor reservoirs

    Czech Academy of Sciences Publication Activity Database

    Melčák, Ivo; Cermanová, Štěpánka; Jirsová, Kateřina; Koberna, Karel; Malínský, Jan; Raška, Ivan

    2000-01-01

    Roč. 11, - (2000), s. 497-510 ISSN 1059-1524 R&D Projects: GA ČR GA302/99/0587; GA ČR GA304/00/1481; GA MŠk VS96129 Grant - others:Wellcome grant(XX) 049949/Z/97/Z/JMW/JPS/CG Institutional research plan: CEZ:AV0Z5039906 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 8.482, year: 2000

  5. CircSMARCA5 Inhibits Migration of Glioblastoma Multiforme Cells by Regulating a Molecular Axis Involving Splicing Factors SRSF1/SRSF3/PTB

    Directory of Open Access Journals (Sweden)

    Davide Barbagallo

    2018-02-01

    Full Text Available Circular RNAs (circRNAs have recently emerged as a new class of RNAs, highly enriched in the brain and very stable within cells, exosomes and body fluids. To analyze their involvement in glioblastoma multiforme (GBM pathogenesis, we assayed the expression of twelve circRNAs, physiologically enriched in several regions of the brain, through real-time PCR in a cohort of fifty-six GBM patient biopsies and seven normal brain parenchymas. We focused on hsa_circ_0001445 (circSMARCA5: it was significantly downregulated in GBM biopsies as compared to normal brain tissues (p-value < 0.00001, student’s t-test, contrary to its linear isoform counterpart that did not show any differential expression (p-value = 0.694, student’s t-test. Analysis of a public dataset revealed a negative correlation between the expression of circSMARCA5 and glioma’s histological grade, suggesting its potential negative role in the progression to malignancy. Overexpressing circSMARCA5 in U87MG cells significantly decreased their migration, but not their proliferation rate. In silico scanning of circSMARCA5 sequence revealed an enrichment in binding motifs for several RNA binding proteins (RBPs, specifically involved in splicing. Among them, serine and arginine rich splicing factor 1 (SRSF1, a splicing factor known to be a positive controller of cell migration and known to be overexpressed in GBM, was predicted to bind circSMARCA5 by three different prediction tools. Direct interaction between circSMARCA5 and SRSF1 is supported by enhanced UV crosslinking and immunoprecipitation (eCLIP data for SRSF1 in K562 cells from Encyclopedia of DNA Elements (ENCODE. Consistently, U87MG overexpressing circSMARCA5 showed an increased expression of serine and arginine rich splicing factor 3 (SRSF3 RNA isoform containing exon 4, normally skipped in a SRSF1-dependent manner, resulting in a non-productive non-sense mediated decay (NMD substrate. Interestingly, SRSF3 is known to interplay

  6. Feline immunodeficiency virus OrfA alters gene expression of splicing factors and proteasome-ubiquitination proteins

    International Nuclear Information System (INIS)

    Sundstrom, Magnus; Chatterji, Udayan; Schaffer, Lana; Rozieres, Sohela de; Elder, John H.

    2008-01-01

    Expression of the feline immunodeficiency virus (FIV) accessory protein OrfA (or Orf2) is critical for efficient viral replication in lymphocytes, both in vitro and in vivo. OrfA has been reported to exhibit functions in common with the human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) accessory proteins Vpr and Tat, although the function of OrfA has not been fully explained. Here, we use microarray analysis to characterize how OrfA modulates the gene expression profile of T-lymphocytes. The primary IL-2-dependent T-cell line 104-C1 was transduced to express OrfA. Functional expression of OrfA was demonstrated by trans complementation of the OrfA-defective clone, FIV-34TF10. OrfA-expressing cells had a slightly reduced cell proliferation rate but did not exhibit any significant alteration in cell cycle distribution. Reverse-transcribed RNA from cells expressing green fluorescent protein (GFP) or GFP + OrfA were hybridized to Affymetrix HU133 Plus 2.0 microarray chips representing more than 47,000 genome-wide transcripts. By using two statistical approaches, 461 (Rank Products) and 277 (ANOVA) genes were identified as modulated by OrfA expression. The functional relevance of the differentially expressed genes was explored by Ingenuity Pathway Analysis. The analyses revealed alterations in genes critical for RNA post-transcriptional modifications and protein ubiquitination as the two most significant functional outcomes of OrfA expression. In these two groups, several subunits of the spliceosome, cellular splicing factors and family members of the proteasome-ubiquitination system were identified. These findings provide novel information on the versatile function of OrfA during FIV infection and indicate a fine-tuning mechanism of the cellular environment by OrfA to facilitate efficient FIV replication

  7. Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice

    Science.gov (United States)

    Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra; Lee, Francis S; Popoli, Maurizio

    2016-01-01

    Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNFVal/Val) and homozygous BDNF Val66Met (BDNFMet/Met) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNFVal/Val but not in BDNFMet/Met mice. Hippocampal neurogenesis was reduced in BDNFMet/Met mice compared with BDNFVal/Val mice. BDNFMet/Met mice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNFMet/Met mice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNFMet/Met muscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise. PMID:27388329

  8. Over-expression of SR-cyclophilin, an interaction partner of nuclear pinin, releases SR family splicing factors from nuclear speckles

    International Nuclear Information System (INIS)

    Lin, C.-L.; Leu, Steve; Lu, M.-C.; Ouyang Pin

    2004-01-01

    Pre-mRNA splicing takes place within a dynamic ribonucleoprotein particle called the spliceosome and occurs in an ordered pathway. Although it is known that spliceosome consists of five small nuclear RNAs and at least 50 proteins, little is known about how the interaction among the proteins changes during splicing. Here we identify that SR-cyp, a Moca family of nuclear cyclophilin, interacts and colocalizes with nuclear pinin (pnn), a SR-related protein involving in pre-mRNA splicing. Nuclear pnn interacts with SR-cyp via its C-terminal RS domain. Upon SR-cyp over-expression, however, the subnuclear distribution of nuclear pnn is altered, resulting in its redistribution from nuclear speckles to a diffuse nucleoplasmic form. The diffuse subnuclear distribution of nuclear pnn is not due to epitope masking, accelerated protein turnover or post-translational modification. Furthermore, we find that SR-cyp regulates the subnuclear distribution of other SR family proteins, including SC35 and SRm300, in a similar manner as it does on nuclear pnn. This result is significant because it suggests that SR-cyp plays a general role in modulating the distribution pattern of SR-like and SR proteins, similar to that of Clk (cdc2-like kinase)/STY on SR family splicing factors. SR-cyp might direct its effect via either alteration of protein folding/conformation or of protein-protein interaction and thus may add another control level of regulation of SR family proteins and modification of their functions

  9. Insulin-like growth factor I (IGF-1 Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

    Directory of Open Access Journals (Sweden)

    Werner Schlegel

    Full Text Available Human insulin-like growth factor 1 Ec (IGF-1Ec, also called mechano growth factor (MGF, is a splice variant of insulin-like growth factor 1 (IGF-1, which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

  10. Insulin-like growth factor I (IGF-1) Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

    Science.gov (United States)

    Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

    2013-01-01

    Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

  11. Systematic Profiling of Poly(A)+ Transcripts Modulated by Core 3’ End Processing and Splicing Factors Reveals Regulatory Rules of Alternative Cleavage and Polyadenylation

    Science.gov (United States)

    Li, Wencheng; You, Bei; Hoque, Mainul; Zheng, Dinghai; Luo, Wenting; Ji, Zhe; Park, Ji Yeon; Gunderson, Samuel I.; Kalsotra, Auinash; Manley, James L.; Tian, Bin

    2015-01-01

    Alternative cleavage and polyadenylation (APA) results in mRNA isoforms containing different 3’ untranslated regions (3’UTRs) and/or coding sequences. How core cleavage/polyadenylation (C/P) factors regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found that several C/P factors can play significant roles in 3’UTR-APA. Whereas Pcf11 and Fip1 enhance usage of proximal poly(A) sites (pAs), CFI-25/68, PABPN1 and PABPC1 promote usage of distal pAs. Strong cis element biases were found for pAs regulated by CFI-25/68 or Fip1, and the distance between pAs plays an important role in APA regulation. In addition, intronic pAs are substantially regulated by splicing factors, with U1 mostly inhibiting C/P events in introns near the 5’ end of gene and U2 suppressing those in introns with features for efficient splicing. Furthermore, PABPN1 inhibits expression of transcripts with pAs near the transcription start site (TSS), a property possibly related to its role in RNA degradation. Finally, we found that groups of APA events regulated by C/P factors are also modulated in cell differentiation and development with distinct trends. Together, our results support an APA code where an APA event in a given cellular context is regulated by a number of parameters, including relative location to the TSS, splicing context, distance between competing pAs, surrounding cis elements and concentrations of core C/P factors. PMID:25906188

  12. Systematic profiling of poly(A+ transcripts modulated by core 3' end processing and splicing factors reveals regulatory rules of alternative cleavage and polyadenylation.

    Directory of Open Access Journals (Sweden)

    Wencheng Li

    2015-04-01

    Full Text Available Alternative cleavage and polyadenylation (APA results in mRNA isoforms containing different 3' untranslated regions (3'UTRs and/or coding sequences. How core cleavage/polyadenylation (C/P factors regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found that several C/P factors can play significant roles in 3'UTR-APA. Whereas Pcf11 and Fip1 enhance usage of proximal poly(A sites (pAs, CFI-25/68, PABPN1 and PABPC1 promote usage of distal pAs. Strong cis element biases were found for pAs regulated by CFI-25/68 or Fip1, and the distance between pAs plays an important role in APA regulation. In addition, intronic pAs are substantially regulated by splicing factors, with U1 mostly inhibiting C/P events in introns near the 5' end of gene and U2 suppressing those in introns with features for efficient splicing. Furthermore, PABPN1 inhibits expression of transcripts with pAs near the transcription start site (TSS, a property possibly related to its role in RNA degradation. Finally, we found that groups of APA events regulated by C/P factors are also modulated in cell differentiation and development with distinct trends. Together, our results support an APA code where an APA event in a given cellular context is regulated by a number of parameters, including relative location to the TSS, splicing context, distance between competing pAs, surrounding cis elements and concentrations of core C/P factors.

  13. Tumour necrosis factor alpha (TNF-α) genetic polymorphisms and ...

    Indian Academy of Sciences (India)

    Sensitivity analysis of the summary odds ratio coefficients on the association between TNF-α-308G/A polymorphism and AILD risk using a random effects model. (A allele vs G allele). Results were computed by omitting each study in turn. Error bars are 95% confidence interval. Journal of Genetics, Vol. 92, No. 3, December ...

  14. Genome-wide survey of allele-specific splicing in humans

    Directory of Open Access Journals (Sweden)

    Scheffler Konrad

    2008-06-01

    Full Text Available Abstract Background Accurate mRNA splicing depends on multiple regulatory signals encoded in the transcribed RNA sequence. Many examples of mutations within human splice regulatory regions that alter splicing qualitatively or quantitatively have been reported and allelic differences in mRNA splicing are likely to be a common and important source of phenotypic diversity at the molecular level, in addition to their contribution to genetic disease susceptibility. However, because the effect of a mutation on the efficiency of mRNA splicing is often difficult to predict, many mutations that cause disease through an effect on splicing are likely to remain undiscovered. Results We have combined a genome-wide scan for sequence polymorphisms likely to affect mRNA splicing with analysis of publicly available Expressed Sequence Tag (EST and exon array data. The genome-wide scan uses published tools and identified 30,977 SNPs located within donor and acceptor splice sites, branch points and exonic splicing enhancer elements. For 1,185 candidate splicing polymorphisms the difference in splicing between alternative alleles was corroborated by publicly available exon array data from 166 lymphoblastoid cell lines. We developed a novel probabilistic method to infer allele-specific splicing from EST data. The method uses SNPs and alternative mRNA isoforms mapped to EST sequences and models both regulated alternative splicing as well as allele-specific splicing. We have also estimated heritability of splicing and report that a greater proportion of genes show evidence of splicing heritability than show heritability of overall gene expression level. Our results provide an extensive resource that can be used to assess the possible effect on splicing of human polymorphisms in putative splice-regulatory sites. Conclusion We report a set of genes showing evidence of allele-specific splicing from an integrated analysis of genomic polymorphisms, EST data and exon array

  15. Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity

    International Nuclear Information System (INIS)

    Azmy, Iman AF; Balasubramanian, Saba P; Wilson, Anthony G; Stephenson, Timothy J; Cox, Angela; Brown, Nicola J; Reed, Malcolm WR

    2004-01-01

    Genetic polymorphisms in the promoter region of the tumour necrosis factor (TNF) gene can regulate gene expression and have been associated with inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter of the TNF gene (-308 G>A and -238 G>A) for their role in breast cancer susceptibility and severity by means of an allelic association study. Using a case–control study design, breast cancer patients (n = 709) and appropriate age-matched and sex-matched controls obtained from the Breast Screening Unit (n = 498) were genotyped for these TNF polymorphisms, using a high-throughput allelic discrimination method. Allele frequencies for both polymorphisms were similar in both breast cancer cases and controls. However, the -308 polymorphism was found to be associated with vascular invasion in breast tumours (P = 0.024). Comparison with other standard prognostic indices did not show any association for either genotype. We demonstrated no association between the -308G>A polymorphism and the -238G>A polymorphism in the promoter region of TNF and susceptibility to breast cancer, in a large North European population. However, the -308 G>A polymorphism was found to be associated with the presence of vascular invasion in breast tumours

  16. Alternative Splicing in Neurogenesis and Brain Development.

    Science.gov (United States)

    Su, Chun-Hao; D, Dhananjaya; Tarn, Woan-Yuh

    2018-01-01

    Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

  17. Alternative Splicing in Neurogenesis and Brain Development

    Directory of Open Access Journals (Sweden)

    Chun-Hao Su

    2018-02-01

    Full Text Available Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

  18. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

    Science.gov (United States)

    Coppieters, Frauke; Roels, Dimitri; De Jaegere, Sarah; Flipts, Helena; De Zaeytijd, Julie; Walraedt, Sophie; Claes, Charlotte; Fransen, Erik; Van Camp, Guy; Depasse, Fanny; Casteels, Ingele; de Ravel, Thomy

    2017-01-01

    Purpose Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5–30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular

  19. Prognostic importance of vascular endothelial growth factor-A expression and vascular endothelial growth factor polymorphisms in epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Smerdel, Maja; Waldstrøm, Marianne; Brandslund, Ivan

    2009-01-01

    INTRODUCTION: Vascular endothelial growth factors (VEGFs) play a central role in angiogenesis and consequently, in various steps of ovarian carcinogenesis. Gene polymorphisms within the VEGF system have revealed a correlation with prognosis in some malignancies. The aim of the present study...... was to examine the possible importance of 2 VEGF polymorphisms and VEGF-A expression in ovarian cancer. METHODS: We investigated 2 single nucleotide polymorphisms VEGF +405G/C and VEGF -460C/T by polymerase chain reaction and also analyzed VEGF-A expression by immunohistochemistry in 159 women with ovarian...... cancer. RESULTS: Vascular endothelial growth factor-A expression revealed a significant correlation with survival in a Cox proportional hazards regression model (P = 0.012). Germline polymorphisms were not correlated with clinicopathological parameters such as stage, type, and histology. Heterozygous...

  20. Modelling reveals kinetic advantages of co-transcriptional splicing.

    Directory of Open Access Journals (Sweden)

    Stuart Aitken

    2011-10-01

    Full Text Available Messenger RNA splicing is an essential and complex process for the removal of intron sequences. Whereas the composition of the splicing machinery is mostly known, the kinetics of splicing, the catalytic activity of splicing factors and the interdependency of transcription, splicing and mRNA 3' end formation are less well understood. We propose a stochastic model of splicing kinetics that explains data obtained from high-resolution kinetic analyses of transcription, splicing and 3' end formation during induction of an intron-containing reporter gene in budding yeast. Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing. Model comparison is used to assess the alternative representations of reactions. Modelling also indicates the functional coupling of transcription and splicing, because both the rate of initiation of transcription and the probability that step one of splicing occurs co-transcriptionally are reduced, when the second step of splicing is abolished in a mutant reporter.

  1. Modelling reveals kinetic advantages of co-transcriptional splicing.

    Science.gov (United States)

    Aitken, Stuart; Alexander, Ross D; Beggs, Jean D

    2011-10-01

    Messenger RNA splicing is an essential and complex process for the removal of intron sequences. Whereas the composition of the splicing machinery is mostly known, the kinetics of splicing, the catalytic activity of splicing factors and the interdependency of transcription, splicing and mRNA 3' end formation are less well understood. We propose a stochastic model of splicing kinetics that explains data obtained from high-resolution kinetic analyses of transcription, splicing and 3' end formation during induction of an intron-containing reporter gene in budding yeast. Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing. Model comparison is used to assess the alternative representations of reactions. Modelling also indicates the functional coupling of transcription and splicing, because both the rate of initiation of transcription and the probability that step one of splicing occurs co-transcriptionally are reduced, when the second step of splicing is abolished in a mutant reporter.

  2. Using a minigene approach to characterize a novel splice site mutation in human F7 gene causing inherited factor VII deficiency in a Chinese pedigree.

    Science.gov (United States)

    Yu, T; Wang, X; Ding, Q; Fu, Q; Dai, J; Lu, Y; Xi, X; Wang, H

    2009-11-01

    Factor VII deficiency which transmitted as an autosomal recessive disorder is a rare haemorrhagic condition. The aim of this study was to identify the molecular genetic defect and determine its functional consequences in a Chinese pedigree with FVII deficiency. The proband was diagnosed as inherited coagulation FVII deficiency by reduced plasma levels of FVII activity (4.4%) and antigen (38.5%). All nine exons and their flanking sequence of F7 gene were amplified by polymerase chain reaction (PCR) for the proband and the PCR products were directly sequenced. The compound heterozygous mutations of F7 (NM_000131.3) c.572-1G>A and F7 (NM_000131.3) c.1165T>G; p.Cys389Gly were identified in the proband's F7 gene. To investigate the splicing patterns associated with F7 c.572-1G>A, ectopic transcripts in leucocytes of the proband were analyzed. F7 minigenes, spanning from intron 4 to intron 7 and carrying either an A or a G at position -1 of intron 5, were constructed and transiently transfected into human embryonic kidney (HEK) 293T cells, followed by RT-PCR analysis. The aberrant transcripts from the F7 c.572-1G>A mutant allele were not detected by ectopic transcription study. Sequencing of the RT-PCR products from the mutant transfectant demonstrated the production of an erroneously spliced mRNA with exon 6 skipping, whereas a normal splicing occurred in the wide type transfectant. The aberrant mRNA produced from the F7 c.572-1G>A mutant allele is responsible for the factor VII deficiency in this pedigree.

  3. Alternative splicing in cancers: From aberrant regulation to new therapeutics.

    Science.gov (United States)

    Song, Xiaowei; Zeng, Zhenyu; Wei, Huanhuan; Wang, Zefeng

    2018-03-01

    Alternative splicing is one of the most common mechanisms for gene regulation in humans, and plays a vital role to increase the complexity of functional proteins. In this article, we seek to provide a general review on the relationships between alternative splicing and tumorigenesis. We briefly introduce the basic rules for regulation of alternative splicing, and discuss recent advances on dynamic regulation of alternative splicing in cancers by highlighting the roles of a variety of RNA splicing factors in tumorigenesis. We further discuss several important questions regarding the splicing of long noncoding RNAs and back-splicing of circular RNAs in cancers. Finally, we discuss the current technologies that can be used to manipulate alternative splicing and serve as potential cancer treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Jerusa Smid

    2013-07-01

    Full Text Available Interaction of prion protein and amyloid-b oligomers has been demonstrated recently. Homozygosity at prion protein gene (PRNP codon 129 is associated with higher risk for Creutzfeldt-Jakob disease. This polymorphism has been addressed as a possible risk factor in Alzheimer disease (AD. Objective To describe the association between codon 129 polymorphisms and AD. Methods We investigated the association of codon 129 polymorphism of PRNP in 99 AD patients and 111 controls, and the association between this polymorphism and cognitive performance. Other polymorphisms of PRNP and additive effect of apolipoprotein E gene (ApoE were evaluated. Results Codon 129 genotype distribution in AD 45.5% methionine (MM, 42.2% methionine valine (MV, 12.1% valine (VV; and 39.6% MM, 50.5% MV, 9.9% VV among controls (p>0.05. There were no differences of cognitive performance concerning codon 129. Stratification according to ApoE genotype did not reveal difference between groups. Conclusion Codon 129 polymorphism is not a risk factor for AD in Brazilian patients.

  5. Alternative Splicing Control of Abiotic Stress Responses.

    Science.gov (United States)

    Laloum, Tom; Martín, Guiomar; Duque, Paula

    2018-02-01

    Alternative splicing, which generates multiple transcripts from the same gene, is an important modulator of gene expression that can increase proteome diversity and regulate mRNA levels. In plants, this post-transcriptional mechanism is markedly induced in response to environmental stress, and recent studies have identified alternative splicing events that allow rapid adjustment of the abundance and function of key stress-response components. In agreement, plant mutants defective in splicing factors are severely impaired in their response to abiotic stress. Notably, mounting evidence indicates that alternative splicing regulates stress responses largely by targeting the abscisic acid (ABA) pathway. We review here current understanding of post-transcriptional control of plant stress tolerance via alternative splicing and discuss research challenges for the near future. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Negative Regulation of Interferon-β Production by Alternative Splicing of Tumor Necrosis Factor Receptor-Associated Factor 3 in Ducks

    Directory of Open Access Journals (Sweden)

    Xiaoqin Wei

    2018-03-01

    Full Text Available Tumor necrosis factor receptor-associated factor 3 (TRAF3, an intracellular signal transducer, is identified as an important component of Toll-like receptors and RIG-I-like receptors induced type I interferon (IFN signaling pathways. Previous studies have clarified TRAF3 function in mammals, but little is known about the role of TRAF3 in ducks. Here, we cloned and characterized the full-length duck TRAF3 (duTRAF3 gene and an alternatively spliced isoform of duTRAF3 (duTRAF3-S lacking the fragment encoding amino acids 217–319, from duck embryo fibroblasts (DEFs. We found that duTRAF3 and duTRAF3-S played different roles in regulating IFN-β production in DEFs. duTRAF3 through its TRAF domain interacted with duMAVS or duTRIF, leading to the production of IFN-β. However, duTRAF3-S, containing the TRAF domain, was unable to bind duMAVS or duTRIF due to the intramolecular binding between the N- and C-terminal of duTRAF3-S that blocked the function of its TRAF domain. Further analysis identified that duTRAF3-S competed with duTRAF3 itself for binding to duTRAF3, perturbing duTRAF3 self-association, which impaired the assembly of duTRAF3-duMAVS/duTRIF complex, ultimately resulted in a reduced production of IFN-β. These findings suggest that duTRAF3 is an important regulator of duck innate immune signaling and reveal a novel mechanism for the negative regulation of IFN-β production via changing the formation of the homo-oligomerization of wild molecules, implying a novel regulatory role of truncated proteins.

  7. A KH-Domain RNA-Binding Protein Interacts with FIERY2/CTD Phosphatase-Like 1 and Splicing Factors and Is Important for Pre-mRNA Splicing in Arabidopsis

    KAUST Repository

    Chen, Tao

    2013-10-17

    Eukaryotic genomes encode hundreds of RNA-binding proteins, yet the functions of most of these proteins are unknown. In a genetic study of stress signal transduction in Arabidopsis, we identified a K homology (KH)-domain RNA-binding protein, HOS5 (High Osmotic Stress Gene Expression 5), as required for stress gene regulation and stress tolerance. HOS5 was found to interact with FIERY2/RNA polymerase II (RNAP II) carboxyl terminal domain (CTD) phosphatase-like 1 (FRY2/CPL1) both in vitro and in vivo. This interaction is mediated by the first double-stranded RNA-binding domain of FRY2/CPL1 and the KH domains of HOS5. Interestingly, both HOS5 and FRY2/CPL1 also interact with two novel serine-arginine (SR)-rich splicing factors, RS40 and RS41, in nuclear speckles. Importantly, FRY2/CPL1 is required for the recruitment of HOS5. In fry2 mutants, HOS5 failed to be localized in nuclear speckles but was found mainly in the nucleoplasm. hos5 mutants were impaired in mRNA export and accumulated a significant amount of mRNA in the nuclei, particularly under salt stress conditions. Arabidopsis mutants of all these genes exhibit similar stress-sensitive phenotypes. RNA-seq analyses of these mutants detected significant intron retention in many stress-related genes under salt stress but not under normal conditions. Our study not only identified several novel regulators of pre-mRNA processing as important for plant stress response but also suggested that, in addition to RNAP II CTD that is a well-recognized platform for the recruitment of mRNA processing factors, FRY2/CPL1 may also recruit specific factors to regulate the co-transcriptional processing of certain transcripts to deal with environmental challenges. © 2013 Chen et al.

  8. A KH-Domain RNA-Binding Protein Interacts with FIERY2/CTD Phosphatase-Like 1 and Splicing Factors and Is Important for Pre-mRNA Splicing in Arabidopsis

    KAUST Repository

    Chen, Tao; Cui, Peng; Chen, Hao; Ali, Shahjahan; Zhang, ShouDong; Xiong, Liming

    2013-01-01

    Eukaryotic genomes encode hundreds of RNA-binding proteins, yet the functions of most of these proteins are unknown. In a genetic study of stress signal transduction in Arabidopsis, we identified a K homology (KH)-domain RNA-binding protein, HOS5 (High Osmotic Stress Gene Expression 5), as required for stress gene regulation and stress tolerance. HOS5 was found to interact with FIERY2/RNA polymerase II (RNAP II) carboxyl terminal domain (CTD) phosphatase-like 1 (FRY2/CPL1) both in vitro and in vivo. This interaction is mediated by the first double-stranded RNA-binding domain of FRY2/CPL1 and the KH domains of HOS5. Interestingly, both HOS5 and FRY2/CPL1 also interact with two novel serine-arginine (SR)-rich splicing factors, RS40 and RS41, in nuclear speckles. Importantly, FRY2/CPL1 is required for the recruitment of HOS5. In fry2 mutants, HOS5 failed to be localized in nuclear speckles but was found mainly in the nucleoplasm. hos5 mutants were impaired in mRNA export and accumulated a significant amount of mRNA in the nuclei, particularly under salt stress conditions. Arabidopsis mutants of all these genes exhibit similar stress-sensitive phenotypes. RNA-seq analyses of these mutants detected significant intron retention in many stress-related genes under salt stress but not under normal conditions. Our study not only identified several novel regulators of pre-mRNA processing as important for plant stress response but also suggested that, in addition to RNAP II CTD that is a well-recognized platform for the recruitment of mRNA processing factors, FRY2/CPL1 may also recruit specific factors to regulate the co-transcriptional processing of certain transcripts to deal with environmental challenges. © 2013 Chen et al.

  9. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy

    2010-01-01

    by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h......-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression...... of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine...

  10. Muscle-specific splicing factors ASD-2 and SUP-12 cooperatively switch alternative pre-mRNA processing patterns of the ADF/cofilin gene in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Genta Ohno

    Full Text Available Pre-mRNAs are often processed in complex patterns in tissue-specific manners to produce a variety of protein isoforms from single genes. However, mechanisms orchestrating the processing of the entire transcript are not well understood. Muscle-specific alternative pre-mRNA processing of the unc-60 gene in Caenorhabditis elegans, encoding two tissue-specific isoforms of ADF/cofilin with distinct biochemical properties in regulating actin organization, provides an excellent in vivo model of complex and tissue-specific pre-mRNA processing; it consists of a single first exon and two separate series of downstream exons. Here we visualize the complex muscle-specific processing pattern of the unc-60 pre-mRNA with asymmetric fluorescence reporter minigenes. By disrupting juxtaposed CUAAC repeats and UGUGUG stretch in intron 1A, we demonstrate that these elements are required for retaining intron 1A, as well as for switching the processing patterns of the entire pre-mRNA from non-muscle-type to muscle-type. Mutations in genes encoding muscle-specific RNA-binding proteins ASD-2 and SUP-12 turned the colour of the unc-60 reporter worms. ASD-2 and SUP-12 proteins specifically and cooperatively bind to CUAAC repeats and UGUGUG stretch in intron 1A, respectively, to form a ternary complex in vitro. Immunohistochemical staining and RT-PCR analyses demonstrate that ASD-2 and SUP-12 are also required for switching the processing patterns of the endogenous unc-60 pre-mRNA from UNC-60A to UNC-60B in muscles. Furthermore, systematic analyses of partially spliced RNAs reveal the actual orders of intron removal for distinct mRNA isoforms. Taken together, our results demonstrate that muscle-specific splicing factors ASD-2 and SUP-12 cooperatively promote muscle-specific processing of the unc-60 gene, and provide insight into the mechanisms of complex pre-mRNA processing; combinatorial regulation of a single splice site by two tissue-specific splicing regulators

  11. Identification of a novel nuclear localization signal and speckle-targeting sequence of tuftelin-interacting protein 11, a splicing factor involved in spliceosome disassembly

    Energy Technology Data Exchange (ETDEWEB)

    Tannukit, Sissada [Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA Rm103, Los Angeles, CA 90033-1004 (United States); Crabb, Tara L.; Hertel, Klemens J. [Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA 92697-4025 (United States); Wen, Xin [Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA Rm103, Los Angeles, CA 90033-1004 (United States); Jans, David A. [Department of Biochemistry and Molecular Biology, Nuclear Signalling Laboratory, Monash University, Clayton, Victoria 3800 (Australia); Paine, Michael L., E-mail: paine@usc.edu [Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA Rm103, Los Angeles, CA 90033-1004 (United States)

    2009-12-18

    Tuftelin-interacting protein 11 (TFIP11) is a protein component of the spliceosome complex that promotes the release of the lariat-intron during late-stage splicing through a direct recruitment and interaction with DHX15/PRP43. Expression of TFIP11 is essential for cell and organismal survival. TFIP11 contains a G-patch domain, a signature motif of RNA-processing proteins that is responsible for TFIP11-DHX15 interactions. No other functional domains within TFIP11 have been described. TFIP11 is localized to distinct speckled regions within the cell nucleus, although excluded from the nucleolus. In this study sequential C-terminal deletions and mutational analyses have identified two novel protein elements in mouse TFIP11. The first domain covers amino acids 701-706 (VKDKFN) and is an atypical nuclear localization signal (NLS). The second domain is contained within amino acids 711-735 and defines TFIP11's distinct speckled nuclear localization. The identification of a novel TFIP11 nuclear speckle-targeting sequence (TFIP11-STS) suggests that this domain directly interacts with additional spliceosomal components. These data help define the mechanism of nuclear/nuclear speckle localization of the splicing factor TFIP11, with implications for it's function.

  12. Serine/arginine rich splicing factor 2 expression and clinic pathological features indicating a prognostic factor in human hepatocellular carcinoma patients.

    Science.gov (United States)

    Wang, Pingan; Guo, Lingyu; Li, Kaipeng; Ning, Shanglei; Shi, Weichen; Liu, Zhaochen; Chen, Yuxin

    2018-02-14

    This research was aimed to study the expression of Serine/arginine rich splicing factor 2 (SRSF2) in tissues of hepatocellular carcinoma, and explore the relationship between the expression and the clinic pathological and prognosis of human hepatocellular carcinoma (HCC). One hundred and fifty-three pairs HCC tissues and adjacent normal tissue were collected from January 2010 to March 2013. The expression of SRSF2 gene was detected by immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction (PCR), and the relationship between the expression and the clinic pathological and prognosis of HCC being analyzed. In 153 cases of hepatocellular carcinoma, SRSF2 was highly expressed in 93 cases, low expression of 60 cases, immunohistochemistry score (6.50 ± 2.82), which was significantly higher than that in adjacent normal tissues (2.94 ± 1.23) (Phepatocellular carcinoma was positively correlated (r = 0.704, Phepatocellular carcinoma were 74.19%, 44.09%, 26.88%, 24.73% and 21.51% at 1 year, 2 years, 3 years, 4 years and 5 years respectively, which were lower than those of SRSF2 low expression group (93.33%, 71.67%, 56.67%, 51.67% and 50.00%). SRSF2 is highly expressed in hepatocellular carcinoma and its expression increases with the degree of tumor differentiation and TNM staging. It is related to lymph node metastasis and metastasis of tumor cells, and is positively related to serum alpha fetoprotein content, and affects the postoperative survival time of HCC patients.

  13. The effects of three factor VII polymorphisms on factor VII coagulant levels in healthy Singaporean Chinese, Malay and Indian newborns.

    Science.gov (United States)

    Quek, S C; Low, P S; Saha, N; Heng, C K

    2006-11-01

    Factor VII (FVII) is an independent risk factor for coronary artery disease. Three polymorphisms of the factor VII gene (F7) were studied in a group of healthy newborns comprising 561 Chinese, 398 Malays and 226 Asian Indians from Singapore. The allele frequencies of 3 polymorphisms (R353Q, Promoter 0/10bp Del/Ins and Intron 7) in the FVII gene were ascertained through genotyping by polymerase chain reaction and restriction digestion of amplified fragments. In Chinese the minor allele frequencies are Q: 0.04, Ins: 0.03, R7: 0.44; Malays, Q: 0.06, Ins: 0.10, R7: 0.41; and Indians, Q: 0.25, Ins: 0.23, R7: 0.43. Strong linkage disequilibrium (Delta > 0.7) is observed between the 0/10 bp and the R353Q sites in all ethnic groups. We conclude that: (i) the prevalence of the minor Q and Ins alleles of the R353Q and 0/10 bp polymorphisms are significantly higher in the Indian newborns than the Chinese and Malays; (ii) the Q allele is significantly associated (p = 0.01) with a lower plasma FVII coagulant level in the Indian and Malay neonates; and this polymorphism explains up to 3.8% of the variance in FVII coagulant levels; (iii) there is no significant difference in allele frequencies of the three polymorphisms between neonates with and without family histories of CAD.

  14. Fibroblast growth factor receptor 4 polymorphism is associated with liver cirrhosis in hepatocarcinoma.

    Directory of Open Access Journals (Sweden)

    Ming-Jen Sheu

    Full Text Available Fibroblast growth factor receptor 4 (FGFR4 polymorphisms are positively correlated with tumor progression in numerous malignant tumors. However, the association between FGFR4 genetic variants and the risk of hepatocellular carcinoma (HCC has not yet been determined. In this study, we investigated the potential associations of FGFR4 single nucleotide polymorphisms (SNPs with HCC susceptibility and its clinicopathological characteristics.Four SNPs in FGFR4 (rs1966265, rs351855, rs2011077, and rs7708357 were analyzed among 884 participants, including 595 controls and 289 patients with HCC. The samples were further analyzed to clarify the associations between these gene polymorphisms and the risk of HCC, and the impact of these SNPs on the susceptibility and clinicopathological characteristics of HCC. After adjusting for other covariants, HCC patients who carrying at least one A genotype (GA and AA at rs351855 were observed to have a higher risk of liver cirrhosis compared with those carrying the wild-type genotype (GG (OR: 2.113, 95% CI: 1.188-3.831. Moreover, the patients with at least one A genotype were particularly showed a high level of alpha-fetoprotein (AFP.Our findings suggest that genetic polymorphism in FGFR4 rs351855 may be associated with the risk of HCC coupled with liver cirrhosis and may markedly increase the AFP level in Taiwanese patients with HCC. In addition, this is the first study that evaluated the risk factors associated with FGFR4 polymorphism variants in Taiwanese patients with HCC.

  15. MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies

    Science.gov (United States)

    Trabzuni, Daniah; Wray, Selina; Vandrovcova, Jana; Ramasamy, Adaikalavan; Walker, Robert; Smith, Colin; Luk, Connie; Gibbs, J. Raphael; Dillman, Allissa; Hernandez, Dena G.; Arepalli, Sampath; Singleton, Andrew B.; Cookson, Mark R.; Pittman, Alan M.; de Silva, Rohan; Weale, Michael E.; Hardy, John; Ryten, Mina

    2012-01-01

    The MAPT (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy, corticobasal degeneration, Parksinson's disease and possibly Alzheimer's disease, but also due its genetic evolution and complex alternative splicing features which are, to some extent, linked and so all the more intriguing. Therefore, obtaining robust information regarding the expression, splicing and genetic regulation of this gene within the human brain is of immense importance. In this study, we used 2011 brain samples originating from 439 individuals to provide the most reliable and coherent information on the regional expression, splicing and regulation of MAPT available to date. We found significant regional variation in mRNA expression and splicing of MAPT within the human brain. Furthermore, at the gene level, the regional distribution of mRNA expression and total tau protein expression levels were largely in agreement, appearing to be highly correlated. Finally and most importantly, we show that while the reported H1/H2 association with gene level expression is likely to be due to a technical artefact, this polymorphism is associated with the expression of exon 3-containing isoforms in human brain. These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene. PMID:22723018

  16. Detection of polymorphism of the insulin-like growth factor-I (IGF-I ...

    African Journals Online (AJOL)

    Molecular genetic selection on individual genes is a promising method to genetically improve economically important traits in chickens. The insulin-like growth factor-I (IGF-I) gene may play important roles in growth of multiple tissues, including muscle cells, cartilage and bone. In the present study, polymorphism of the ...

  17. Tumor necrosis factor alpha gene polymorphism in multiple sclerosis and optic neuritis

    DEFF Research Database (Denmark)

    Fugger, L; Morling, N; Sandberg-Wollheim, M

    1990-01-01

    The NcoI tumor necrosis factor (TNF alpha) polymorphism was studied in relapsing/remitting multiple sclerosis and monosymptomatic optic neuritis. The frequency of the NcoI marker phenotypes did not differ between healthy controls and the two disease groups. No extra or missing DNA fragments were...

  18. Association of apolipoprotein E polymorphisms and dietary factors in colorectal cancer

    OpenAIRE

    Mrkonjic, M; Chappell, E; Pethe, V V; Manno, M; Daftary, D; Greenwood, C M; Gallinger, S; Zanke, B W; Knight, J A; Bapat, B

    2009-01-01

    ApoE single nucleotide polymorphisms (SNPs) Cys112Arg (Epsilon-4), and Arg158Cys (Epsilon-2) have been implicated in cardiovascular and Alzheimer's disease, but their role in colorectal cancer (CRC) has not been extensively studied. We investigated whether ApoE polymorphisms alone or in combination with dietary factors selectively contribute to mismatch-repair (MMR) proficient (microsatellite stable/low or MSS/L) vs deficient (microsatellite unstable or MSI-H) CRCs. We carried out a case?cont...

  19. An in vivo genetic screen for genes involved in spliced leader trans-splicing indicates a crucial role for continuous de novo spliced leader RNP assembly.

    Science.gov (United States)

    Philippe, Lucas; Pandarakalam, George C; Fasimoye, Rotimi; Harrison, Neale; Connolly, Bernadette; Pettitt, Jonathan; Müller, Berndt

    2017-08-21

    Spliced leader (SL) trans-splicing is a critical element of gene expression in a number of eukaryotic groups. This process is arguably best understood in nematodes, where biochemical and molecular studies in Caenorhabditis elegans and Ascaris suum have identified key steps and factors involved. Despite this, the precise details of SL trans-splicing have yet to be elucidated. In part, this is because the systematic identification of the molecules involved has not previously been possible due to the lack of a specific phenotype associated with defects in this process. We present here a novel GFP-based reporter assay that can monitor SL1 trans-splicing in living C. elegans. Using this assay, we have identified mutants in sna-1 that are defective in SL trans-splicing, and demonstrate that reducing function of SNA-1, SNA-2 and SUT-1, proteins that associate with SL1 RNA and related SmY RNAs, impairs SL trans-splicing. We further demonstrate that the Sm proteins and pICln, SMN and Gemin5, which are involved in small nuclear ribonucleoprotein assembly, have an important role in SL trans-splicing. Taken together these results provide the first in vivo evidence for proteins involved in SL trans-splicing, and indicate that continuous replacement of SL ribonucleoproteins consumed during trans-splicing reactions is essential for effective trans-splicing. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. Mechanical rebar splicing

    Directory of Open Access Journals (Sweden)

    Milosavljević Branko

    2014-01-01

    Full Text Available Different mechanical rebar splicing systems are presented, and design situations where mechanical splicing has advantage over reinforcement splicing by overlapping and welding are defined in this paper. New international standards for testing and proof of systems for mechanical rebar splicing quality are considered. Mechanical splicing system for rebar and bolt connection, usable in steel and reinforced concrete structural elements connections, is presented in this paper. There are only few examples of mechanical rebar splicing in our country. The most significant one - the pylon and beam connection at Ada Bridge in Belgrade is presented in the paper. Intensive development of production and use of mechanical rebar splicing systems, research in this area, as well as the publication of international standards prescribing requirements for quality and procedures for proof of quality, represent very good base for development of the corresponding technical norms in Serbia. The legislation in this area would quicken proof of quality procedures, attest and approval issuing for individual products, leading to wider use of this system in all situations where it is in advantage over the classical reinforcement splicing.

  1. spliceR

    DEFF Research Database (Denmark)

    Vitting-Seerup, Kristoffer; Porse, Bo Torben; Sandelin, Albin

    2014-01-01

    RNA-seq data is currently underutilized, in part because it is difficult to predict the functional impact of alternate transcription events. Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing...

  2. Association of cytokine gene polymorphisms and risk factors with otitis media proneness in children.

    Science.gov (United States)

    Miljanović, Olivera; Cikota-Aleksić, Bojana; Likić, Dragan; Vojvodić, Danilo; Jovićević, Ognjen; Magić, Zvonko

    2016-06-01

    In order to assess the association between gene polymorphisms and otitis media (OM) proneness, tumor necrosis factor alpha (TNFA) -308, interleukin (IL) 10-1082 and -3575, IL6 -597, IL2 -330, and CD14 -159 genotyping was performed in 58 OM-prone children and 85 controls who were exposed to similar number and frequency of environmental and host risk factors. The frequencies of genotypes (wild type vs. genotypes containing at least one polymorphic allele) were not significantly different between groups, except for IL10 -1082. Polymorphic genotypes IL10 -1082 GA and GG were more frequent in OM-prone children than in control group (RR 1.145, 95 % CI 1.011-1.298; p = 0.047). However, logistic regression did not confirm IL10 -1082 polymorphic genotypes as an independent risk factor for OM proneness. The present study indicates that high-producing IL10 -1082 GA/GG genotypes may increase the risk for OM proneness in its carriers when exposed to other environmental/host risk factors (day care attendance, passive smoking, male sex, respiratory infections, and atopic manifestations). This study revealed no significant independent genetic association, but the lack of breastfeeding in infancy was found to be the only independent risk factor for development of OM-prone phenotype, implying that breastfeeding had a protective role in development of susceptibility to OM. • The pathogenesis of OM is of multifactorial nature, dependent on infection, environmental factors, and immune response of the child. • Cytokines and CD14 play an important role in the presentation and clinical course of otitis media, but a clear link with otitis media proneness was not established. What is new: • This is the first clinical and genetic study on Montenegrin children with the otitis media-prone phenotype. • The study revealed that high-producing IL10 -1082 genotypes may influence otitis media proneness in children exposed to other environmental/host risk factors.

  3. Polymorphisms in tumor necrosis factor genes and susceptibility to visceral leishmaniasis in Moroccan children

    Directory of Open Access Journals (Sweden)

    Rajaa Ejghal

    2015-05-01

    Full Text Available Objective: To examine whether polymorphic alleles at these two loci are involved in the susceptibility to visceral leishmaniasis (VL in Moroccan children. Methods: We have genotyped polymorphisms by PCR-restricted fragment length polymorphisms in 102 patients with VL, 92 asymptomatic carriers [positive skin test delayedtype hypersensitivity (DTH+] and 40 healthy controls (negative skin test delayed-type hypersensitivity, with no history of Leishmania infection. Results: Regression analysis showed no significant association between polymorphisms of tumor necrosis factors-ααwhen comparing VL and DTH + group (P > 0.05. The associations were detected between VL and negative skin test delayed-type hypersensitivity for the heterozygote genotype (P = 0.021, the recessive model: 1/2 + 2/2 (P = 0.044 and the minor allele 2 (P = 0.019. The resistance to VL was found to be under the recessive model 1/2 + 2/2 of tumor necrosis factors-β, when comparing VL and DTH + group (odds ratios: 0.558, 95%; confidence interval: 0.316-0.987; P = 0.044. Conclusions: These results must be regarded to preliminary but suggestive that further study with larger populations is worthwhile.

  4. The Relationship between Vascular Endothelial Growth Factor 1154G/A Polymorphism and Recurrent Implantation Failure

    Science.gov (United States)

    Vagnini, Laura D.; Nascimento, Adriana M.; Canas, Maria do Carmo T.; Renzi, Adriana; Oliveira-Pelegrin, Gabriela R.; Petersen, Claudia G.; Mauri, Ana L.; Oliveira, João Batista A.; Baruffi, Ricardo L.R.; Cavagna, Mario; Franco, José G.

    2015-01-01

    Objective The aim of this study was to investigate the relationship between herpesvirus-associated ubiquitin-specific protease (HAUSP A/G, rs1529916), tumor protein p53 (TP53 Arg/Pro, rs1042522), leukemia inhibitory factor (LIF G/T, rs929271), glycoprotein 130 (gp130 A/T, rs1900173) and vascular endothelial growth factor (VEGF G/A, rs1570360) polymorphisms and recurrent implantation failure (RIF) in Brazilian women. Subjects and Methods A total of 120 women with RIF (i.e. those with ≥5 cleaved embryos transferred and a minimum of 2 failed in vitro fertilization/intracytoplasmic sperm injection attempts) were included. The control group involved 89 women who had experienced at least 1 live birth (without any infertility treatment). DNA was extracted from the peripheral blood of all participants, and the abovementioned single-nucleotide polymorphisms (SNPs) were genotyped by real-time polymerase chain reaction. The data were evaluated using Fisher's test. Results A significant difference between the RIF and control groups was found in the VEGF gene where the GG genotype showed a 2.1-fold increased chance of not being included in the RIF group, while the presence of an A allele increased this risk 1.6-fold. No significant differences were found for the other polymorphisms. Conclusion This study showed an association between the VEGF -1154G/A polymorphism and RIF in Brazilian women. PMID:26305668

  5. Pre-mRNA Splicing in Plants: In Vivo Functions of RNA-Binding Proteins Implicated in the Splicing Process

    Directory of Open Access Journals (Sweden)

    Katja Meyer

    2015-07-01

    Full Text Available Alternative pre-messenger RNA splicing in higher plants emerges as an important layer of regulation upon exposure to exogenous and endogenous cues. Accordingly, mutants defective in RNA-binding proteins predicted to function in the splicing process show severe phenotypic alterations. Among those are developmental defects, impaired responses to pathogen threat or abiotic stress factors, and misregulation of the circadian timing system. A suite of splicing factors has been identified in the model plant Arabidopsis thaliana. Here we summarize recent insights on how defects in these splicing factors impair plant performance.

  6. Frequencies of VNTR and RFLP polymorphisms associated with factor VIII gene in Singapore

    Energy Technology Data Exchange (ETDEWEB)

    Fong, I.; Lai, P.S.; Ouah, T.C. [National Univ. of Singapore (Malaysia)] [and others

    1994-09-01

    The allelic frequency of any polymorphism within a population determines its usefulness for genetic counselling. This is important in populations of non-Caucasian origin as RFLPs may significantly differ among ethnic groups. We report a study of five intragenic polymorphisms in factor VIII gene carried out in Singapore. The three PCR-based RFLP markers studied were Intron 18/Bcl I, Intron 19/Hind III and Intron 22/Xba I. In an analysis of 148 unrelated normal X chromosomes, the allele frequencies were found to be A1 = 0.18, A2 = 0.82 (Bcl I RFLP), A1 = 0.80, A2 = 0.20 (Hind III RFLP) and A1 = 0.58, and A2 = 0.42 (Xba I RFLP). The heterozygosity rates of 74 females analyzed separately were 31%, 32% and 84.2%, respectively. Linkage disequilibrium was also observed to some degree between Bcl I and Hind III polymorphism in our population. We have also analyzed a sequence polymorphism in Intron 7 using hybridization with radioactive-labelled {sup 32}P allele-specific oligonucleotide probes. This polymorphism was not very polymorphic in our population with only 2% of 117 individuals analyzed being informative. However, the use of a hypervariable dinucleotide repeat sequence (VNTR) in Intron 13 showed that 25 of our of 27 (93%) females were heterozygous. Allele frequencies ranged from 1 to 55 %. We conclude that a viable strategy for molecular analysis of Hemophilia A families in our population should include the use of Intron 18/Bcl I and Intron 22/Xba I RFLP markers and the Intron 13 VNTR marker.

  7. TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population

    Directory of Open Access Journals (Sweden)

    M.A.C. Smith

    2007-11-01

    Full Text Available TP53, a tumor suppressor gene, has a critical role in cell cycle, apoptosis and cell senescence and participates in many crucial physiological and pathological processes. Identification of TP53 polymorphism in older people and age-related diseases may provide an understanding of its physiology and pathophysiological role as well as risk factors for complex diseases. TP53 codon 72 (TP53:72 polymorphism was investigated in 383 individuals aged 66 to 97 years in a cohort from a Brazilian Elderly Longitudinal Study. We investigated allele frequency, genotype distribution and allele association with morbidities such as cardiovascular disease, type II diabetes, obesity, neoplasia, low cognitive level (dementia, and depression. We also determined the association of this polymorphism with serum lipid fractions and urea, creatinine, albumin, fasting glucose, and glycated hemoglobin levels. DNA was isolated from blood cells, amplified by PCR using sense 5'-TTGCCGTCCCAAGCAATGGATGA-3' and antisense 5'-TCTGGGAAGGGACAGAAGATGAC-3' primers and digested with the BstUI enzyme. This polymorphism is within exon 4 at nucleotide residue 347. Descriptive statistics, logistic regression analysis and Student t-test using the multiple comparison test were used. Allele frequencies, R (Arg = 0.69 and P (Pro = 0.31, were similar to other populations. Genotype distributions were within Hardy-Weinberg equilibrium. This polymorphism did not show significant association with any age-related disease or serum variables. However, R allele carriers showed lower HDL levels and a higher frequency of cardiovascular disease than P allele subjects. These findings may help to elucidate the physiopathological role of TP53:72 polymorphism in Brazilian elderly people.

  8. Association of tumor necrosis factor alpha gene polymorphism G-308A with pseudoexfoliative glaucoma in the Pakistani population.

    NARCIS (Netherlands)

    Khan, M.I.; Micheal, S.; Rana, N.; Akhtar, F.; Hollander, A.I. den; Ahmed, A.; Qamar, R.

    2009-01-01

    PURPOSE: The purpose of the present study was to determine the role of the tumor necrosis factor alpha (TNF-alpha) gene polymorphism G-308A and total serum immunoglobulin E (TsIgE) levels in the onset of pseudoexfoliation glaucoma (PEXG) in Pakistani patients. METHODS: The TNF-alpha polymorphism

  9. A method of predicting changes in human gene splicing induced by genetic variants in context of cis-acting elements

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    Hicks Chindo

    2010-01-01

    Full Text Available Abstract Background Polymorphic variants and mutations disrupting canonical splicing isoforms are among the leading causes of human hereditary disorders. While there is a substantial evidence of aberrant splicing causing Mendelian diseases, the implication of such events in multi-genic disorders is yet to be well understood. We have developed a new tool (SpliceScan II for predicting the effects of genetic variants on splicing and cis-regulatory elements. The novel Bayesian non-canonical 5'GC splice site (SS sensor used in our tool allows inference on non-canonical exons. Results Our tool performed favorably when compared with the existing methods in the context of genes linked to the Autism Spectrum Disorder (ASD. SpliceScan II was able to predict more aberrant splicing isoforms triggered by the mutations, as documented in DBASS5 and DBASS3 aberrant splicing databases, than other existing methods. Detrimental effects behind some of the polymorphic variations previously associated with Alzheimer's and breast cancer could be explained by changes in predicted splicing patterns. Conclusions We have developed SpliceScan II, an effective and sensitive tool for predicting the detrimental effects of genomic variants on splicing leading to Mendelian and complex hereditary disorders. The method could potentially be used to screen resequenced patient DNA to identify de novo mutations and polymorphic variants that could contribute to a genetic disorder.

  10. Approaches to link RNA secondary structures with splicing regulation

    DEFF Research Database (Denmark)

    Plass, Mireya; Eyras, Eduardo

    2014-01-01

    In higher eukaryotes, alternative splicing is usually regulated by protein factors, which bind to the pre-mRNA and affect the recognition of splicing signals. There is recent evidence that the secondary structure of the pre-mRNA may also play an important role in this process, either by facilitat...... describes the steps in the analysis of the secondary structure of the pre-mRNA and its possible relation to splicing. As a working example, we use the case of yeast and the problem of the recognition of the 3' splice site (3'ss).......In higher eukaryotes, alternative splicing is usually regulated by protein factors, which bind to the pre-mRNA and affect the recognition of splicing signals. There is recent evidence that the secondary structure of the pre-mRNA may also play an important role in this process, either...

  11. MicroRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Yin-Hung Chu

    Full Text Available BACKGROUND: Micro RNAs (miRNAs are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and real-time PCR were used to analyze miRNA146a (rs2910164, miRNA149 (rs2292832, miRNA196 (rs11614913, and miRNA499 (rs3746444 genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88-4.30. In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52-8.70; AOR = 3.38, 95% CI = 1.68-6.80. CONCLUSIONS: These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility.

  12. Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with schizophrenia

    Directory of Open Access Journals (Sweden)

    Kadasah S

    2017-04-01

    Full Text Available Saeed Kadasah,1 Misbahul Arfin,2 Sadaf Rizvi,2 Mohammed Al-Asmari,2 Abdulrahman Al-Asmari2 1Department of Psychiatry, 2Division of Molecular Biology & Genetics, Scientific Research Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Background: Schizophrenia is one of the most common devastating psychiatric disorders that negatively affects the quality of life and psychosocial functions. Its etiology involves the interplay of complex polygenic influences and environmental risk factors. Inflammatory markers are well-known etiological factors for psychiatric disorders, including schizophrenia. Objective: The aim of this study was to investigate the association of proinflammatory cytokine genes, tumor necrosis factor (TNF-α (-308G/A and TNF-β (+252A/G polymorphisms with schizophrenia susceptibility. Subjects and methods: TNF-α and TNF-β genes were amplified using amplification refractory mutation system primers in 180 schizophrenia patients and 200 healthy matched controls recruited from the Psychiatry Clinic of Prince Sultan Military Medical City, Riyadh. The frequencies of alleles and genotypes of TNF-α (-308G/A and TNF-β (+252A/G polymorphisms in patients were compared with those in controls. Results: The frequencies of TNF-α (-308 allele A and genotype GA were significantly higher, while those of allele G and genotype GG were lower in schizophrenia patients as compared to controls, indicating that genotype GA and allele A of TNF-α (-308G/A may increase susceptibility to schizophrenia, while genotype GG and allele G may reduce it. On the other hand, the distribution of alleles and genotypes of TNF-β (+252A/G polymorphism does not differ significantly in patients from controls; however, the frequency of genotype GG of TNF-β (+252A/G was significantly higher in male patients than in female patients. The distribution of TNF-α (-308G/A and TNF-β (+252A/G polymorphisms was almost similar in schizophrenia patients with

  13. Tumor necrosis factor-alpha and interleukin-4 gene polymorphisms in Chinese patients with gout.

    Science.gov (United States)

    Chen, M-L; Tsai, F-J; Tsai, C-H; Huang, C-M

    2007-01-01

    The purpose of this study was to examine whether polymorphisms of interleukin-4 (IL-4) (promoter-590 and intron 3) and tumor necrosis factor-alpha (TNF-alpha) promoter-308 genes are markers of susceptibility to or clinical manifestations of gout in Taiwanese patients. The study included 196 Taiwanese patients with gout and 103 unrelated healthy control subjects living in central Taiwan. Polymorphisms of the IL-4 (promoter-590 and intron 3) and TNF-alpha (promoter-308) genes were typed from genomic DNA. Allelic frequencies and carriage rates were then compared between gout patients and control subjects. The correlation between allelic frequencies, carriage rates and clinical manifestations of gout were evaluated. No significant differences were observed in the allelic frequencies and carriage rates of the IL-4 (promoter-590 and intron 3) and TNF-alpha gene polymorphisms between patients with gout and healthy control subjects. Furthermore, the IL-4 (promoter-590 and intron 3) and TNF-alpha genotypes were not found to be associated with the clinical and laboratory profiles in gout patients. However, there was a significant difference in the TNF-alphapolymorphism genotype between patients with and without hypertriglyceridemia (P=0.001, xi2=11.47, OR=10.3, 95%CI=3.57-29.7). The results of our study suggest that polymorphisms of the IL-4 (promoter-590 and intron 3) and TNF-alpha promoter-308 genes are not related to gout in Chinese patients in Taiwan.

  14. Interferon regulatory factor 5 gene polymorphism in Egyptian children with systemic lupus erythematosus.

    Science.gov (United States)

    Hammad, A; Mossad, Y M; Nasef, N; Eid, R

    2017-07-01

    Background Increased expression of interferon-inducible genes is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Interferon regulatory factor 5 (IRF5) is one of the transcription factors regulating interferon and was proved to be implicated in the pathogenesis of SLE in different populations. Objectives The objective of this study was to investigate the correlation between polymorphisms of the IRF5 gene and SLE susceptibility in a cohort of Egyptian children and to investigate their association with clinico-pathological features, especially lupus nephritis. Subjects and methods Typing of interferon regulatory factor 5 rs10954213, rs2004640 and rs2280714 polymorphisms were done using polymerase chain reaction-restriction fragment length polymorphism for 100 children with SLE and 100 matched healthy controls. Results Children with SLE had more frequent T allele and TT genotype of rs2004640 ( P c  = 0.003 and 0.024, respectively) compared to controls. Patients with nephritis had more frequent T allele of rs2004640 compared to controls ( P c  = 0.003). However the allele and genotype frequencies of the three studied polymorphisms did not show any difference in patients with nephritis in comparison to those without nephritis. Haplotype GTA of rs10954213, rs2004640 and rs2280714, respectively, was more frequent in lupus patients in comparison to controls ( p = 0.01) while the haplotype GGG was more frequent in controls than lupus patients ( p = 0.011). Conclusion The rs2004640 T allele and TT genotype and GTA haplotype of rs rs10954213, rs2004640, and rs2280714, respectively, can be considered as risk factors for the development of SLE. The presence of the rs2004640 T allele increases the risk of nephritis development in Egyptian children with SLE.

  15. Genetic Effects of Polymorphisms in Myogenic Regulatory Factors on Chicken Muscle Fiber Traits

    Directory of Open Access Journals (Sweden)

    Zhi-Qin Yang

    2015-06-01

    Full Text Available The myogenic regulatory factors is a family of transcription factors that play a key role in the development of skeletal muscle fibers, which are the main factors to affect the meat taste and texture. In the present study, we performed candidate gene analysis to identify single-nucleotide polymorphisms in the MyoD, Myf5, MyoG, and Mrf4 genes using polymerase chain reaction-single strand conformation polymorphism in 360 Erlang Mountain Chickens from three different housing systems (cage, pen, and free-range. The general linear model procedure was used to estimate the statistical significance of association between combined genotypes and muscle fiber traits of chickens. Two polymorphisms (g.39928301T>G and g.11579368C>T were detected in the Mrf4 and MyoD gene, respectively. The diameters of thigh and pectoralis muscle fibers were higher in birds with the combined genotypes of GG-TT and TT-CT (p0.05. Our findings suggest that the combined genotypes of TT-CT and GG-TT might be advantageous for muscle fiber traits, and could be the potential genetic markers for breeding program in Erlang Mountain Chickens.

  16. CCR5 gene polymorphism is a genetic risk factor for radiographic severity of rheumatoid arthritis.

    Science.gov (United States)

    Han, S W; Sa, K H; Kim, S I; Lee, S I; Park, Y W; Lee, S S; Yoo, W H; Soe, J S; Nam, E J; Lee, J; Park, J Y; Kang, Y M

    2012-11-01

    The chemokine receptor [C-C chemokine receptor 5 (CCR5)] is expressed on diverse immune effecter cells and has been implicated in the pathogenesis of rheumatoid arthritis (RA). This study sought to determine whether single-nucleotide polymorphisms (SNPs) in the CCR5 gene and their haplotypes were associated with susceptibility to and severity of RA. Three hundred fifty-seven patients with RA and 383 healthy unrelated controls were recruited. Using a pyrosequencing assay, we examined four polymorphisms -1118 CTAT(ins) (/del) (rs10577983), 303 A>G (rs1799987), 927 C>T (rs1800024), and 4838 G>T (rs1800874) of the CCR5 gene, which were distributed over the promoter region as well as the 5' and 3' untranslated regions. No significant difference in the genotype, allele, and haplotype frequencies of the four selected SNPs was observed between RA patients and controls. CCR5 polymorphisms of -1118 CTAT(del) (P = 0.012; corrected P = 0.048) and 303 A>G (P = 0.012; corrected P = 0.048) showed a significant association with radiographic severity in a recessive model, and, as a result of multivariate logistic regression analysis, were found to be an independent predictor of radiographic severity. When we separated the erosion score from the total Sharp score, the statistical significance of CCR5 polymorphisms showed an increase; -1118 CTAT(ins) (/del) (P = 0.007; corrected P = 0.028) and 303 A>G (P = 0.007; corrected P = 0.028). Neither SNPs nor haplotypes of the CCR5 gene showed a significant association with joint space narrowing score. These results indicate that genetic polymorphisms of CCR5 are an independent risk factor for radiographic severity denoted by modified Sharp score, particularly joint erosion in RA. © 2012 John Wiley & Sons A/S.

  17. Optical Fiber Fusion Splicing

    CERN Document Server

    Yablon, Andrew D

    2005-01-01

    This book is an up-to-date treatment of optical fiber fusion splicing incorporating all the recent innovations in the field. It provides a toolbox of general strategies and specific techniques that the reader can apply when optimizing fusion splices between novel fibers. It specifically addresses considerations important for fusion splicing of contemporary specialty fibers including dispersion compensating fiber, erbium-doped gain fiber, polarization maintaining fiber, and microstructured fiber. Finally, it discusses the future of optical fiber fusion splicing including silica and non-silica based optical fibers as well as the trend toward increasing automation. Whilst serving as a self-contained reference work, abundant citations from the technical literature will enable readers to readily locate primary sources.

  18. The emerging role of alternative splicing in senescence and aging.

    Science.gov (United States)

    Deschênes, Mathieu; Chabot, Benoit

    2017-10-01

    Deregulation of precursor mRNA splicing is associated with many illnesses and has been linked to age-related chronic diseases. Here we review recent progress documenting how defects in the machinery that performs intron removal and controls splice site selection contribute to cellular senescence and organismal aging. We discuss the functional association linking p53, IGF-1, SIRT1, and ING-1 splice variants with senescence and aging, and review a selection of splicing defects occurring in accelerated aging (progeria), vascular aging, and Alzheimer's disease. Overall, it is becoming increasingly clear that changes in the activity of splicing factors and in the production of key splice variants can impact cellular senescence and the aging phenotype. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  19. Numerical modeling of polymorphic transformation of oleic acid via near-infrared spectroscopy and factor analysis

    Science.gov (United States)

    Liu, Ling; Cheng, Yuliang; Sun, Xiulan; Pi, Fuwei

    2018-05-01

    Near-infrared (NIR) spectroscopy as a tool for direct and quantitatively screening the minute polymorphic transitions of bioactive fatty acids was assessed basing on a thermal heating process of oleic acid. Temperature-dependent NIR spectral profiles indicate that dynamical variances of COOH group dominate its γ → α phase transition, while the transition from active α to β phase mainly relates to the conformational transfer of acyl chain. Through operating multivariate curve resolution-alternating least squares with factor analysis, instantaneous contribution of each active polymorph during the transition process was illustrated for displaying the progressive evolutions of functional groups. Calculated contributions reveal that the α phase of oleic acid initially is present at around -18 °C, but sharply grows up around -2.2 °C from the transformation of γ phase and finally disappears at the melting point. On the other hand, the β phase of oleic acid is sole self-generation after melt even it embryonically appears at -2.2 °C. Such mathematical approach based on NIR spectroscopy and factor analysis calculation provides a volatile strategy in quantitatively exploring the transition processes of bioactive fatty acids; meanwhile, it maintains promising possibility for instantaneous quantifying each active polymorph of lipid materials.

  20. Fat phenotype, associated factors and rs9939609 polymorphism of the FTO gene

    Directory of Open Access Journals (Sweden)

    William Alves Lima

    2010-02-01

    Full Text Available The purpose of this work was to review the main results of studies that have analysed the relationship between the rs9939609 single nucleotide polymorphism (SNP of the FTO gene and the manifestation of overweight/obesity with its associated co-morbidity, and to discuss the interaction of this polymorphism with the other factors which cause obesity. The search was performed using the MEDLINE, Highwire, Science Direct and SciELO databases, applying the following key words: FTO rs9939609, obesity genetic, gene associated obesity, FTO contributes obesity. Inclusion criteria were: original articles where the search was performed in humans and including the rs9939609. Articles that analysed the FTO gene associated with preinstalled hormonal diseases were excluded. Of the several SNP associated with the FTO gene, rs9939609 has been the most researched (studied. This SNP comprises the A and T alleles, with the A homozygote being most susceptible to the development of overweight/obesity in all age ranges, especially in the caucasian population. In this situation, the control of environmental factors (alimentation and physical activity can prevent the excessive build up of fats. Obesity is related to the development of non-transmissible chronic illnesses. Association of rs9939609 polymorphism with the lipidic profile and glycemia were observed. The practicing of physical exercise and feeding habits seem to be the main contributors in the development of overweight/obesity and its resulting co-morbidity.

  1. Association of apolipoprotein e gene polymorphisms with blood lipids and their interaction with dietary factors

    DEFF Research Database (Denmark)

    Shatwan, Israa M.; Winther, Kristian Hillert; Ellahi, Basma

    2018-01-01

    of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. Methods: The population studied for this investigation included 660 individuals from...... the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ......Background: Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association...

  2. Glutathione S Transferases Polymorphisms Are Independent Prognostic Factors in Lupus Nephritis Treated with Cyclophosphamide.

    Directory of Open Access Journals (Sweden)

    Alexandra Audemard-Verger

    Full Text Available To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs in lupus nephritis (LN treated with cyclophosphamide (CYC. CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST.We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR was defined as proteinuria ≤0.33g/day and serum creatinine ≤124 µmol/l. Partial remission (PR was defined as proteinuria ≤1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline.Most patients were women (84% and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile→105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile→105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR (OR = 5.01 95% CI [1.02-24.51] and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064-10.58]. No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed.This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.

  3. A polymorphism (rs1042522) in TP53 gene is a risk factor for Down Syndrome in Sicilian mothers.

    Science.gov (United States)

    Salemi, Michele; Barone, Concetta; Salluzzo, Maria Grazia; Giambirtone, Mariaconcetta; Scillato, Francesco; Galati Rando, Rosanna; Romano, Carmelo; Morale, Maria Concetta; Ridolfo, Federico; Romano, Corrado

    2017-11-01

    Trisomy 21 is the most frequent genetic cause of intellectual disability. Tumor Protein 53 (TP53) gene down-regulation triggers chromosomal instability. A TP53 gene polymorphism c.215G > C (rs1042522) is associated with accumulation of aneuploid cells. We analyzed the TP53 c.215G > C (rs1042522) polymorphism in Sicilian mothers of subjects with Down Syndrome (DS) within a case-control study. Nucleotide polymorphism was detected by pyrosequencing technology. The distribution of TP53 c.215G > C polymorphism showed significant difference between mothers of subjects with DS and controls. Our data show that TP53 c.215G > C polymorphism is a risk factor for DS in Sicilian mothers.

  4. Coagulation factor VII, serum-triglycerides and the R/Q353 polymorphism: differences between older men and women

    NARCIS (Netherlands)

    Mennen, L. I.; de Maat, M. P.; Schouten, E. G.; Kluft, C.; de Jong, P. T.; Hofman, A.; Grobbee, D. E.

    1997-01-01

    Coagulation factor VII activity (FVII:C) is a risk indicator for cardiovascular disease. It is related to serum-triglycerides and the R/Q353 polymorphism (alleles R and Q) in the gene coding for factor VII is strongly associated with factor VII. The association of serum-triglycerides with factor VII

  5. Coagulation factor VII, serum-triglycerides and the R/Q353 polymorphism: Differences between older men and women

    NARCIS (Netherlands)

    Mennen, L.I.; Maat, M.P.M. de; Schouten, E.G.; Kluft, C.; Jong, P.T.V.M. de; Hofman, A.; Grobbee, D.E.

    1997-01-01

    Coagulation factor VII activity (FVII:C) is a risk indicator for cardiovascular disease. It is related to serum-triglycerides and the R/Q353 polymorphism (alleles R and Q) in the gene coding for factor VII is strongly associated with factor VU[. The association of serum-triglycerides with factor VII

  6. Vitamin D and alternative splicing of RNA.

    Science.gov (United States)

    Zhou, Rui; Chun, Rene F; Lisse, Thomas S; Garcia, Alejandro J; Xu, Jianzhong; Adams, John S; Hewison, Martin

    2015-04-01

    The active form of vitamin D (1α,25-dihydroxyvitamin D, 1,25(OH)2D) exerts its genomic effects via binding to a nuclear high-affinity vitamin D receptor (VDR). Recent deep sequencing analysis of VDR binding locations across the complete genome has significantly expanded our understanding of the actions of vitamin D and VDR on gene transcription. However, these studies have also promoted appreciation of the extra-transcriptional impact of vitamin D on gene expression. It is now clear that vitamin D interacts with the epigenome via effects on DNA methylation, histone acetylation, and microRNA generation to maintain normal biological functions. There is also increasing evidence that vitamin D can influence pre-mRNA constitutive splicing and alternative splicing, although the mechanism for this remains unclear. Pre-mRNA splicing has long been thought to be a post-transcription RNA processing event, but current data indicate that this occurs co-transcriptionally. Several steroid hormones have been recognized to coordinately control gene transcription and pre-mRNA splicing through the recruitment of nuclear receptor co-regulators that can both control gene transcription and splicing. The current review will discuss this concept with specific reference to vitamin D, and the potential role of heterogeneous nuclear ribonucleoprotein C (hnRNPC), a nuclear factor with an established function in RNA splicing. hnRNPC, has been shown to be involved in the VDR transcriptional complex as a vitamin D-response element-binding protein (VDRE-BP), and may act as a coupling factor linking VDR-directed gene transcription with RNA splicing. In this way hnRNPC may provide an additional mechanism for the fine-tuning of vitamin D-regulated target gene expression. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. A hypoxia-inducible factor (HIF)-3α splicing variant, HIF-3α4 impairs angiogenesis in hypervascular malignant meningiomas with epigenetically silenced HIF-3α4

    Energy Technology Data Exchange (ETDEWEB)

    Ando, Hitoshi [Department of Neurosurgery, Nagoya University School of Medicine, Nagoya (Japan); Department of Neurosurgery, Fukushima Medical University School of Medicine, Fukushima (Japan); Natsume, Atsushi, E-mail: anatsume@med.nagoya-u.ac.jp [Department of Neurosurgery, Nagoya University School of Medicine, Nagoya (Japan); Iwami, Kenichiro; Ohka, Fumiharu [Department of Neurosurgery, Nagoya University School of Medicine, Nagoya (Japan); Kuchimaru, Takahiro; Kizaka-Kondoh, Shinae [Department of Biomolecular Engineering, Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology, Yokohama (Japan); Ito, Kengo [National Center for Geriatrics and Gerontology, Aichi (Japan); Saito, Kiyoshi [Department of Neurosurgery, Fukushima Medical University School of Medicine, Fukushima (Japan); Sugita, Sachi; Hoshino, Tsuneyoshi [MICRON Inc.Medical Facilities Support Department, Aichi (Japan); Wakabayashi, Toshihiko [Department of Neurosurgery, Nagoya University School of Medicine, Nagoya (Japan)

    2013-03-29

    Highlights: ► HIF-3α4 is silenced by DNA methylation in meningiomas. ► Induction of HIF-3α4 impaired angiogenesis in meningiomas. ► Induction of HIF-3α4 impaired proliferation and oxygen-dependent metabolism. -- Abstract: Hypoxia inducible factor is a dominant regulator of adaptive cellular responses to hypoxia and controls the expression of a large number of genes regulating angiogenesis as well as metabolism, cell survival, apoptosis, and other cellular functions in an oxygen level-dependent manner. When a neoplasm is able to induce angiogenesis, tumor progression occurs more rapidly because of the nutrients provided by the neovasculature. Meningioma is one of the most hypervascular brain tumors, making anti-angiogenic therapy an attractive novel therapy for these tumors. HIF-3α has been conventionally regarded as a dominant-negative regulator of HIF-1α, and although alternative HIF-3α splicing variants are extensively reported, their specific functions have not yet been determined. In this study, we found that the transcription of HIF-3α4 was silenced by the promoter DNA methylation in meningiomas, and inducible HIF-3α4 impaired angiogenesis, proliferation, and metabolism/oxidation in hypervascular meningiomas. Thus, HIF-3α4 could be a potential molecular target in meningiomas.

  8. Pharmacological profile of brain-derived neurotrophic factor (BDNF) splice variant translation using a novel drug screening assay: a "quantitative code".

    Science.gov (United States)

    Vaghi, Valentina; Polacchini, Alessio; Baj, Gabriele; Pinheiro, Vera L M; Vicario, Annalisa; Tongiorgi, Enrico

    2014-10-03

    The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5'- and 3'UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5'- and 3'UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5'UTR or a 3'UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5'UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3'UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent "a quantitative code" for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Undernutrition regulates the expression of a novel splice variant of myostatin and insulin-like growth factor 1 in ovine skeletal muscle.

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    Jeanplong, F; Osepchook, C C; Falconer, S J; Smith, H K; Bass, J J; McMahon, C D; Oldham, J M

    2015-07-01

    Undernutrition suppresses the growth of skeletal muscles and alters the expression of insulin-like growth factor 1 (IGF1), a key mitogen, and myostatin, a potent inhibitor of myogenesis. These changes can explain, at least in part, the reduced growth of skeletal muscles in underfed lambs. We have recently identified a myostatin splice variant (MSV) that binds to and antagonizes the canonical signaling of myostatin. In the present study, we hypothesized that the expression of MSV would be reduced in conjunction with myostatin and IGF1 in response to underfeeding in skeletal muscles of sheep. Young growing ewes were fed either ad libitum or an energy-restricted diet (30% of maintenance requirements) for 28 d. This regime of underfeeding resulted in a 24% reduction in body mass (P myostatin mRNA was not altered in semitendinosus muscles. Unlike the reduced expression of mRNA, the abundance of MSV protein was increased (P myostatin protein. Our results suggest that undernutrition for 28 d decreases the signaling of myostatin by increasing the abundance of MSV protein. Although this action may reduce the growth inhibitory activity of myostatin, it cannot prevent the loss of growth of skeletal muscles during undernutrition. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. A hypoxia-inducible factor (HIF)-3α splicing variant, HIF-3α4 impairs angiogenesis in hypervascular malignant meningiomas with epigenetically silenced HIF-3α4

    International Nuclear Information System (INIS)

    Ando, Hitoshi; Natsume, Atsushi; Iwami, Kenichiro; Ohka, Fumiharu; Kuchimaru, Takahiro; Kizaka-Kondoh, Shinae; Ito, Kengo; Saito, Kiyoshi; Sugita, Sachi; Hoshino, Tsuneyoshi; Wakabayashi, Toshihiko

    2013-01-01

    Highlights: ► HIF-3α4 is silenced by DNA methylation in meningiomas. ► Induction of HIF-3α4 impaired angiogenesis in meningiomas. ► Induction of HIF-3α4 impaired proliferation and oxygen-dependent metabolism. -- Abstract: Hypoxia inducible factor is a dominant regulator of adaptive cellular responses to hypoxia and controls the expression of a large number of genes regulating angiogenesis as well as metabolism, cell survival, apoptosis, and other cellular functions in an oxygen level-dependent manner. When a neoplasm is able to induce angiogenesis, tumor progression occurs more rapidly because of the nutrients provided by the neovasculature. Meningioma is one of the most hypervascular brain tumors, making anti-angiogenic therapy an attractive novel therapy for these tumors. HIF-3α has been conventionally regarded as a dominant-negative regulator of HIF-1α, and although alternative HIF-3α splicing variants are extensively reported, their specific functions have not yet been determined. In this study, we found that the transcription of HIF-3α4 was silenced by the promoter DNA methylation in meningiomas, and inducible HIF-3α4 impaired angiogenesis, proliferation, and metabolism/oxidation in hypervascular meningiomas. Thus, HIF-3α4 could be a potential molecular target in meningiomas

  11. R497K polymorphism in epidermal growth factor receptor gene is associated with the risk of acute coronary syndrome

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    Pan Xin-Min

    2008-07-01

    Full Text Available Abstract Background Previous studies suggested that genetic polymorphisms in the epidermal growth factor receptor (EGFR gene had been implicated in the susceptibility to some tumors and inflammatory diseases. EGFR has been recently implicated in vascular pathophysiological processes associated with excessive remodeling and atherosclerosis. Acute coronary syndrome (ACS is a clinical manifestation of preceding atherosclerosis. Our purpose was to investigate the association of the EGFR polymorphism with the risk of ACS. In this context, we analyzed the HER-1 R497K and EGFR intron 1 (CAn repeat polymorphisms in 191 patients with ACS and 210 age- and sex-matched controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP strategy and direct sequencing. Results There were significant differences in the genotype and allele distribution of R497K polymorphism of the EGFR gene between cases and controls. The Lys allele had a significantly increased risk of ACS compared with the Arg allele (adjusted OR = 1.49, 95% CI: 1.12–1.98, adjusted P = 0.006. However, no significant relationship between the number of (CAn repeats of EGFR intron 1 (both alleles P = 0.911. Considering these two polymorphisms together, there was no statistically significant difference between the two groups. Conclusion R497K polymorphism of the EGFR gene is significantly associated with the risk of ACS. Our data suggests that R497K polymorphism may be used as a genetic susceptibility marker of the ACS.

  12. The Polymorphism of Pituitary Factor 1 (POU1F1 in Cattle

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    Teodora Crina Carsai

    2012-05-01

    Full Text Available The development and function of mammary gland is mainly controlled by growth hormone and prolactin, twoprotein hormones secreted by the anterior pituitary gland. Their synthesis is under regulatory influence of pituitaryfactor 1 (PIT1 or POU1F1, a protein factor produced in hypothalamic nuclei. In cattle, it was shown that a HinfIpolymorphism located in exon 6 of PIT1 gene may have significant influence on milk quantity. In particular A allelewas associated with a higher milk yield and could be a valuable genetic marker for improving milk quantity in cattle.In an effort to better understand the possible influence of this polymorphism on mammary gland development andfunction in cattle, we have studied the frequency this polymorphism in Romanian Black and White breed, a highmilk production cattle breed versus Romanian Grey Steppe breed, a primitive breed with very low milk production.In both breeds the frequency of B allele is much higher as compared with the frequency of A allele. The study ofPIT1 polymorphism in Romanian cattle breeds is a part of a more complex study targeting several key genesinvolved in mammary gland function.

  13. Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration in a Turkish population

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    Yunus Bulgu

    2014-10-01

    Full Text Available AIM:To assess the association between age-related macular degeneration (AMD and three single nucleotide polymorphisms (SNPs related to the vascular endothelial growth factor (VEGF gene.METHODS: The patients who were diagnosed with AMD were included in this prospective study. Three SNPs (rs1413711, rs2146323, and rs3025033 of the VEGF gene were genotyped by real-time polymerase chain reaction in the genomic DNA isolated from peripheral blood samples of the 82 patients and 80 controls.RESULTS: The genotype frequencies of rs1413711 and rs2146323 were not significantly different between the study group and the control group (P=0.072 and P=0.058. However, there was a significant difference in the genotype frequencies of these SNPs between the wet type AMD and dry type AMD (P=0.005 and P=0.010, respectively. One of the SNPs (rs1413711 was also found to be associated with the severity of AMD (P=0.001 with significant genotype distribution between early, intermediate, and advanced stages of the disease. The ancestral alleles were protective for both SNPs while the polymorphic alleles increased the risk for dry AMD.CONCLUSION: VEGF SNPs rs1413711 and rs2146323 polymorphisms are significantly associated with AMD subtypes in our population.

  14. Matrix metalloproteinase-3, vitamin D receptor gene polymorphisms, and occupational risk factors in lumbar disc degeneration.

    Science.gov (United States)

    Zawilla, N H; Darweesh, H; Mansour, N; Helal, S; Taha, F M; Awadallah, M; El Shazly, R

    2014-06-01

    Lumbar disc degeneration (LDD) is a process that begins early in life, contributing to the development of low back pain. LDD is a consequence of a variety of factors, and its etiology remains poorly understood. Objectives to investigate occupational and genetic risk factors inducing lumbar disc degeneration, and to evaluate the possible association of genetic polymorphisms of matrix metalloproteinase 3 (MMP-3) and vitamin D receptor (VDR) with the severity of LDD in an Egyptian population. A case control study involving 84 LDD and 60 controls was carried out. Five types of work related factors were investigated by questionnaire, complete neurological examination for all subjects and MRI for the cases. Polymerase chain reaction and restriction fragment length polymorphism methods were applied to detect polymorphisms in MMP-3 Promoter (-1,171 6A/5A) (rs 731236) and VDR-Apa (rs 35068180). We found that family history, back injury, smoking, high level of sitting, bending/twisting, physical workload, lifting, whole body vibration, mutant allele 5A of MMP-3 and mutant allele T of VDR were significantly associated with LDD (OR = 2.9, 3.1, 2.1, 11.1, 15.9, 11.7, 8.2, 12.6, 2.5 and 3.1 respectively, p < 0.05). Cases that carry allele 5A and/or allele T were associated with LDD severity. LDD is closely associated in occurrence and severity with occupational, environmental risk factors and susceptibility genes namely MMP-3, and VDR (ApaI). This study throws light on the importance of screening for early detection of susceptible individuals and disease prevention.

  15. Interleukin-6 Gene Promoter Polymorphisms and Cardiovascular Risk Factors. A family study

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    Iris Paola Guzmán-Guzmán

    2010-01-01

    Full Text Available Interleukin-6 (IL-6 is a cytokine involved in inflammatory process, as well as in glucose and lipid metabolism. Several studies of the biological relevance of IL-6 gene polymorphisms have indicated a relationship with cardiovascular disease. The aim of this study was to assess whether the –174 G/C and –572 G/C of IL-6 gene polymorphisms are associated with cardiovascular risk factors in Mexican families. Ninety members of 30 Mexican families, in which an index case (proband had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical and hematological parameters. High sensitivity C- reactive protein levels were measurement for nephelometric analysis. Screening for both polymorphisms studied was performed by PCR-RFLP. In the parents, both polymorphisms were in Hardy-Weinberg's equilibrium. The genotypes –174 GC/CC were associated with T2D (OR = 1.23, IC95% 1.01–1.5 and highest levels of hsCRP (p = 0.02, whereas genotype –572 GG was associated with T2D (OR = 1.24, IC95% 1.04–1.47 with an inflammatory state determined by the increase in the leukocyte count (OR = 1.24, IC95% 1.02–1.51. The genotypes –174 GC/CC and –572 GG may confer susceptibility for the development of subclinical inflammation and type 2 diabetes in Mexican families.

  16. Alternative Splicing as a Target for Cancer Treatment.

    Science.gov (United States)

    Martinez-Montiel, Nancy; Rosas-Murrieta, Nora Hilda; Anaya Ruiz, Maricruz; Monjaraz-Guzman, Eduardo; Martinez-Contreras, Rebeca

    2018-02-11

    Alternative splicing is a key mechanism determinant for gene expression in metazoan. During alternative splicing, non-coding sequences are removed to generate different mature messenger RNAs due to a combination of sequence elements and cellular factors that contribute to splicing regulation. A different combination of splicing sites, exonic or intronic sequences, mutually exclusive exons or retained introns could be selected during alternative splicing to generate different mature mRNAs that could in turn produce distinct protein products. Alternative splicing is the main source of protein diversity responsible for 90% of human gene expression, and it has recently become a hallmark for cancer with a full potential as a prognostic and therapeutic tool. Currently, more than 15,000 alternative splicing events have been associated to different aspects of cancer biology, including cell proliferation and invasion, apoptosis resistance and susceptibility to different chemotherapeutic drugs. Here, we present well established and newly discovered splicing events that occur in different cancer-related genes, their modification by several approaches and the current status of key tools developed to target alternative splicing with diagnostic and therapeutic purposes.

  17. Asthma treatment outcome in children is associated with vascular endothelial growth factor A (VEGFA) polymorphisms.

    Science.gov (United States)

    Balantic, Mateja; Rijavec, Matija; Skerbinjek Kavalar, Maja; Suskovic, Stanislav; Silar, Mira; Kosnik, Mitja; Korosec, Peter

    2012-06-01

    Asthma is a common chronic disease characterized by airway inflammation and structural remodeling. Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, is elevated in asthma patients. VEGF contributes to airway responsiveness and remodeling. It has been shown that treatment of asthma patients decreases VEGF levels, and inhibition of VEGF diminishes asthma symptoms in mice. Therefore, polymorphisms in the vascular endothelial growth factor A (VEGFA) gene might be associated with asthma treatment response. This study enrolled 131 children with asthma treated with different therapies - specifically, the inhaled corticosteroid (ICS) fluticasone propionate or the leukotriene receptor antagonist (LTRA) montelukast. We performed an association analysis between improvement of lung function - assessed by measurement of the percentage of the predicted forced expiratory volume in 1 second (%predicted FEV(1)), the ratio between the FEV(1) and the forced vital capacity (FEV(1)/FVC) after 6 and 12 months of treatment, and asthma control after 12 months of treatment - and two polymorphisms, rs2146323 and rs833058, in the VEGFA gene. Polymorphism rs2146323 A>C in VEGFA was associated with response to ICS therapy. Asthma patients with the AA genotype had a greater improvement in the %predicted FEV(1) than those with the AC or CC genotype (p = 0.018). Conversely, the AA genotype in rs2146323 was associated with uncontrolled asthma in patients regularly receiving LTRA therapy (p = 0.020) and a worse FEV(1)/FVC ratio in patients who episodically used LTRA therapy (p = 0.044). Furthermore, polymorphism rs833058 C>T was associated with treatment response to episodically used LTRA therapy. A subgroup of patients with the TT genotype had an improvement in the %predicted FEV(1), compared with no improvement in patients with the CT or CC genotype (p = 0.029). Our results showed that treatment response to commonly used asthma therapies (ICS or LTRA) is associated

  18. Antitumorigenic potential of STAT3 alternative splicing modulation.

    Science.gov (United States)

    Zammarchi, Francesca; de Stanchina, Elisa; Bournazou, Eirini; Supakorndej, Teerawit; Martires, Kathryn; Riedel, Elyn; Corben, Adriana D; Bromberg, Jacqueline F; Cartegni, Luca

    2011-10-25

    Signal transducer and activator of transcription 3 (STAT3) plays a central role in the activation of multiple oncogenic pathways. Splicing variant STAT3β uses an alternative acceptor site within exon 23 that leads to a truncated isoform lacking the C-terminal transactivation domain. Depending on the context, STAT3β can act as a dominant-negative regulator of transcription and promote apoptosis. We show that modified antisense oligonucleotides targeted to a splicing enhancer that regulates STAT3 exon 23 alternative splicing specifically promote a shift of expression from STAT3α to STAT3β. Induction of endogenous STAT3β leads to apoptosis and cell-cycle arrest in cell lines with persistent STAT3 tyrosine phosphorylation compared with total STAT3 knockdown obtained by forced splicing-dependent nonsense-mediated decay (FSD-NMD). Comparison of the molecular effects of splicing redirection to STAT3 knockdown reveals a unique STAT3β signature, with a down-regulation of specific targets (including lens epithelium-derived growth factor, p300/CBP-associated factor, CyclinC, peroxisomal biogenesis factor 1, and STAT1β) distinct from canonical STAT3 targets typically associated with total STAT3 knockdown. Furthermore, similar in vivo redirection of STAT3 alternative splicing leads to tumor regression in a xenograft cancer model, demonstrating how pharmacological manipulation of a single key splicing event can manifest powerful antitumorigenic properties and validating endogenous splicing reprogramming as an effective cancer therapeutic approach.

  19. Connecting the dots: chromatin and alternative splicing in EMT.

    Science.gov (United States)

    Warns, Jessica A; Davie, James R; Dhasarathy, Archana

    2016-02-01

    Nature has devised sophisticated cellular machinery to process mRNA transcripts produced by RNA Polymerase II, removing intronic regions and connecting exons together, to produce mature RNAs. This process, known as splicing, is very closely linked to transcription. Alternative splicing, or the ability to produce different combinations of exons that are spliced together from the same genomic template, is a fundamental means of regulating protein complexity. Similar to transcription, both constitutive and alternative splicing can be regulated by chromatin and its associated factors in response to various signal transduction pathways activated by external stimuli. This regulation can vary between different cell types, and interference with these pathways can lead to changes in splicing, often resulting in aberrant cellular states and disease. The epithelial to mesenchymal transition (EMT), which leads to cancer metastasis, is influenced by alternative splicing events of chromatin remodelers and epigenetic factors such as DNA methylation and non-coding RNAs. In this review, we will discuss the role of epigenetic factors including chromatin, chromatin remodelers, DNA methyltransferases, and microRNAs in the context of alternative splicing, and discuss their potential involvement in alternative splicing during the EMT process.

  20. Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-α−193 (G/A

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    A. Essadik

    2015-01-01

    Full Text Available Polymorphisms in tumor necrosis factor alpha (TNF-α gene are emerging as key determinants of gastric diseases. The TNF-α−308 (G/A and TNF-α−238 (G/A single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-α gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions −308 and −238 in TNF-α gene were genotyped in 244 individuals (170 patients and 74 healthy controls. Odds ratios (ORs and 95% confidence intervals (CI were estimated using logistic regression analysis. The TNF-α−238 (G/A genotype was significantly associated with a high risk of gastritis and gastric cancer (GC (P=0.001 and P=0.002, resp.. Furthermore, a new polymorphism located in the promoter region at position −193 in TNF-α gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-α−193 (G/A genotype and high risk of ulcer was significant (P=0.03. These results suggest that the TNF-α−193 (G/A allele has a protective function against gastric cancer by developing ulcer.

  1. The neurogenetics of alternative splicing.

    Science.gov (United States)

    Vuong, Celine K; Black, Douglas L; Zheng, Sika

    2016-05-01

    Alternative precursor-mRNA splicing is a key mechanism for regulating gene expression in mammals and is controlled by specialized RNA-binding proteins. The misregulation of splicing is implicated in multiple neurological disorders. We describe recent mouse genetic studies of alternative splicing that reveal its critical role in both neuronal development and the function of mature neurons. We discuss the challenges in understanding the extensive genetic programmes controlled by proteins that regulate splicing, both during development and in the adult brain.

  2. Pre-mRNA mis-splicing of sarcomeric genes in heart failure.

    Science.gov (United States)

    Zhu, Chaoqun; Chen, Zhilong; Guo, Wei

    2017-08-01

    Pre-mRNA splicing is an important biological process that allows production of multiple proteins from a single gene in the genome, and mainly contributes to protein diversity in eukaryotic organisms. Alternative splicing is commonly governed by RNA binding proteins to meet the ever-changing demands of the cell. However, the mis-splicing may lead to human diseases. In the heart of human, mis-regulation of alternative splicing has been associated with heart failure. In this short review, we focus on alternative splicing of sarcomeric genes and review mis-splicing related heart failure with relatively well studied Sarcomeric genes and splicing mechanisms with identified regulatory factors. The perspective of alternative splicing based therapeutic strategies in heart failure has also been discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Expression Profile of Three Splicing Factors in Pleural Cells Based on the Underlying Etiology and Its Clinical Values in Patients with Pleural Effusion

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    A-Lum Han

    2018-02-01

    Full Text Available Splicing factors (SFs are involved in oncogenesis or immune modulation, the common underlying processes giving rise to pleural effusion (PE. The expression profiles of three SFs (HNRNPA1, SRSF1, and SRSF3 and their clinical values have never been assessed in PE. The three SFs (in pellets of PE and conventional tumor markers were analyzed using PE samples in patients with PE (N = 336. The sum of higher–molecular weight (Mw forms of HNRNPA1 (Sum-HMws-HNRNPA1 and SRSF1 (Sum-HMws-SRSF1 and SRSF3 levels were upregulated in malignant PE (MPE compared to benign PE (BPE; they were highest in cytology-positive MPE, followed by tuberculous PE and parapneumonic PE. Meanwhile, the lowest-Mw HNRNPA1 (LMw-HNRNPA1 and SRSF1 (LMw-SRSF1 levels were not upregulated in MPE. Sum-HMws-HNRNPA1, Sum-HMws-SRSF1, and SRSF3, but neither LMw-HNRNPA1 nor LMw-SRSF1, showed positive correlations with cancer cell percentages in MPE. The detection accuracy for MPE was high in the order of carcinoembryonic antigen (CEA, 85%, Sum-HMws-HNRNPA1 (76%, Sum-HMws-SRSF1 (68%, SRSF3, cytokeratin-19 fragments (CYFRA 21-1, LMw-HNRNPA1, and LMw-SRSF1. Sum-HMws-HNRNPA1 detected more than half of the MPE cases that were undetected by cytology and CEA. Sum-HMws-HNRNPA1, but not other SFs or conventional tumor markers, showed an association with longer overall survival among patients with MPE receiving chemotherapy. Our results demonstrated different levels of the three SFs with their Mw-specific profiles depending on the etiology of PE. We suggest that Sum-HMws-HNRNPA1 is a supplementary diagnostic marker for MPE and a favorable prognostic indicator for patients with MPE receiving chemotherapy.

  4. Vascular endothelial growth factor (VEGF-634G/C) polymorphism and retinopathy of prematurity: a meta-analysis

    Science.gov (United States)

    Malik, Manzoor Ahmad; Shukla, Swati; Azad, Shorya Vardhan; Kaur, Jasbir

    2014-01-01

    Purpose Vascular endothelial growth factor polymorphism (VEGF-634G/C, rs 2010963) has been considered a risk factor for the development of retinopathy of prematurity (ROP). However, the results remain controversial. Therefore, the aim of the present meta-analysis was to determine the association between VEGF-634G/C polymorphism and ROP risk. Methods Published literature from PubMed and other databases were retrieved. All studies evaluating the association between VEGF-634G/C polymorphism and ROP risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random or fixed effects model. A total of six case-control studies including 355 cases and 471 controls were included. Results By pooling all the studies, we found that VEGF-634G/C polymorphism was not associated with ROP risk at co-dominant and allele levels and no association was also found in dominant and recessive models. While stratifying on ethnicity level no association was observed in Caucasian and Asian population. Discussion This meta-analysis suggests that VEGF-634G/C polymorphism may not be associated with ROP risk, the association between single VEGF-634G/C polymorphism and ROP risk awaits further investigation. PMID:25473347

  5. Lipid regulatory genes polymorphism in children with and without obesity and cardiometabolic risk factors: The CASPIAN-III study.

    Science.gov (United States)

    Hovsepian, Silva; Javanmard, Shaghayegh Haghjooy; Mansourian, Marjan; Hashemipour, Mahin; Tajadini, Mohamadhasan; Kelishadi, Roya

    2018-01-01

    Genetically, predisposed children are considered as at-risk individuals for cardiovascular disease. In this study, we aimed to compare the frequency of four-lipid regulatory polymorphism in obese and normal-weight children with and without cardiometabolic risk factors. In this nested case-control study, 600 samples of four groups of participants consisted of those with normal weight with and without cardiometabolic risk factors and obese with and without cardiometabolic risk factors. Allelic and genotypic frequencies of GCKR (rs780094), GCKR (rs1260333), MLXIPL (rs3812316), and FADS (rs174547) polymorphisms were compared in the four studied groups. Data of 528 samples were complete and included in this study. The mean (standard deviation) age of participants was 15.01 (2.21) years. Frequency of tt allele (minor allele) of GCKR (rs1260333) polymorphism was significantly lower in normal weight metabolically healthy participants than metabolically unhealthy normal weight (MUHNW) and obese children with and without cardiometabolic risk factor ( P = 0.01). Frequency of ga allele of GCKR (rs780094) polymorphism was significantly higher in normal weight children with cardiometabolic risk factor than in their obese counterparts with cardiometabolic risk factor ( P = 0.04). Frequency of cg and gg alleles (minor type) of MLXIPL (rs3812316) polymorphism in normal weight metabolically healthy participants was significantly higher than MUHNW ( P = 0.04) and metabolically healthy obese children ( P = 0.04). The findings of our study indicated that the minor allele of GCKR (rs1260333) single nucleotide polymorphisms (SNPs) could have pathogenic effect for obesity and cardiometabolic risk factors. Ga allele of GCKR (rs780094) SNPs had a protective effect on obesity. Minor alleles of MLXIPL (rs3812316) could have a protective effect for obesity and cardiometabolic risk factors.

  6. Interplay between DMD point mutations and splicing signals in Dystrophinopathy phenotypes.

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    Jonàs Juan-Mateu

    Full Text Available DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements.

  7. Systematic profiling of alternative splicing signature reveals prognostic predictor for ovarian cancer.

    Science.gov (United States)

    Zhu, Junyong; Chen, Zuhua; Yong, Lei

    2018-02-01

    The majority of genes are alternatively spliced and growing evidence suggests that alternative splicing is modified in cancer and is associated with cancer progression. Systematic analysis of alternative splicing signature in ovarian cancer is lacking and greatly needed. We profiled genome-wide alternative splicing events in 408 ovarian serous cystadenocarcinoma (OV) patients in TCGA. Seven types of alternative splicing events were curated and prognostic analyses were performed with predictive models and splicing network built for OV patients. Among 48,049 mRNA splicing events in 10,582 genes, we detected 2,611 alternative splicing events in 2,036 genes which were significant associated with overall survival of OV patients. Exon skip events were the most powerful prognostic factors among the seven types. The area under the curve of the receiver-operator characteristic curve for prognostic predictor, which was built with top significant alternative splicing events, was 0.937 at 2,000 days of overall survival, indicating powerful efficiency in distinguishing patient outcome. Interestingly, splicing correlation network suggested obvious trends in the role of splicing factors in OV. In summary, we built powerful prognostic predictors for OV patients and uncovered interesting splicing networks which could be underlying mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

    Science.gov (United States)

    Savva, Athina; Brouwer, Matthijs C.; Valls Serón, Mercedes; Le Roy, Didier; Ferwerda, Bart; van der Ende, Arie; Bochud, Pierre-Yves; van de Beek, Diederik; Calandra, Thierry

    2016-01-01

    Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (−794 CATT5–8; rs5844572) and a single-nucleotide polymorphism (−173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and −173 C high-expression MIF alleles were associated with unfavorable outcome (P = 0.005 and 0.003) and death (P = 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P = 0.02] and carriage of the CATT7 allele (OR 5.12, P = 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P = 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy. PMID:26976591

  9. Quantitative assessment of the influence of tumor necrosis factor alpha polymorphism with gastritis and gastric cancer risk.

    Science.gov (United States)

    Li, Ming; Wang, Yinping; Gu, Yahong

    2014-02-01

    Tumor necrosis factor alpha (TNFA) is an important molecule in inflammatory, infectious, and tumoral processes. Inflammation is one of the early phases in the development of gastric cancer (GC). Therefore, several studies have examined the association of polymorphism in TNFA with gastritis and GC risk. A functional polymorphism, -308G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. To date, a number of studies have been carried out to investigate the relationship between the polymorphism and gastritis or GC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 36 studies for TNFA -308G>A polymorphism to evaluate the effect of TNFA on genetic susceptibility for gastritis and GC. An overall random-effects per-allele odds ratio of 1.16 (95 % confidence interval 1.04-1.29, P = 0.008) was found for the polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians, whereas no significant associations were found among East Asians and other ethnic populations. No associations between the polymorphism and gastritis were observed. In addition, our data indicate that TNFA is involved in GC susceptibility and confers its effect primarily in diffuse type of tumors. Besides, -308G>A polymorphism was found to be significantly associated with both cardiac and noncardiac tumors. This meta-analysis demonstrated that the TNFA -308G>A polymorphism is a risk factor for developing GC, but the associations vary in different ethnic populations.

  10. Polymorphisms in Non-coding RNA Genes and Their Targets Sites as Risk Factors of Sporadic Colorectal Cancer

    Czech Academy of Sciences Publication Activity Database

    Vodička, Pavel; Pardini, Barbara; Vymetálková, Veronika; Naccarati, Alessio

    2016-01-01

    Roč. 937, č. 2016 (2016), s. 123-149 ISSN 0065-2598 R&D Projects: GA MZd(CZ) NV15-26535A; GA ČR(CZ) GA15-08239S Institutional support: RVO:68378041 Keywords : colorectal cancer * polymorphism * risk factors Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.881, year: 2016

  11. Evaluation of human epidermal growth factor receptor 2 (HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors.

    Science.gov (United States)

    Furrer, Daniela; Lemieux, Julie; Côté, Marc-André; Provencher, Louise; Laflamme, Christian; Barabé, Frédéric; Jacob, Simon; Michaud, Annick; Diorio, Caroline

    2016-12-01

    Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Glucokinase links Kruppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease

    NARCIS (Netherlands)

    Bechmann, Lars P.; Gastaldelli, Amalia; Vetter, Diana; Patman, Gillian L.; Pascoe, Laura; Hannivoort, Rebekka A.; Lee, Ursula E.; Fiel, Isabel; Munoz, Ursula; Ciociaro, Demetrio; Lee, Young-Min; Buzzigoli, Emma; Miele, Luca; Hui, Kei Y.; Bugianesi, Elisabetta; Burt, Alastair D.; Day, Christopher P.; Mari, Andrea; Agius, Loranne; Walker, Mark; Friedman, Scott L.; Reeves, Helen L.

    The polymorphism, KLF6-IVS1-27A, in the Kruppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development

  13. Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20.

    Science.gov (United States)

    Rexiati, Maimaiti; Sun, Mingming; Guo, Wei

    2018-01-05

    Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy. Here, we review our current knowledge of muscle-specific splicing factors and heart disease, with an emphasis on RBM20 and its targets, RBM20-dependent alternative splicing mechanism, RBM20 disease origin in induced Pluripotent Stem Cells (iPSCs), and RBM20 mutations in dilated cardiomyopathy. In the end, we will discuss the multifunctional role of RBM20 and manipulation of RBM20 as a potential therapeutic target for heart disease.

  14. Factor IX[sub Madrid 2]: A deletion/insertion in Facotr IX gene which abolishes the sequence of the donor junction at the exon IV-intron d splice site

    Energy Technology Data Exchange (ETDEWEB)

    Solera, J. (Unidades de Genetica Molecular, Madrid (Spain)); Magallon, M.; Martin-Villar, J. (Hemofilia Hospital, Madrid (Spain)); Coloma, A. (Departamento deBioquimica de la Facultad de Medicina de la Universidad Autonoma, Madrid (Spain))

    1992-02-01

    DNA from a patient with severe hemophilia B was evaluated by RFLP analysis, producing results which suggested the existence of a partial deletion within the factor IX gene. The deletion was further localized and characterized by PCR amplification and sequencing. The altered allele has a 4,442-bp deletion which removes both the donor splice site located at the 5[prime] end of intron d and the two last coding nucleotides located at the 3[prime] end of exon IV in the normal factor IX gene; this fragment has been inserted in inverted orientation. Two homologous sequences have been discovered at the ends of the deleted DNA fragment.

  15. Association of transforming growth-factor alpha gene polymorphisms with nonsyndromic cleft palate only (CPO)

    Energy Technology Data Exchange (ETDEWEB)

    Shiang, R. (Univ. of California, Irvine, CA (United States)); Lidral, A.C.; Ardinger, H.H.; Murray, J.C.; Romitti, P.A.; Munger, R.G.; Buetow, K.H.

    1993-10-01

    Genetic analysis and tissue-specific expression studies support a role for transforming growth-factor alpha (TGFA) in craniofacial development. Previous studies have confirmed an association of alleles for TGFA with nonsyndromic cleft lip with or without cleft palate (CL/P) in humans. The authors carried out a retrospective association study to determine whether specific allelic variants of the TGFA gene are also associated with cleft palate only (CPO). The PCR products from 12 overlapping sets of primers to the TGFA cDNA were examined by using single-strand conformational polymorphism analysis. Four DNA polymorphic sites for TGFA were identified in the 3[prime] untranslated region of the TGFA gene. These variants, as well as previously identified RFLPs for TGFA, were characterized in case and control populations for CPO by using X[sup 2] analysis. A significant association between alleles of TGFA and CPO was identified which further supports a role for this gene as one of the genetic determinants of craniofacial development. Sequence analysis of the variants disclosed a cluster of three variable sites within 30 bp of each other in the 3[prime] untranslated region previously associated with an antisense transcript. These studies extend the role for TGFA in craniofacial morphogenesis and support an interrelated mechanism underlying nonsyndromic forms of CL/P. 46 refs., 3 figs., 3 tabs.

  16. Association of interleukin 10 and transforming growth factor β gene polymorphisms with chronic idiopathic urticaria.

    Science.gov (United States)

    Tavakol, Marzieh; Movahedi, Masoud; Amirzargar, Ali Akbar; Aryan, Zahra; Bidoki, Alireza Zare; Heidari, Kimia; Soltani, Samaneh; Gharagozlou, Mohammad; Aghamohammadi, Asghar; Nabavi, Mohammad; Nasiri, Rasoul; Ahmadvand, Alireza; Rezaei, Nima

    2014-01-01

    Transforming growth factor β (TGF-β) and interleukin 10 (IL-10) are two anti-inflammatory cytokines that are implicated in the pathogenesis of urticaria. The goal of this study was to examine the possible association of polymorphisms of TGF-β and IL-10 genes with susceptibility to chronic idiopathic urticaria (CIU). This study was conducted on 90 patients with CIU. Polymerase chain reaction (PCR) was done to determine the genotype at 5 polymorphic sites; TGF-β (codon10C/T and codon25G/C) and IL-10 (-1082G/A, -819C/T, and -592C/A). The C allele at codon 25 of TGF-β was more prevalent in CIU patients compared to controls (OR = 9.5, 95% CI = 5.4-16.8, P<0.001). Genotypes of CT and CG at 10 and 25 codons of TGF-β gene, respectively, and AG, CT, and CA for loci of -1082, -819, and -592 of IL-10 gene were significantly higher in CIU patients (P<0.001). In haplotype analysis, frequency of TGF-β haplotypes differed between patients with CIU and controls; CC haplotype was overrepresented, while CG and TG haplotypes were underrepresented (P<0.001). These results suggest that TGF-β and IL-10 genetic variability could contribute to susceptibility to CIU. Additionally, patients with CIU seem to have genotypes leading to high production of TGF-β and IL-10.

  17. Macrophage Migration Inhibitory Factor Polymorphism Is Associated with Susceptibility to Inflammatory Coronary Heart Disease

    Directory of Open Access Journals (Sweden)

    Kangting Ji

    2015-01-01

    Full Text Available Background. Macrophage migration inhibitory factor (MIF is a proinflammatory cytokine. This study explored the association of 173G/C polymorphism of the MIF gene with coronary heart disease (CHD. Methods. Sequencing was carried out after polymerase chain reaction with DNA specimens from 186 volunteers without CHD and 70 patients with CHD. Plasma MIF levels on admission were measured by ELISA. Patients were classified into either stable angina pectoris (SAP or unstable angina pectoris (UAP. Genotype distribution between cases and controls and the association of patients’ genotypes with MIF level and plaque stability were statistically evaluated (ethical approval number: 2012-01. Results. The frequency of the C genotype was higher in CHD patients than in the control (P=0.014. The frequency of the 173*CC genotype was higher in CHD patients than in the control (P=0.005. The plasma MIF level was higher in MIF173*C carriers than in MIF173*G carriers (P=0.033. CHD patients had higher plasma MIF levels than the control (P=0.000. Patients with UAP had higher plasma MIF levels than patients with SAP (P=0.014. Conclusions. These data suggest that MIF −173G/C polymorphism may be related to the development of CHD in a Chinese population. Plasma MIF level is a predictor of plaque stability. This trial is registered with NCT01750502 .

  18. Common polymorphisms and cardiovascular factors in patients with myocardial infarction of Costa Rica

    Directory of Open Access Journals (Sweden)

    Lizbeth Salazar-Sánchez

    2006-03-01

    Full Text Available Eight common polymorphisms of known myocardial infarction (MIrisk factors (factor V Leiden (FVL, factor V HR2 (FVHR2,factor II 20210G>A (FII,factor VII IVS7 (FVII IVS7,factor VII Arg353Gln (FVII, factor XIII Val34Leu (FXIII,Methylenetetrahydrofolate reductase C677T (MTHFR, Angiotensin Converting Enzyme (ACEand environmental risk factors were analyzed in a MI patients of Costa Rica.This case-control study included 186 MI subjects,95 of them Se estudiaron ocho polimorfismos comunes asociados como factores de riesgo para el infarto al miocardio (IM:factor V Leiden (FVL,factor VHR2 (FVHR2, factor II 20210G>A (FII,factor VII IVS7 (FVII IVS7, factor VIIArg353Gln (FVII,factor XIIIVal34Leu (FXIII, metilentetrahidrofolato reductase C677T (MTHFR, enzima convertidora de la angiotensina (ACE y factores ambientales de riesgo,en pacientes costarricenses.Este es un estudio de casos y controles,donde participan 186 pacientes,95 de ellos con edades <45 años y 201 sujetos controles.Se utilizó la técnica de reacción en cadena de la polimerasa (PCRy por medio de entrevistas personales se recolectó información epidemiológica adicional.Se encontró que la hipercolesterolemia y el fumado estan asociados como factores de riesgo en los pacientes jóvenes.Niveles elevados del fibrinógeno fueron detectados como un factor de riesgo importante y se observo interacción entre fumado y estos valores aumentados de fibrinógeno. El genotipo 34LeuLeu del FXIII presentó un efecto protector significante mientras que los otros polimorfimos estudiados no mostraron diferencia estadísticamente significativa entre los casos y controles. Los polimorfismos del FVII y FXIII demostraron interación con el fibrinógeno,según el análisis estadístico aplicado. Se evidencia, la interación entre factores de riesgo común y ciertos polimorfismos (FVII;FXIIIen la patogénesis del IM.Este es uno de los primeros informes sobre estos marcadores moleculares y su asociación con IM en

  19. The polymorphism -863C/A in tumour necrosis factor-alpha gene contributes an independent association to gout.

    Science.gov (United States)

    Chang, S-J; Tsai, P-C; Chen, C-J; Lai, H-M; Ko, Y-C

    2007-11-01

    To investigate the associations between polymorphisms in the promoter of the tumour necrosis factor-alpha (TNF-alpha) gene and gout. The polymorphisms -308G/A and -863C/A in the TNF-alpha gene were determined in 106 gout patients and 159 healthy controls among male Taiwanese using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. The biochemical markers, including Glutamic-oxaloacetic transaminase (GOT), Glutamic-pyruvic transaminase (GPT), uric acid, creatinine, total cholesterol (TC), triglycerides (TG), body mass index (BMI) and hypertension, as well as alcohol consumption were measured. The gout patients had 9.43% (10/106) with genotype AA at polymorphism -863C/A showing a significantly higher fraction than controls (0.63%; 1/159, P gout patients had significantly higher portions of abnormal GOT, GPT, creatinine, TC, TG, alcohol consumption, hypertension and hyperuricaemia than controls (P 0.05). After adjustment by a stepwise logistic regression method, the hyperuricaemia, creatinine, GPT, TG and alcohol consumption as well as genotype AA at polymorphism -863C/A were found to be significantly associated with gout. The genotype AA at polymorphism -863C/A in a recessive model showed a significant association with developing gout independent of hyperuricaemia, abnormal creatinine, higher TG, GPT and alcohol consumption.

  20. Methylenetetrahydrofolate Reductase Gene Polymorphism (C677T) as a Risk Factor for Arterial Thrombosis in Georgian Patients.

    Science.gov (United States)

    Garakanidze, Sopio; Costa, Elísio; Bronze-Rocha, Elsa; Santos-Silva, Alice; Nikolaishvili, Giorgi; Nakashidze, Irina; Kakauridze, Nona; Glonti, Salome; Khukhunaishvili, Rusudan; Koridze, Marina; Ahmad, Sarfraz

    2018-01-01

    Methylenetetrahydrofolate reductase ( MTHFR) gene polymorphism (C677T)] is a well-recognized genetic risk factor for venous thrombosis; however, its association with arterial thrombosis is still under debate. Herein, we evaluated the prevalence of MTHFR C677T polymorphism in Georgian patients in comparison with healthy individuals and its association with arterial thrombosis. We enrolled 214 participants: 101 with arterial thrombosis (71.3% males; mean age: 66.3 ± 12.1 years) and 113 controls (67.3% males; mean age: 56.6 ± 11.3 years). Genomic DNA was extracted from dry blood spot on Whatman filter paper. Polymerase chain reaction was performed to determine MTHFR C677T polymorphism. Frequency of C677T allele polymorphism in controls was 21.2%, which corresponded to heterozygous and homozygous stage frequencies of 35.4% and 3.5%, respectively. In patient group, an allelic frequency of 33.2% was found, which corresponded to the presence of 48.5% of heterozygous and 8.9% of homozygous individuals. Comparing the frequency of mutated alleles between the 2 groups, a significantly high frequency of mutated alleles was found in patient group ( P < .05). In conclusion, high frequency of MTHFR C677T polymorphism found in arterial thrombosis patient group suggests that this polymorphism might increase the risk of arterial thrombosis in Georgian patients.

  1. Relationships between genetic polymorphisms in inflammation-related factor gene and the pathogenesis of nasopharyngeal cancer.

    Science.gov (United States)

    Qu, Yan-Li; Yu, Hong; Chen, Yan-Zhi; Zhao, Yu-Xia; Chen, Guang-Jun; Bai, Lu; Liu, Dan; Su, Hong-Xin; Wang, He-Tong

    2014-09-01

    Our study aims to discuss the association between inflammation-related factors such as single nucleotide polymorphisms (SNPs) with susceptibility and recurrence in nasopharyngeal carcinoma. We used Taqman real-time polymerase chain reaction (PCR) to characterize the genetic variation of five SNPs in 194 nasopharyngeal carcinoma patients and 231 healthy subjects. All statistical analysis is performed with statistical product and service solutions v13.0; odds ratio (OR) value and 95 % confidence interval (CI) were calculated. There is no relationship between TGFβ1 -869 T/C, IL-6 -634C/G, TGFβ1 -509C/T, IL1 -511C/T and nasopharyngeal carcinoma susceptibility. Both single factor and multiple factors analysis showed that IL1a -889 T/T genotype is significantly associated with nasopharyngeal carcinoma in decreasing the risk of nasopharyngeal carcinoma. A highly significant association was found between IL1a -889 T/T genotype and protective genotype as defined by various pathological types. This is more obvious in the protective genotype of the non-keratin-type squamous carcinoma undifferentiated type. We also discovered that genotype G/G and C/G + G/G of IL6 -634 gene are associated with reduced recurrence of nasopharyngeal carcinoma. IL1a -889 gene polymorphism and susceptibility is related to nasopharyngeal carcinoma and can potentially decrease the risk of nasopharyngeal carcinoma in the Han Chinese population in north China. IL1-889 TT genotype is protective genotype for nasopharyngeal carcinoma. We have provided evidence that the GG genotype of the IL6 -634 gene is associated with recurrent risk of nasopharyngeal carcinoma. The G allele is the protective gene of nasopharyngeal carcinoma recurrence.

  2. The tumor necrosis factor alpha - 308G>A polymorphism is associated with dementia in the oldest-old

    DEFF Research Database (Denmark)

    Bruunsgaard, Helle; Benfield, Thomas L; Andersen-Ranberg, Karen

    2004-01-01

    OBJECTIVES: To test the hypothesis that the tumor necrosis factor (TNF) -308 G>A promoter gene polymorphism is a risk factor in age-related dementia and longevity. DESIGN: A cross-sectional and a longitudinal study. SETTING: A population-based sample of Danish centenarians. PARTICIPANTS: One...... was investigated (Fischer exact test). Furthermore, whether the TNF -308 G>A polymorphism was associated with the prevalence of dementia (logistic regression analysis), the plasma level of TNF-alpha (analysis of variance), and mortality in the following 5 years (Cox regression analysis) within the cohort...... higher plasma levels of TNF-alpha, but the significance was questionable due to a low number of subjects with this genotype. CONCLUSION: It is possible that the TNF -308 A allele is maintained during aging because subjects who are heterozygous for this polymorphism possess the optimal inflammatory...

  3. Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities

    Science.gov (United States)

    2016-10-01

    for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data...Olender (PhD graduate student) 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: nhlee@gwu. edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION...inhibitory effects of idelalisib. 15. SUBJECT TERMS prostate cancer, cancer health disparities, alternative splicing, African American, European

  4. Genetic variations and alternative splicing. The Glioma associated oncogene 1, GLI1.

    Directory of Open Access Journals (Sweden)

    Peter eZaphiropoulos

    2012-07-01

    Full Text Available Alternative splicing is a post-transcriptional regulatory process that is attaining stronger recognition as a modulator of gene expression. Alternative splicing occurs when the primary RNA transcript is differentially processed into more than one mature RNAs. This is the result of a variable definition/inclusion of the exons, the sequences that are excised from the primary RNA to form the mature RNAs. Consequently, RNA expression can generate a collection of differentially spliced RNAs, which may distinctly influence subsequent biological events, such as protein synthesis or other biomolecular interactions. Still the mechanisms that control exon definition and exon inclusion are not fully clarified. This mini-review highlights advances in this field as well as the impact of single nucleotide polymorphisms in affecting splicing decisions. The Glioma associated oncogene 1, GLI1, is taken as an example in addressing the role of nucleotide substitutions for splicing regulation.

  5. No evidence that polymorphisms of the vanishing white matter disease genes are risk factors in multiple sclerosis

    NARCIS (Netherlands)

    Pronk, J.C.; Scheper, G.C.; Andel, R.J.; van Berkel, C.G.M.; Polman, C.H.; Uitdehaag, B.M.J.; van der Knaap, M.S.

    2008-01-01

    Febrile infections are known to cause exacerbations in the white matter disorders 'vanishing white matter' (VWM) and multiple sclerosis (MS). We hypothesized that polymorphisms in EIF2B1-5, the genes involved in VWM, might be risk factors for the development of MS or temperature sensitivity in

  6. Relationship of 5-HTTLPR Polymorphism with Various Factors of Pain Processing : Subjective Experience, Motor Responsiveness and Catastrophizing

    NARCIS (Netherlands)

    Kunz, Miriam; Hennig, Juergen; Karmann, Anna J.; Lautenbacher, Stefan

    2016-01-01

    Although serotonin is known to play an important role in pain processing, the relationship between the polymorphism in 5-HTTLPR and pain processing is not well understood. To examine the relationship more comprehensively, various factors of pain processing having putative associations with 5-HT

  7. Detection of Helicobacter pylori virulence factors and interleukin-1 polymorphisms in patients with abdominal complaint

    International Nuclear Information System (INIS)

    Anarkhuu, B.; Munguntsetseg, B.; Khosbayar, T.; Enkh-Amar, A.; Bayasgalan, P.; Yadamjav, Ch.; Oyuntsetseg, K.; Bira, N.; Choi, P.W.

    2007-01-01

    Full text: Gastric Cancer is the second leading cause of cancer related death in Mongolia (National Cancer Center, report-2006). Chronic infection with Helicobacter pylori affects approximately half the world and results in malignancy in a small subset of this population. There was sufficient evidence that the Working Group of the International Agency for Research on Cancer (IARC-1994) classified it as a class I carcinogen, the only bacterial agent on this list. The aim of the study is to detect and define the role of H.pylori virulence factors and host IL-1 polymorphisms to prevent further gastric cancer. In the future, this combined bacterial/host genotyping may provide an important opportunity to identify patients who are at high risk for the development of gastric carcinoma long before malignancy occurs. Patients and biopsy specimens. Two biopsy specimens and 5ml of blood samples were collected from each of 59 patients who had abdominal complaint, after informed consent was obtained. All patients lived in Ulaanbaatar, Mongolia, 100% were of Mongolian nationality. Their mean age was 40.33 years (range, 1575 years). One biopsy specimen was used to test urease, and another was stored for molecular testing. DNA isolation from blood and tissue sample was performed with ''Promega'' kit, according to the manufacturer's instruction. Tissue samples were homogenized treated with proteinase K prior to DNA extraction. H. pylori detection and genotyping. For H.pylori, detection was by UreC primer. For virulence gene typing of H.pylori cagA and vacA, gene specific primer were used. Genotyping of IL-1 polymorphisms. IL-1B polymorphisms were distinguished by 2 methods, 5-nuclease PCR assay and restriction fragment length polymorphism analysis (RFLP). Result. Strain characteristics of H. pylori were investigated in all 59 patients. 66,7% (40/59) and 76,3% (29/36) of the patients were infected with H. pylori by UreC PCR and by urea test, respectively. The vacAs1 genotype was

  8. Alternative RNA splicing and cancer

    Science.gov (United States)

    Liu, Sali; Cheng, Chonghui

    2015-01-01

    Alternative splicing of pre-messenger RNA (mRNA) is a fundamental mechanism by which a gene can give rise to multiple distinct mRNA transcripts, yielding protein isoforms with different, even opposing, functions. With the recognition that alternative splicing occurs in nearly all human genes, its relationship with cancer-associated pathways has emerged as a rapidly growing field. In this review, we summarize recent findings that have implicated the critical role of alternative splicing in cancer and discuss current understandings of the mechanisms underlying dysregulated alternative splicing in cancer cells. PMID:23765697

  9. Interleukin-1 gene polymorphisms in chronic gastritis patients infected with Helicobacter pylori as risk factors of gastric cancer development.

    Science.gov (United States)

    Hnatyszyn, Andrzej; Wielgus, Karolina; Kaczmarek-Rys, Marta; Skrzypczak-Zielinska, Marzena; Szalata, Marlena; Mikolajczyk-Stecyna, Joanna; Stanczyk, Jerzy; Dziuba, Ireneusz; Mikstacki, Adam; Slomski, Ryszard

    2013-12-01

    Epidemiological investigations indicated association of the Helicobacter pylori infections with the occurrence of inflammatory conditions of the gastric mucosa and development of chronic gastritis and intestinal type of gastric cancer. IL1A and IL1B genes have been proposed as key factors in determining risk of gastritis and malignant transformation. The aim of this paper was to evaluate association of interleukin-1 gene polymorphisms with chronic gastritis, atrophy, intestinal metaplasia, dysplasia and intestinal type of gastric cancer in H. pylori-infected patients. Patients subjected to analysis represent group of 144 consecutive cases that suffered from dyspepsia with coexisting infection of H. pylori and chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer. Molecular studies involved analysis of -889C>T polymorphism of IL1A gene and +3954C>T polymorphism of IL1B gene. Statistical analysis of association of polymorphism -889C>T of gene IL1A with changes in gastric mucosa showed lack of significance, whereas +3954C>T polymorphism of IL1B gene showed significant association. Frequency of allele T of +3954C>T polymorphism of IL1B gene was higher in group of patients with chronic gastritis, atrophy, intestinal metaplasia, dysplasia or intestinal type of gastric cancer (32.1 %) as compared with population group (23 %), χ(2) = 4.61 and p = 0.03. This corresponds to odds ratio: 1.58, 95 % CI: 1.04-2.4. Our results indicate that +3954C>T polymorphism of IL1B gene increase susceptibility to inflammatory response of gastric mucosa H. pylori-infected patients and plays a significant role in the development of chronic gastritis, atrophy, intestinal metaplasia, dysplasia and the initiation of carcinogenesis.

  10. Effect of epidermal growth factor receptor gene polymorphisms on prognosis in glioma patients

    Science.gov (United States)

    Li, Jingjie; Yan, Mengdan; Xie, Zhilan; Zhu, Yuanyuan; Chen, Chao; Jin, Tianbo

    2016-01-01

    Previous studies suggested that single nucleotide polymorphisms (SNPs) in epidermal growth factor receptor (EGFR) are associated with risk of glioma. However, the associations between these SNPs and glioma patient prognosis have not yet been fully investigated. Therefore, the present study was aimed to evaluate the effects of EGFR polymorphisms on the glioma patient prognosis. We retrospectively evaluated 269 glioma patients and investigated associations between EGFR SNPs and patient prognosis using Cox proportional hazard models and Kaplan-Meier curves. Univariate analysis revealed that age, gross-total resection and chemotherapy were associated with the prognosis of glioma patients (p < 0.05). In addition, four EGFR SNPs (rs11506105, rs3752651, rs1468727 and rs845552) correlated with overall survival (OS) (Log-rank p = 0.011, 0.020, 0.008, and 0.009, respectively) and progression-free survival PFS (Log-rank p = 0.026, 0.024, 0.019 and 0.009, respectively). Multivariate analysis indicated that the rs11506105 G/G genotype, the rs3752651 and rs1468727 C/C genotype and the rs845552 A/A genotype correlated inversely with OS and PFS. In addition, OS among patients with the rs730437 C/C genotype (p = 0.030) was significantly lower OS than among patients with A/A genotype. These data suggest that five EGFR SNPs (rs11506105, rs3752651, rs1468727, rs845552 and rs730437) correlated with glioma patient prognosis, and should be furthered validated in studies of ethnically diverse patients. PMID:27437777

  11. Investigating the association between polymorphisms in connective tissue growth factor and susceptibility to colon carcinoma.

    Science.gov (United States)

    Ahmad, Abrar; Askari, Shlear; Befekadu, Rahel; Hahn-Strömberg, Victoria

    2015-04-01

    There have been numerous studies on the gene expression of connective tissue growth factor (CTGF) in colorectal cancer, however very few have investigated polymorphisms in this gene. The present study aimed to determine whether single nucleotide polymorphisms (SNPs) in the CTGF gene are associated with a higher susceptibility to colon cancer and/or an invasive tumor growth pattern. The CTGF gene was genotyped for seven SNPs (rs6918698, rs1931002, rs9493150, rs12526196, rs12527705, rs9399005 and rs12527379) by pyrosequencing. Formalin‑fixed paraffin‑embedded tissue samples (n=112) from patients diagnosed with colon carcinoma, and an equal number of blood samples from healthy controls, were selected for genomic DNA extraction. The complexity index was measured using images of tumor samples (n=64) stained for cytokeratin‑8. The images were analyzed and correlated with the identified CTGF SNPs and clinicopathological parameters of the patients, including age, gender, tumor penetration, lymph node metastasis, systemic metastasis, differentiation and localization of tumor. It was demonstrated that the frequency of the SNP rs6918698 GG genotype was significantly associated (P=0.05) with an increased risk of colon cancer, as compared with the GC and CC genotypes. The other six SNPs (rs1931002, rs9493150, rs12526196, rs12527705, rs9399005 and rs12527379) exhibited no significant difference in the genotype and allele frequencies between patients diagnosed with colon carcinoma and the normal healthy population. A trend was observed between genotype variation at rs6918698 and the complexity index (P=0.052). The complexity index and genotypes for any of the studied SNPs were not significantly correlated with clinical or pathological parameters of the patients. These results indicate that the rs6918698 GG genotype is associated with an increased risk of developing colon carcinoma, and genetic variations at the rs6918698 are associated with the growth pattern of the tumor

  12. Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns

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    Weischenfeldt, Joachim Lütken; Waage, Johannes Eichler; Tian, Geng

    2012-01-01

    ABSTRACT: BACKGROUND: Nonsense-mediated mRNA decay (NMD) affects the outcome of alternative splicing by degrading mRNA isoforms with premature termination codons. Splicing regulators constitute important NMD targets; however, the extent to which loss of NMD causes extensive deregulation...... of alternative splicing has not previously been assayed in a global, unbiased manner. Here, we combine mouse genetics and RNA-seq to provide the first in vivo analysis of the global impact of NMD on splicing patterns in two primary mouse tissues ablated for the NMD factor UPF2. RESULTS: We developed...... importance, the latter events are associated with high intronic conservation. CONCLUSIONS: Our data demonstrate that NMD regulates alternative splicing outcomes through an intricate web of splicing regulators and that its loss leads to the deregulation of a panoply of splicing events, providing novel...

  13. Diversification of the muscle proteome through alternative splicing.

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    Nakka, Kiran; Ghigna, Claudia; Gabellini, Davide; Dilworth, F Jeffrey

    2018-03-06

    Skeletal muscles express a highly specialized proteome that allows the metabolism of energy sources to mediate myofiber contraction. This muscle-specific proteome is partially derived through the muscle-specific transcription of a subset of genes. Surprisingly, RNA sequencing technologies have also revealed a significant role for muscle-specific alternative splicing in generating protein isoforms that give specialized function to the muscle proteome. In this review, we discuss the current knowledge with respect to the mechanisms that allow pre-mRNA transcripts to undergo muscle-specific alternative splicing while identifying some of the key trans-acting splicing factors essential to the process. The importance of specific splicing events to specialized muscle function is presented along with examples in which dysregulated splicing contributes to myopathies. Though there is now an appreciation that alternative splicing is a major contributor to proteome diversification, the emergence of improved "targeted" proteomic methodologies for detection of specific protein isoforms will soon allow us to better appreciate the extent to which alternative splicing modifies the activity of proteins (and their ability to interact with other proteins) in the skeletal muscle. In addition, we highlight a continued need to better explore the signaling pathways that contribute to the temporal control of trans-acting splicing factor activity to ensure specific protein isoforms are expressed in the proper cellular context. An understanding of the signal-dependent and signal-independent events driving muscle-specific alternative splicing has the potential to provide us with novel therapeutic strategies to treat different myopathies.

  14. Interactions between environmental factors and melatonin receptor type 1A polymorphism in relation to oral cancer susceptibility and clinicopathologic development.

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    Feng-Yan Lin

    Full Text Available The purpose of this study was to explore the combined effect of melatonin receptor type 1A (MTNR1A gene polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of oral cancer.Three polymorphisms of the MTNR1A gene from 618 patients with oral cancer and 560 non-cancer controls were analyzed by real-time polymerase chain reaction (PCR. The CTA haplotype of the studied MTNR1A polymorphisms (rs2119882, rs13140012, rs6553010 was related to a higher risk of oral cancer. Moreover, MTNR1A gene polymorphisms exhibited synergistic effects of environmental factors (betel quid and tobacco use on the susceptibility of oral cancer. Finally, oral-cancer patients with betel quid-chewing habit who had T/T allele of MTNR1A rs13140012 were at higher risk for developing an advanced clinical stage and lymph node metastasis.These results support gene-environment interactions of MTNR1A polymorphisms with smoking and betel quid-chewing habits possibly altering oral-cancer susceptibility and metastasis.

  15. The tumor necrosis factor-α-238 polymorphism and digestive system cancer risk: a meta-analysis.

    Science.gov (United States)

    Hui, Ming; Yan, Xiaojuan; Jiang, Ying

    2016-08-01

    Many studies have reported the association between tumor necrosis factor-α (TNF-α)-238 polymorphism and digestive system cancer susceptibility, but the results were inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship between TNF-α-238 G/A polymorphism and digestive system cancer risk. Pooled analysis for the TNF-α-238 G/A polymorphism contained 26 studies with a total of 4849 cases and 8567 controls. The meta-analysis observed a significant association between TNF-α-238 G/A polymorphism and digestive system cancer risk in the overall population (GA vs GG: OR 1.19, 95 % CI 1.00-1.40, P heterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03-1.39, P heterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02-1.41, P heterpgeneity = 0.012). In the analysis of the ethnic subgroups, however, similar results were observed only in the Asian population, but not in the Caucasian population. Therefore, this meta-analysis suggests that TNF-α-238 G/A polymorphism is associated with a significantly increased risk of digestive system cancer. Further large and well-designed studies are needed to confirm these findings.

  16. Mutual interdependence of splicing and transcription elongation.

    Science.gov (United States)

    Brzyżek, Grzegorz; Świeżewski, Szymon

    2015-01-01

    Transcription and splicing are intrinsically linked, as splicing needs a pre-mRNA substrate to commence. The more nuanced view is that the rate of transcription contributes to splicing regulation. On the other hand there is accumulating evidence that splicing has an active role in controlling transcription elongation by DNA-dependent RNA polymerase II (RNAP II). We briefly review those mechanisms and propose a unifying model where splicing controls transcription elongation to provide an optimal timing for successive rounds of splicing.

  17. Aberrant and alternative splicing in skeletal system disease.

    Science.gov (United States)

    Fan, Xin; Tang, Liling

    2013-10-01

    The main function of skeletal system is to support the body and help movement. A variety of factors can lead to skeletal system disease, including age, exercise, and of course genetic makeup and expression. Pre-mRNA splicing plays a crucial role in gene expression, by creating multiple protein variants with different biological functions. The recent studies show that several skeletal system diseases are related to pre-mRNA splicing. This review focuses on the relationship between pre-mRNA splicing and skeletal system disease. On the one hand, splice site mutation that leads to aberrant splicing often causes genetic skeletal system disease, like COL1A1, SEDL and LRP5. On the other hand, alternative splicing without genomic mutation may generate some marker protein isoforms, for example, FN, VEGF and CD44. Therefore, understanding the relationship between pre-mRNA splicing and skeletal system disease will aid in uncovering the mechanism of disease and contribute to the future development of gene therapy. © 2013 Elsevier B.V. All rights reserved.

  18. Association study of a brain-derived neurotrophic factor polymorphism and short-term antidepressant response in major depressive disorders

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    Lung-Cheng Huang

    2008-10-01

    Full Text Available Eugene Lin1,7, Po See Chen2,6,7, Lung-Cheng Huang3,4, Sen-Yen Hsu51Vita Genomics, Inc., Wugu Shiang, Taipei, Taiwan; 2Department of Psychiatry, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Psychiatry, National Taiwan University Hospital Yun-Lin Branch, Taiwan; 4Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Psychiatry, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 6Department of Psychiatry, National Cheng Kung University Hospital, Dou-liou Branch, Yunlin, Taiwan; 7These authors contributed equally to this workAbstract: Major depressive disorder (MDD is one of the most common mental disorders worldwide. Single nucleotide polymorphisms (SNPs can be used in clinical association studies to determine the contribution of genes to drug efficacy. A common SNP in the brain-derived neurotrophic factor (BDNF gene, a methionine (Met substitution for valine (Val at codon 66 (Val66Met, is a candidate SNP for influencing antidepressant treatment outcome. In this study, our goal was to determine the relationship between the Val66Met polymorphism in the BDNF gene and the rapid antidepressant response to venlafaxine in a Taiwanese population with MDD. Overall, the BDNF Val66Met polymorphism was found not to be associated with short-term venlafaxine treatment outcome. However, the BDNF Val66Met polymorphism showed a trend to be associated with rapid venlafaxine treatment response in female patients. Future research with independent replication in large sample sizes is needed to confirm the role of the BDNF Val66Met polymorphism identified in this study.Keywords: antidepressant response, brain-derived neurotrophic factor, major depressive disorder, serotonin and norepinephrine reuptake inhibitor, single nucleotide polymorphisms

  19. Association of a transforming growth factor-β1 polymorphism with acute coronary syndrome in a Chinese Han population.

    Science.gov (United States)

    Yang, Y N; Zhao, B; Li, X M; Xie, X; Liu, F; Chen, B D

    2014-04-03

    Acute coronary syndrome (ACS) is a complex multifactorial and polygenic disorder that is thought to result from the interaction between an individual's genetic makeup and various environmental factors. The aim of this study was to investigate the association of a transforming growth factor-β1 (TGF-β1) polymorphism (-509C>T) with ACS in a Chinese Han population. The TGF-β1 polymorphism was evaluated in 336 patients with ACS and 396 healthy control subjects by polymerase chain reaction-restriction fragment length polymorphism. The genotype distributions of the control and ACS groups were in Hardy-Weinberg equilibrium (X(2) = 3.54 and X(2) = 1.72, respectively, P > 0.05). The frequencies of the CC, CT, and TT genotypes were 22.61, 53.57, and 20.83% in the ACS group, respectively, whereas they were 8.33, 48.74, and 42.17% in controls. There were significant differences between controls and ACS patients in the frequencies of the CC genotype and the C allele. These results suggest that the promoter polymorphism (-509C>T) in TGF-β1 is associated with ACS in this population. The CC genotype and the C allele of TGF-β1 might be a specific risk factor of ACS in the Chinese Han population in Xinjiang.

  20. The thrombospondin-1 N700S polymorphism is associated with early myocardial infarction without altering von Willebrand factor multimer size.

    Science.gov (United States)

    Zwicker, Jeffrey I; Peyvandi, Flora; Palla, Roberta; Lombardi, Rossana; Canciani, Maria Teresa; Cairo, Andrea; Ardissino, Diego; Bernardinelli, Luisa; Bauer, Kenneth A; Lawler, Jack; Mannucci, Pier

    2006-08-15

    The N700S polymorphism of thrombospondin-1 (TSP-1) has been identified as a potential genetic risk factor for myocardial infarction (MI). In a large case-control study of 1425 individuals who survived a myocardial infarction prior to age 45, the N700S polymorphism was a significant risk factor for myocardial infarction in both homozygous (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.3, P = .01) and heterozygous carriers of the S700 allele (OR 1.4, 95% CI 1.1-3.3, P = .01). TSP-1 has been shown to reduce von Willebrand factor (VWF) multimer size, and the domain responsible for VWF-reducing activity has been localized to the calcium-binding C-terminal sequence. As the N700S polymorphism was previously shown to alter the function of this domain, we investigated whether the altered VWF-reducing activity of TSP-1 underlies the observed prothrombotic phenotype. The TSP1 N700S polymorphism did not influence VWF multimer size in patients homozygous for either allele nor was there a significant reduction of VWF multimer size following incubation with recombinant N700S fragments or platelet-derived TSP-1.

  1. Association of Polymorphisms in Connective Tissue Growth Factor and Epidermal Growth Factor Receptor Genes With Human Longevity.

    Science.gov (United States)

    Donlon, Timothy A; Morris, Brian J; He, Qimei; Chen, Randi; Masaki, Kamal H; Allsopp, Richard C; Willcox, D Craig; Tranah, Gregory J; Parimi, Neeta; Evans, Daniel S; Flachsbart, Friederike; Nebel, Almut; Kim, Duk-Hwan; Park, Joobae; Willcox, Bradley J

    2017-08-01

    Growth pathways play key roles in longevity. The present study tested single-nucleotide polymorphisms (SNPs) in the connective tissue growth factor gene (CTGF) and the epidermal growth factor receptor gene (EGFR) for association with longevity. Comparison of allele and genotype frequencies of 12 CTGF SNPs and 41 EGFR SNPs between 440 American men of Japanese ancestry aged ≥95 years and 374 men of average life span revealed association with longevity at the p cases, consistent with heterozygote advantage in living to extreme old age. No associations of the most significant SNPs were observed in whites or Koreans. In conclusion, the present findings indicate that genetic variation in CTGF and EGFR may contribute to the attainment of extreme old age in Japanese. More research is needed to confirm that genetic variation in CTGF and EGFR contributes to the attainment of extreme old age across human populations. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Histone and RNA-binding protein interaction creates crosstalk network for regulation of alternative splicing.

    Science.gov (United States)

    Kim, Yong-Eun; Park, Chungoo; Kim, Kyoon Eon; Kim, Kee K

    2018-04-30

    Alternative splicing is an essential process in eukaryotes, as it increases the complexity of gene expression by generating multiple proteins from a single pre-mRNA. However, information on the regulatory mechanisms for alternative splicing is lacking, because splicing occurs over a short period via the transient interactions of proteins within functional complexes of the spliceosome. Here, we investigated in detail the molecular mechanisms connecting alternative splicing with epigenetic mechanisms. We identified interactions between histone proteins and splicing factors such as Rbfox2, Rbfox3, and splicing factor proline and glutamine rich protein (SFPQ) by in vivo crosslinking and immunoprecipitation. Furthermore, we confirmed that splicing factors were bound to specific modified residues of histone proteins. Additionally, changes in histone methylation due to histone methyltransferase inhibitor treatment notably affected alternative splicing in selected genes. Therefore, we suggested that there may be crosstalk mechanisms connecting histone modifications and RNA-binding proteins that increase the local concentration of RNA-binding proteins in alternative exon loci of nucleosomes by binding specific modified histone proteins, leading to alternative splicing. This crosstalk mechanism may play a major role in epigenetic processes such as histone modification and the regulation of alternative splicing. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Impacts of microRNA gene polymorphisms on the susceptibility of environmental factors leading to carcinogenesis in oral cancer.

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    Yin-Hung Chu

    Full Text Available BACKGROUND: MicroRNAs (miRNAs have been regarded as a critical factor in targeting oncogenes or tumor suppressor genes in tumorigenesis. The genetic predisposition of miRNAs-signaling pathways related to the development of oral squamous cell carcinoma (OSCC remains unresolved. This study examined the associations of polymorphisms with four miRNAs with the susceptibility and clinicopathological characteristics of OSCC. METHODOLOGY/PRINCIPAL FINDINGS: A total of 895 male subjects, including 425 controls and 470 male oral cancer patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and real-time PCR were used to analyze miRNA146a, miRNA196, miRNA499 and miRNA149 genetic polymorphisms between the control group and the case group. This study determined that a significant association of miRNA499 with CC genotype, as compared to the subjects with TT genotype, had a higher risk (AOR = 4.52, 95% CI = 1.24-16.48 of OSCC. Moreover, an impact of those four miRNAs gene polymorphism on the susceptibility of betel nut and tobacco consumption leading to oral cancer was also revealed. We found a protective effect between clinical stage development (AOR = 0.58, 95% CI = 0.36-0.94 and the tumor size growth (AOR = 0.47, 95% CI = 0.28-0.79 in younger patients (age<60. CONCLUSIONS: Our results suggest that genetic polymorphism of miRNA499 is associated with oral carcinogenesis, and the interaction of the miRNAs genetic polymorphism and environmental carcinogens is also related to an increased risk of oral cancer in Taiwanese.

  4. Association of TNF polymorphisms with sarcoidosis, its prognosis and tumour necrosis factor (TNF)-α levels in Asian Indians

    Science.gov (United States)

    Sharma, S; Ghosh, B; Sharma, S K

    2008-01-01

    Tumour necrosis factor (TNF)-α, an important proinflammatory cytokine, has been implicated in the pathogenesis of sarcoidosis, a multi-systemic granulomatous disorder of unknown aetiology. Here, we report for the first time the association of TNF haplotypes and genotypes with sarcoidosis and its prognosis in the Indian population. Five potentially functional promoter polymorphisms in the TNFA gene and a LTA_NcoI polymorphism (+252 position) of the LTA gene were genotyped in a clinically well-defined cohort of North-Indian patients with sarcoidosis (n = 96) and their regional controls (n = 155). Serum TNF-α (sTNF-α) and serum angiotensin converting enzyme (SACE) levels were measured and correlated with genotypes and haplotypes. The TNFA_-1031 and TNFA_-863 polymorphisms were identified as markers for disease onset (FET P = 0·006 and 0·042 for TNFA_-1031 and TNFA_-863, respectively). Additionally, the allele A of LTA_NcoI polymorphism was shown to be prevalent in the ‘no treatment’ group (FET P = 0·005), while the G allele was associated with frequent relapses on drug withdrawal (P = 0·057). Furthermore, the TNFA-308G>A and the TNFA-238G>A polymorphisms were found to influence sTNF-α (P = 0·054 and 0·0005, respectively) and SACE levels (P = 0·0017 and 0·056, respectively). The haplotype frequencies were significantly different in the patients and the controls (P = 0·0067). The haplotype GTCCGG was identified as the major risk/susceptibility haplotype (P = 0·003) and was associated with increased SACE levels in the patient population. In conclusion, our study suggests an association of TNF polymorphisms with sarcoidosis. PMID:18062795

  5. T regulatory cells and related immunoregulatory factors in polymorphic light eruption following ultraviolet A1 challenge.

    Science.gov (United States)

    Gambichler, T; Terras, S; Kampilafkos, P; Kreuter, A; Skrygan, M

    2013-12-01

    Polymorphic light eruption (PLE) is considered to be an autoimmune-mediated skin condition in which the normal ultraviolet (UV)-induced local immunosuppression appears to be absent, leading to recognition of photoinduced autoantigens and subsequent inflammation. To investigate T regulatory cells (Tregs) and related immunoregulatory factors in PLE lesions and controls. Skin biopsies were performed in 13 patients with UVA1-challenged PLE, 12 female patients with chronic discoid lupus erythematosus (CDLE) and 11 healthy controls who had exposure to UVA1. Immunohistochemistry and four-colour immunofluorescence studies were performed. Patients with CDLE and UVA1-exposed controls showed significantly decreased epidermal immunoreactivity for CD1a compared with patients with PLE (P = 0·0001). Four-colour immunofluorescence revealed a median percentage of CD4+CD25+FOXP3+ Tregs of 7·6% (range 3·7-13·6%) in PLE, a median of 11·7% (range 9·5-13·9%) in CDLE and a median of 3·4% (range 0-6·8%) in controls. Compared with UVA1-exposed controls, PLE and CDLE lesions showed significantly decreased transforming growth factor (TGF)-β1 immunoreactivity in the epidermis (P = 0·0003). In PLE lesions, we observed significantly decreased interleukin (IL)-10 expression compared with CDLE (P = 0·022). In the dermis, receptor activator of nuclear factor-κB ligand (RANKL) expression was increased in UVA1-exposed controls compared with PLE and CDLE (P = 0·018). Similar to CDLE lesions, UVA1-challenged PLE lesions display an altered immunoregulatory network, as indicated by decreased epidermal or dermal expression of TGF-β1, IL-10 and RANKL, and a relatively low number of Tregs, particularly when compared with other inflammatory skin conditions reported in the literature. © 2013 British Association of Dermatologists.

  6. Irf3 polymorphism alters induction of interferon beta in response to Listeria monocytogenes infection.

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    Oleg Garifulin

    2007-09-01

    Full Text Available Genetic makeup of the host plays a significant role in the course and outcome of infection. Inbred strains of mice display a wide range of sensitivities to Listeria monocytogenes infection and thus serve as a good model for analysis of the effect of genetic polymorphism. The outcome of L. monocytogenes infection in mice is influenced by the ability of this bacterium to induce expression of interferon beta mRNA, encoded in mouse by the Ifnb1 (interferon beta 1, fibroblast gene. Mouse strains that lack components of the IFN beta signaling pathway are substantially more resistant to infection. We found that macrophages from the ByJ substrain of the common C57BL/6 inbred strain of mice are impaired in their ability to induce Ifnb1 expression in response to bacterial and viral infections. We mapped the locus that controls differential expression of Ifnb1 to a region on Chromosome 7 that includes interferon regulatory factor 3 (Irf3, which encodes a transcription factor responsible for early induction of Ifnb1 expression. In C57BL/6ByJ mice, Irf3 mRNA was inefficiently spliced, with a significant proportion of the transcripts retaining intron 5. Analysis of the Irf3 locus identified a single base-pair polymorphism and revealed that intron 5 of Irf3 is spliced by the atypical U12-type spliceosome. We found that the polymorphism disrupts a U12-type branchpoint and has a profound effect on the efficiency of splicing of Irf3. We demonstrate that a naturally occurring change in the splicing control element has a dramatic effect on the resistance to L. monocytogenes infection. Thus, the C57BL/6ByJ mouse strain serves as an example of how a mammalian host can counter bacterial virulence strategies by introducing subtle alteration of noncoding sequences.

  7. Taq I polymorphism in the 5' region of the von Willebrand Factor (vWF) gene

    Energy Technology Data Exchange (ETDEWEB)

    Lavergne, J M; Bahnak, B R; Assouline, Z; Pietu, G; Kerbiriou-Nabias, D; Meulien, P; Pavirani, A; Meyer, D

    1988-03-25

    pvWFIPC8 is a 2.28 Kb partial cDNA clone for human von Willebrand factor (vWF) isolated from a human lung cDNA library and inserted into the EcoRI site of pUC9. The sequence includes the last 1330 nucleotides that encode for vWF propeptide and 950 nucleotides that encode for mature vWF. Taq I (TCGA) identifies plural invariant bands and two variant bands with alleles at 2.3 (Al) and 1.0 (A2). The frequency was determined in 33 unrelated European and North American caucasians. The extreme 3' region of pvWFIPC8 corresponds to the 5' boundary of an area that could possibly hybridize with similar sequences on human chromosome 22. The 5' 1.74 Kb portion of pvWFIPC8 generated by Bam HI digestion that corresponds to sequences only on chromosome 12 also demonstrates the polymorphism. Co-dominant segregation was demonstrated in 6 families of 48 individuals.

  8. Bayesian pedigree inference with small numbers of single nucleotide polymorphisms via a factor-graph representation.

    Science.gov (United States)

    Anderson, Eric C; Ng, Thomas C

    2016-02-01

    We develop a computational framework for addressing pedigree inference problems using small numbers (80-400) of single nucleotide polymorphisms (SNPs). Our approach relaxes the assumptions, which are commonly made, that sampling is complete with respect to the pedigree and that there is no genotyping error. It relies on representing the inferred pedigree as a factor graph and invoking the Sum-Product algorithm to compute and store quantities that allow the joint probability of the data to be rapidly computed under a large class of rearrangements of the pedigree structure. This allows efficient MCMC sampling over the space of pedigrees, and, hence, Bayesian inference of pedigree structure. In this paper we restrict ourselves to inference of pedigrees without loops using SNPs assumed to be unlinked. We present the methodology in general for multigenerational inference, and we illustrate the method by applying it to the inference of full sibling groups in a large sample (n=1157) of Chinook salmon typed at 95 SNPs. The results show that our method provides a better point estimate and estimate of uncertainty than the currently best-available maximum-likelihood sibling reconstruction method. Extensions of this work to more complex scenarios are briefly discussed. Published by Elsevier Inc.

  9. Combined effect of genetic polymorphisms of AURKA and environmental factors on oral cancer development in Taiwan.

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    Chia-Hsuan Chou

    Full Text Available Oral squamous cell carcinoma (OSCC is the sixth and fourth most common cause of cancer death in men worldwide and in Taiwan, respectively. AURKA, which encodes a centrosome-related serine/threonine kinase, is frequently amplified and overexpressed in many human cancers, particularly advanced OSCC. We conducted a hospital-based case-control study to estimate AURKA single-nucleotide polymorphisms (SNPs and environmental risk factors to determine OSCC susceptibility and clinicopathological characteristics.We enrolled a total of 876 OSCC patients and 1200 controls. Four SNPs of AURKA, namely rs1047972, rs2273535, rs2064863, and rs6024836, were analyzed using real-time polymerase chain reaction (PCR. Among the 1420 smokers, the AURKA polymorphism carriers with the betel nut chewing habit had a higher risk of oral cancer than AURKA wild-type (WT carriers without the betel nut chewing habit. Patients with the AURKA rs2064863 gene had a 1.365-fold higher risk of stage III or IV OSCC (95% confidence interval [CI] 1.029-1.811 than those with the rs2064863 WT gene. Furthermore, carriers of the AURKA rs1047972/rs2273535/rs2064863 C-A-T haplotype had a 1.736-fold (95% CI 1.110-2.715 higher risk of OSCC than controls (C-T-T, the most common haplotype. Among patients with the betel quid chewing habit, carriers of other haplotypes (C-T-T, C-A-G, T-A-T, T-A-G, T-T-T, and C-T-G had a 12.857-fold (95% CI 10.731-15.404 increased risk, and carriers of the C-A-T haplotype had the highest risk (AOR: 31.120; 95% CI 13.864-69.850 of OSCC, compared with those without the betel quid chewing who harbored other haplotypes.In conclusion, betel nut chewing combined with the AURKA C-A-T haplotypes lead to a high risk of OSCC. These findings reveal a novel genetic-environmental predisposition for oral tumorigenesis.

  10. Polymorphisms in the TNFA and IL6 Genes Represent Risk Factors for Autoimmune Thyroid Disease

    Science.gov (United States)

    Alvelos, Inês; Mendes, Adélia; Santos, Liliana R.; Machado, José Carlos; Melo, Miguel; Esteves, César; Neves, Celestino; Sobrinho-Simões, Manuel; Soares, Paula

    2014-01-01

    Background Autoimmune thyroid disease (AITD) comprises diseases including Hashimoto's thyroiditis and Graves' disease, both characterized by reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating hormone receptor. AITD is the most common thyroid disease and the leading form of autoimmune disease in women. Cytokines are key regulators of the immune and inflammatory responses; therefore, genetic variants at cytokine-encoding genes are potential risk factors for AITD. Methods Polymorphisms in the IL6-174 G/C (rs1800795), TNFA-308 G/A (rs1800629), IL1B-511 C/T (rs16944), and IFNGR1-56 T/C (rs2234711) genes were assessed in a case-control study comprising 420 Hashimoto's thyroiditis patients, 111 Graves' disease patients and 735 unrelated controls from Portugal. Genetic variants were discriminated by real-time PCR using TaqMan SNP genotyping assays. Results A significant association was found between the allele A in TNFA-308 G/A and Hashimoto's thyroiditis, both in the dominant (OR = 1.82, CI = 1.37–2.43, p-value = 4.4×10−5) and log-additive (OR = 1.64, CI = 1.28–2.10, p-value = 8.2×10−5) models. The allele C in IL6-174 G/C is also associated with Hashimoto's thyroiditis, however, only retained significance after multiple testing correction in the log-additive model (OR = 1.28, CI = 1.06–1.54, p-value = 8.9×10−3). The group with Graves' disease also registered a higher frequency of the allele A in TNFA-308 G/A compared with controls both in the dominant (OR = 1.85, CI = 1.19–2.87, p-value = 7.0×10−3) and log-additive (OR = 1.69, CI = 1.17–2.44, p-value = 6.6×10−3) models. The risk for Hashimoto's thyroiditis and Graves' disease increases with the number of risk alleles (OR for two risk alleles is, respectively, 2.27 and 2.59). Conclusions This study reports significant associations of genetic variants in TNFA and

  11. Polymorphisms in the TNFA and IL6 genes represent risk factors for autoimmune thyroid disease.

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    Cecília Durães

    Full Text Available Autoimmune thyroid disease (AITD comprises diseases including Hashimoto's thyroiditis and Graves' disease, both characterized by reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating hormone receptor. AITD is the most common thyroid disease and the leading form of autoimmune disease in women. Cytokines are key regulators of the immune and inflammatory responses; therefore, genetic variants at cytokine-encoding genes are potential risk factors for AITD.Polymorphisms in the IL6-174 G/C (rs1800795, TNFA-308 G/A (rs1800629, IL1B-511 C/T (rs16944, and IFNGR1-56 T/C (rs2234711 genes were assessed in a case-control study comprising 420 Hashimoto's thyroiditis patients, 111 Graves' disease patients and 735 unrelated controls from Portugal. Genetic variants were discriminated by real-time PCR using TaqMan SNP genotyping assays.A significant association was found between the allele A in TNFA-308 G/A and Hashimoto's thyroiditis, both in the dominant (OR = 1.82, CI = 1.37-2.43, p-value = 4.4×10(-5 and log-additive (OR = 1.64, CI = 1.28-2.10, p-value = 8.2×10(-5 models. The allele C in IL6-174 G/C is also associated with Hashimoto's thyroiditis, however, only retained significance after multiple testing correction in the log-additive model (OR = 1.28, CI = 1.06-1.54, p-value = 8.9×10(-3. The group with Graves' disease also registered a higher frequency of the allele A in TNFA-308 G/A compared with controls both in the dominant (OR = 1.85, CI = 1.19-2.87, p-value = 7.0×10(-3 and log-additive (OR = 1.69, CI = 1.17-2.44, p-value = 6.6×10(-3 models. The risk for Hashimoto's thyroiditis and Graves' disease increases with the number of risk alleles (OR for two risk alleles is, respectively, 2.27 and 2.59.This study reports significant associations of genetic variants in TNFA and IL6 with the risk for AITD, highlighting the

  12. NcoI restriction fragment length polymorphism (RFLP) of the tumour necrosis factor (TNF alpha) region in primary biliary cirrhosis and in healthy Danes

    DEFF Research Database (Denmark)

    Fugger, L; Morling, N; Ryder, L P

    1989-01-01

    The restriction fragment length polymorphism of the human tumour necrosis factor (TNF alpha) region was investigated by means of 20 different restriction enzymes and a human TNF alpha cDNA probe. Only one of the enzymes, NcoI, revealed a polymorphic pattern consisting of fragments of 10.5 and 5.5...

  13. Contribution of coagulation factor VII R353Q polymorphism to the ...

    African Journals Online (AJOL)

    Hanan Azzam

    2016-12-05

    Dec 5, 2016 ... Conclusion: FVII R353Q polymorphism did not contribute to an increased risk of thrombosis (arterial and venous); also .... smoking and obesity were assessed in the AMI and DVT groups as well as the control ..... perspectives.

  14. Effects of NFKB1 and NFKBIA gene polymorphisms on susceptibility to environmental factors and the clinicopathologic development of oral cancer.

    Directory of Open Access Journals (Sweden)

    Chiao-Wen Lin

    Full Text Available Oral cancer, which is the fourth most common cancer in Taiwanese men, is associated with environmental carcinogens. The possibility that genetic predisposition in nuclear factor-kappa B (NF-κB-signaling pathways activation is linked to the development of oral squamous cell carcinoma (OSCC requires investigation. The current study examines associations between polymorphisms within promoter regions of NFKB1 encoding NF-κB1 and NFKBIA encoding IkappaBalpha (IκBα with both the susceptibility to develop OSCC and the clinicopathological characteristics of the tumors.Genetic polymorphisms of NFKB1 and NFKBIA were analyzed by a real-time polymerase chain reaction (real-time PCR for 462 patients with oral cancer and 520 non-cancer controls. We found that NFKB1 -94 ATGG1/ATGG2, -94 ATGG2/ATGG2, and the combination of -94 ATGG1/ATGG2 and ATGG2/ATGG2 genotypes NFKBIA -826 T (CT+TT and -881 G (AG+GG allelic carriages, were more prevalent in OSCC patients than in non-cancer participants. Moreover, we found that NFKB1 or NFKBIA gene polymorphisms seem to be related to susceptibility to develop oral cancer linked to betel nut and tobacco consumption. Finally, patients with oral cancer who had at least one -519 T allele of the NFKBIA gene were at higher risk for developing distant metastasis (P<.05, compared with those patients CC homozygotes.Our results suggest that NFKB1 -94 ATTG2, NFKBIA -826 T, and -881 G alleles are associated with oral carcinogenesis. The combination of NFKB1 or NFKBIA gene polymorphisms and environmental carcinogens appears related to an increased risk of oral cancer. More importantly, the genetic polymorphism of NFKBIA -519 might be a predictive factor for the distal metastasis of OSCC in Taiwanese.

  15. Increased Tumor Necrosis Factor (TNF)-α and Its Promoter Polymorphisms Correlate with Disease Progression and Higher Susceptibility towards Vitiligo

    Science.gov (United States)

    Laddha, Naresh C.; Dwivedi, Mitesh; Begum, Rasheedunnisa

    2012-01-01

    Abstract Tumor Necrosis Factor (TNF)-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes advocates

  16. The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

    Science.gov (United States)

    Azeredo, Lucas A de; De Nardi, Tatiana; Levandowski, Mateus L; Tractenberg, Saulo G; Kommers-Molina, Julia; Wieck, Andrea; Irigaray, Tatiana Q; Silva, Irênio G da; Grassi-Oliveira, Rodrigo

    2017-01-01

    Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

  17. The brain-derived neurotrophic factor (BDNF gene Val66Met polymorphism affects memory performance in older adults

    Directory of Open Access Journals (Sweden)

    Lucas A. de Azeredo

    Full Text Available Objective: Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Methods: Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR, delayed verbal recall (DVR, and memory retention rate. Results: BDNF Met allele carriers had lower DVR scores (p = 0.004 and a decline in memory retention (p = 0.017 when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088. Conclusion: These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

  18. The rs4285184 polymorphism of the MGAT1 gene as a risk factor for obesity in the Mexican population.

    Science.gov (United States)

    Tapia-Rivera, José C; Baltazar-Rodríguez, Luz M; Cárdenas-Rojas, Martha I; Álvarez, Alan; Bustos-Saldaña, Rafael; Delgado-Enciso, Iván; Valdez-Velázquez, Laura L; Guzmán-Esquivel, José; Ramírez-Flores, Mario

    2017-02-23

    Obesity is a factor that contributes to the morbidity of certain diseases and to worldwide mortality. MGAT1 is a glycosyltransferase involved in the synthesis of protein-bound and lipid-bound oligosaccharides and its polymorphisms are possibly involved in the etiology of obesity. We investigated the association of the rs4285184 polymorphism of the MGAT1 gene with obesity in adults in the State of Colima, Mexico. A case-control study was conducted that included 244 subjects. All of them were grouped according to their percentage of body fat, determined through bioelectrical impedance, and they were genotyped for the rs4285184 polymorphism of the MGAT1 gene through PCR-RFLP. The results were analyzed for their association with the percentage of body fat. The G allele had a frequency of 49.19 and 38.75% for the cases and controls, respectively (P=.020) (OR 1.53; 95% CI 1.068-2.193). The frequency of the A/G+G/G genotype was 75% in the obese patients, which was significantly higher compared with the 57.5% of the control group (P=.004) (OR 2.217; 95% CI 1.287-3.821). The presence of the rs4285184 polymorphism of the MGAT1 gene increased the risk for developing body fat associated with obesity in the Mexican population. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  19. A Polymorphism in Hepatocyte Nuclear Factor 1 Alpha, rs7310409, Is Associated with Left Main Coronary Artery Disease

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    Rui Liu

    2014-01-01

    Full Text Available Coronary artery disease is the leading cause of mortality and morbidity in the world. Left main coronary artery disease (LMCAD is a particularly severe phenotypic form of CAD and has a genetic basis. We hypothesized that some inflammation- and hyperhomocysteinemia-related gene polymorphisms may contribute to LMCAD susceptibility in a Chinese population. We studied the association between polymorphisms in the genes hepatocyte nuclear factor 1 alpha (HNF1A; rs7310409, G/A, C-reactive protein (rs1800947 and rs3093059 T/C, methylenetetrahydrofolate reductase (rs1801133, C/T, and methylenetetrahydrofolate dehydrogenase (rs1076991, A/G in 402 LMCAD and 804 more peripheral CAD patients in a Chinese population. Genotyping was performed using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. When the HNF1A rs7310409 GG homozygote genotype was used as the reference group, both the individual, GA and AA, and combined GA/AA genotypes were associated with an increased risk of LMCAD. This single nucleotide polymorphism (rs7310409 is strongly associated with plasma CRP levels. In conclusion, the present study provides evidence that the HNF1A rs7310409 G/A functional polymorphism may contribute to the risk of LMCAD.

  20. Interplay between estrogen receptor and AKT in estradiol-induced alternative splicing.

    Science.gov (United States)

    Bhat-Nakshatri, Poornima; Song, Eun-Kyung; Collins, Nikail R; Uversky, Vladimir N; Dunker, A Keith; O'Malley, Bert W; Geistlinger, Tim R; Carroll, Jason S; Brown, Myles; Nakshatri, Harikrishna

    2013-06-11

    Alternative splicing is critical for generating complex proteomes in response to extracellular signals. Nuclear receptors including estrogen receptor alpha (ERα) and their ligands promote alternative splicing. The endogenous targets of ERα:estradiol (E2)-mediated alternative splicing and the influence of extracellular kinases that phosphorylate ERα on E2-induced splicing are unknown. MCF-7 and its anti-estrogen derivatives were used for the majority of the assays. CD44 mini gene was used to measure the effect of E2 and AKT on alternative splicing. ExonHit array analysis was performed to identify E2 and AKT-regulated endogenous alternatively spliced apoptosis-related genes. Quantitative reverse transcription polymerase chain reaction was performed to verify alternative splicing. ERα binding to alternatively spliced genes was verified by chromatin immunoprecipitation assay. Bromodeoxyuridine incorporation-ELISA and Annexin V labeling assays were done to measure cell proliferation and apoptosis, respectively. We identified the targets of E2-induced alternative splicing and deconstructed some of the mechanisms surrounding E2-induced splicing by combining splice array with ERα cistrome and gene expression array. E2-induced alternatively spliced genes fall into at least two subgroups: coupled to E2-regulated transcription and ERα binding to the gene without an effect on rate of transcription. Further, AKT, which phosphorylates both ERα and splicing factors, influenced ERα:E2 dependent splicing in a gene-specific manner. Genes that are alternatively spliced include FAS/CD95, FGFR2, and AXIN-1. E2 increased the expression of FGFR2 C1 isoform but reduced C3 isoform at mRNA level. E2-induced alternative splicing of FAS and FGFR2 in MCF-7 cells correlated with resistance to FAS activation-induced apoptosis and response to keratinocyte growth factor (KGF), respectively. Resistance of MCF-7 breast cancer cells to the anti-estrogen tamoxifen was associated with ER

  1. TP53 genetic polymorphisms, interactions with lifestyle factors and lung cancer risk: a case control study in a Chinese population

    OpenAIRE

    Li, Yanli; Chang, Shen-Chih; Niu, Rungui; Liu, Li; Crabtree-Ide, Christina R; Zhao, Baoxing; Shi, Jianping; Han, Xiaoyou; Li, Jiawei; Su, Jia; Cai, Lin; Yu, Shunzhang; Zhang, Zuo-Feng; Mu, Lina

    2013-01-01

    Abstract Background A pathway-based genotyping analysis suggested rs2078486 was a novel TP53 SNP, but very few studies replicate this association. TP53 rs1042522 is the most commonly studied SNP, but very few studies examined its potential interaction with environmental factors in relation to lung cancer risk. This study aims to examine associations between two TP53 single-nucleotide polymorphisms (SNPs) (rs2078486, rs1042522), their potential interac...

  2. Brain-derived neurotrophic factor Val66Met polymorphism and hippocampal activation during episodic encoding and retrieval tasks

    OpenAIRE

    Dennis, Nancy A.; Cabeza, Roberto; Need, Anna C.; Waters-Metenier, Sheena; Goldstein, David B.; LaBar, Kevin S.

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin which has been shown to regulate cell survival and proliferation, as well as synaptic growth and hippocampal long-term potentiation. A naturally occurring single nucleotide polymorphism in the human BDNF gene (val66met) has been associated with altered intercellular trafficking and regulated secretion of BDNF in met compared to val carriers. Additionally, previous studies have found a relationship between the BDNF val66met genotype an...

  3. Effects of secondary structure on pre-mRNA splicing: hairpins sequestering the 5' but not the 3' splice site inhibit intron processing in Nicotiana plumbaginifolia.

    Science.gov (United States)

    Liu, H X; Goodall, G J; Kole, R; Filipowicz, W

    1995-01-16

    We have performed a systematic study of the effect of artificial hairpins on pre-mRNA splicing in protoplasts of a dicot plant, Nicotiana plumbaginifolia. Hairpins with a potential to form 18 or 24 bp stems strongly inhibit splicing when they sequester the 5' splice site or are placed in the middle of short introns. However, similar 24 bp hairpins sequestering the 3' splice site do not prevent this site from being used as an acceptor. Utilization of the stem-located 3' site requires that the base of the stem is separated from the upstream 5' splice site by a minimum of approximately 45 nucleotides and that another 'helper' 3' splice site is present downstream of the stem. The results indicate that the spliceosome or factors associated with it may have a potential to unfold secondary structure present in the downstream portion of the intron, prior to or at the step of the 3' splice site selection. The finding that the helper 3' site is required for utilization of the stem-located acceptor confirms and extends previous observations, obtained with HeLa cell in vitro splicing systems, indicating that the 3' splice site may be recognized at least twice during spliceosome assembly.

  4. U2AF1 mutations alter splice site recognition in hematological malignancies.

    Science.gov (United States)

    Ilagan, Janine O; Ramakrishnan, Aravind; Hayes, Brian; Murphy, Michele E; Zebari, Ahmad S; Bradley, Philip; Bradley, Robert K

    2015-01-01

    Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3' splice site recognition factor U2AF1 alter its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3' splice site motif in patients, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1's zinc finger domains. © 2015 Ilagan et al.; Published by Cold Spring Harbor Laboratory Press.

  5. [Relationship between Ghrelin polymorphism and serum lipoprotein levels in Han Chinese with or without coronary heart disease risk factors].

    Science.gov (United States)

    Xie, Xuan; Zhang, Jing; Wang, Yu-huan; Wang, Jun-hong; Zhang, Chun-hong; Ni, Hong-yan; Yuan, Xiao-hong

    2008-04-01

    To investigate the relationship between polymorphism of Ghrelin gene and serum levels of lipoprotein in Han Chinese with or without coronary heart disease (CHD) risk factors. PCR restriction fragment length polymorphism assay was used to detect the distribution of genotypes of Ghrelin gene in 225 Han Chinese (40 to 69 years-old) with CHD risk factors, 78 subjects without CHD risk factors served as normal controls. Serum levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) and very low-density lipoprotein (VLDL) were measured to analyze the relationship with the polymorphism of Ghrelin gene. Ghrelin genotype frequencies of AA, AG, GG (0.975, 0.025, 0.00 in control group and 0.956, 0.040, 0.004 in the high-risk group, all P > 0.05) as well as the allele frequencies of A, G (0.987, 0.013 in control group and 0.976, 0.024 in the high-risk group, all P > 0.05) were similar between the groups. HDL-C levels of the Arg/Gln carriers were significantly lower than those of Arg/Arg carriers in control group and in the high-risk group (all P < 0.05). Arg/Gln carriers were associated lower HDL-C levels in Han Chinese.

  6. Transforming growth factor beta receptor II polymorphisms are associated with Kawasaki disease

    Directory of Open Access Journals (Sweden)

    Yu Mi Choi

    2012-01-01

    Full Text Available Purpose : Transforming growth factor beta receptor 2 (TGFBR2 is a tumor suppressor gene that plays a role in the differentiation of striated cells and remodeling of coronary arteries. Single nucleotide polymorphisms (SNPs of this gene are associated with Marfan syndrome and sudden death in patients with coronary artery disease. Cardiovascular remodeling and T cell activation of TGFBR2 gene suggest that the TGFBR2 gene SNPs are related to the pathogenesis of Kawasaki disease (KD and coronary artery lesion (CAL. Methods : The subjects were 105 patients with KD and 500 healthy adults as controls. Mean age of KD group was 32 months age and 26.6% of those had CAL. We selected TGFBR2 gene SNPs from serum and performed direct sequencing. Results : The sequences of the eleven SNPs in the TGFBR2 gene were compared between the KD group and controls. Three SNPs (rs1495592, rs6550004, rs795430 were associated with development of KD (P=0.019, P=0.026, P=0.016, respectively. One SNP (rs1495592 was associated with CAL in KD group (P=0.022. Conclusion : Eleven SNPs in TGFBR2 gene were identified at that time the genome wide association. But, with the change of the data base, only six SNPs remained associated with the TGFBR2 gene. One of the six SNPs (rs6550004 was associated with development of KD. One SNP associated with CAL (rs1495592 was disassociated from the TGFBR2 gene. The other five SNPs were not functionally identified, but these SNPs are notable because the data base is changing. Further studies involving larger group of patients with KD are needed.

  7. Abnormalities in Alternative Splicing of Apoptotic Genes and Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Zodwa Dlamini

    2015-11-01

    Full Text Available Apoptosis is required for normal heart development in the embryo, but has also been shown to be an important factor in the occurrence of heart disease. Alternative splicing of apoptotic genes is currently emerging as a diagnostic and therapeutic target for heart disease. This review addresses the involvement of abnormalities in alternative splicing of apoptotic genes in cardiac disorders including cardiomyopathy, myocardial ischemia and heart failure. Many pro-apoptotic members of the Bcl-2 family have alternatively spliced isoforms that lack important active domains. These isoforms can play a negative regulatory role by binding to and inhibiting the pro-apoptotic forms. Alternative splicing is observed to be increased in various cardiovascular diseases with the level of alternate transcripts increasing elevated in diseased hearts compared to healthy subjects. In many cases these isoforms appear to be the underlying cause of the disease, while in others they may be induced in response to cardiovascular pathologies. Regardless of this, the detection of alternate splicing events in the heart can serve as useful diagnostic or prognostic tools, while those splicing events that seem to play a causative role in cardiovascular disease make attractive future drug targets.

  8. Association of polymorphisms in virulence factor of Helicobacter pylori and gastroduodenal diseases in South Korea.

    Science.gov (United States)

    Kim, Ji Yeon; Kim, Nayoung; Nam, Ryoung Hee; Suh, Ji Hyung; Chang, Hyun; Lee, Jung Won; Kim, Young Sun; Kim, Jung Mogg; Choi, Jae Won; Park, Jung Geun; Lee, Yeon Suk; Lee, Dong Ho; Jung, Hyun Chae

    2014-05-01

    Clinical outcomes of Helicobacter pylori (HP) infection have been shown to be dependent on the variability of virulence factors. The aim of this study was to evaluate the prevalence of each virulence factor and the association between polymorphisms of the virulence factors of HP, and the clinical outcome of gastroduodenal diseases in South Korea. Four hundred one HP colonies were analyzed (75 colonies from 45 controls; 71 colonies from 39 benign gastric ulcer [BGU] patients; 102 colonies from 54 duodenal ulcer [DU] patients; 121 colonies from 77 stomach cancer patients; and 32 colonies from 25 dysplasia patients). Polymerase chain reaction amplifications for vacA, cagA, iceA, oipA, and dupA were performed using DNA extract from HP isolates cultured from mucosal biopsy specimens. dupA was regarded as positive when all of jph0718, jph0719, and dupA were positive. Most colonies were composed of vacA s1 (100.0%), i1 (100.0%) and m1 (92.9%), cagA-positive (87.2%), iceA1 (95.8%), oipA-positive (91.2%), and dupA-negative (52.0%) genotypes. dupA was more frequently expressed in BGU (81.3%), DU (74.7%), and dysplasia (41.7%) than control (16.7%) (P dupA-positive HP showed an increased risk of BGU (odds ratio 33.06, 95% confidence interval 11.91-91.79) and DU (odds ratio 15.60, 95% confidence interval 6.49-37.49). HP infection in South Koreans appears to be closely related to highly virulent strains (vacA s1/i1/m1, cagA(+), iceA1(+), and oipA(+)), except dupA. dupA has an intimate association with the development of peptic ulcer diseases. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  9. Interleukin-6 and tumor necrosis factor-alpha gene polymorphisms in chronic idiopathic urticaria.

    Science.gov (United States)

    Tavakol, M; Amirzargar, A A; Movahedi, M; Aryan, Z; Bidoki, A Z; Gharagozlou, M; Aghamohammadi, A; Nabavi, M; Ahmadvand, A; Behniafard, N; Heidari, K; Soltani, S; Rezaei, N

    2014-01-01

    This study was performed to evaluate association of gene polymorphisms among proinflammatory cytokines and susceptibility to chronic idiopathic urticaria (CIU). Ninety patients with prolonged urticaria more than 6 weeks were included as case group. Single nucleotide polymorphisms (SNPs) of IL-6 (G/C -174, G/A nt565) and TNF-α (G/A -308, G/A -238) were evaluated, using polymerase chain reaction (PCR); and the results were compared to the control group. G allele was significantly higher in the patients at locus of -238 of promoter of TNF-α gene (p<0.001). Frequency of following genotypes were significantly lower in patients with CIU, compared to controls: AG at -308 and GA at -238 of TNF-α gene (p<0.05 and p<0.001, respectively), CG at -174 and GG at +565 of IL-6 gene (p<0.05). Additionally, following genotypes were more common among patients with CIU: GG at -308 and -238 of TNF-α gene (p<0.05 and p<0.001, respectively), GG at -174 and GA at +565 of IL-6 gene (p<0.05). Pro-inflammatory cytokine gene polymorphisms can affect susceptibility to CIU. TNF-α promoter polymorphisms as well as IL-6 gene polymorphisms are associated with CIU. Copyright © 2013 SEICAP. Published by Elsevier Espana. All rights reserved.

  10. Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence.

    Science.gov (United States)

    Sundquist, Kristina; Wang, Xiao; Svensson, Peter J; Sundquist, Jan; Hedelius, Anna; Larsson Lönn, Sara; Zöller, Bengt; Memon, Ashfaque A

    2015-11-25

    Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmö Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5-3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3-2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent.

  11. Effect of Complement Factor B Gene Polymorphisms on Age-Related Macular Degeneration in North-East of Iran Population

    Directory of Open Access Journals (Sweden)

    N. Roshani Pour

    2017-09-01

    Full Text Available Aims: Age-related macular degeneration (AMD is the most prevalent cause of irreversible blindness and debilitating in old stages, in developed and developing countries that engage the central part of the retina or macula. The aim of this study was to evaluate the relationship of the rs4151667 position of the complement factor B gene polymorphism with AMD (dry type with geographic atrophy phenotype in the North East of Iran population. ­Materials & Methods:­ In this descriptive cross-sectional study in 2015-2016, 44 AMD patients (dry type with geographic atrophy phenotype were randomly selected from Gonabad City, Iran, health centers as the patient group. 50 healthy individuals from the same society that have no relative relations with each other or the patients, but were adapted by age and sex to the patient group, were selected as the control group. The ­­polymorphism of rs4151667 (c.26T>A­ position of the complement factor B gene was determined for all samples by Restriction Fragment Length Polymorphism (RFLP. Data was analyzed the Chi-square test in 2x2.Contingency software. Findings: The frequency of TT genotype in AMD patients (95.5% was significantly (p=0.048 more than the control group (88.0%, but the frequency of AT genotype in AMD patients (4.5% was significantly (p=0.025 less than the control group (12.0%. Conclusion: The polymorphism of rs4151667 (c.26T>A position of complement factor B is effective on the development of AMD in North East of Iran population.

  12. Handbook of knotting and splicing

    CERN Document Server

    Hasluck, Paul N

    2005-01-01

    Clearly written and amply illustrated with 208 figures, this classic guide ranges from simple and useful knots to complex varieties. Additional topics include rope splicing, working cordage, hammock making, more.

  13. Genome-wide analysis of SRSF10-regulated alternative splicing by deep sequencing of chicken transcriptome

    Directory of Open Access Journals (Sweden)

    Xuexia Zhou

    2014-12-01

    Full Text Available Splicing factor SRSF10 is known to function as a sequence-specific splicing activator that is capable of regulating alternative splicing both in vitro and in vivo. We recently used an RNA-seq approach coupled with bioinformatics analysis to identify the extensive splicing network regulated by SRSF10 in chicken cells. We found that SRSF10 promoted both exon inclusion and exclusion. Functionally, many of the SRSF10-verified alternative exons are linked to pathways of response to external stimulus. Here we describe in detail the experimental design, bioinformatics analysis and GO/pathway enrichment analysis of SRSF10-regulated genes to correspond with our data in the Gene Expression Omnibus with accession number GSE53354. Our data thus provide a resource for studying regulation of alternative splicing in vivo that underlines biological functions of splicing regulatory proteins in cells.

  14. An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36

    Directory of Open Access Journals (Sweden)

    Stehouwer Coen DA

    2005-06-01

    Full Text Available Abstract Objective To investigate whether IGF-I promoter polymorphism was associated with birth weight and risk factors for cardiovascular disease (CVD and type 2 diabetes (T2DM, and whether the birth weight – risk factor relationship was the same for each genotype. Design and participants 264 subjects (mean age 36 years had data available on birth weight, IGF-I promoter polymorphism genotype, CVD and T2DM risk factors. Student's t-test and regression analyses were applied to analyse differences in birth weight and differences in the birth weight – risk factors relationship between the genotypes. Results Male variant carriers (VCs of the IGF-I promoter polymorphism had a 0.2 kg lower birth weight than men with the wild type allele (p = 0.009. Of the risk factors for CVD and T2DM, solely LDL concentration was associated with the genotype for the polymorphism. Most birth weight – risk factor relationships were stronger in the VC subjects; among others the birth weight – systolic blood pressure relationship: 1 kg lower birth weight was related to an 8.0 mmHg higher systolic blood pressure Conclusion The polymorphism in the promoter region of the IGF-I gene is related to birth weight in men only, and to LDL concentration only. Furthermore, the genotype for this polymorphism modified the relationships between birth weight and the risk factors, especially for systolic and diastolic blood pressure.

  15. A genetic association study between growth differentiation factor 5 (GDF 5 polymorphism and knee osteoarthritis in Thai population

    Directory of Open Access Journals (Sweden)

    Sura Thanyachai

    2011-09-01

    Full Text Available Abstract Objective Osteoarthritis (OA is a multi-factorial disease and genetic factor is one of the important etiologic risk factors. Various genetic polymorphisms have been elucidated that they might be associated with OA. Recently, several studies have shown an association between Growth Differentiation Factor 5(GDF5 polymorphism and knee OA. However, the role of genetic predisposing factor in each ethnic group cannot be replicated to all, with conflicting data in the literatures. Therefore, the aim of this study was to investigate the association between GDF5 polymorphism and knee OA in Thai population. Materials and Methods One hundred and ninety three patients aged 54-88 years who attended Ramathibodi Hospital were enrolled. Ninety cases with knee OA according to American College of Rheumatology criteria and one hundred and three cases in control group gave informed consent. Blood sample (5 ml were collected for identification of GDF5 (rs143383 single nucleotide polymorphism by PCR/RFLP according to a standard protocol. This study protocol was approved by the Ethics Committee on human experimentation of Ramathibodi Hospital Faculty of Medicine, Mahidol University. Odds ratios (OR and 95% confidence intervals were calculated for the risk of knee OA by genotype (TT, TC and CC and allele (T/C analyses. Results The baseline characteristics between two groups including job, smoking and activity were not different, except age and BMI. The entire cases and controls were in Hardy-Weinberg equilibrium (p > 0.05. The OA knee group (n = 90 had genotypic figure which has shown by TT 42.2% (n = 38, TC 45.6% (n = 41 and CC 12% (n = 11, whereas the control group (n = 103 revealed TT 32% (n = 33, TC 45.6% (n = 47, and CC 22.3% (n = 23, respectively. Genotypic TT increased risk of knee OA as compared to CC [OR = 2.41 (P = 0.04, 95%CI = 1.02-5.67]. In the allele analysis, the T allele was found to be significantly associated with knee OA [OR = 1.53 (P = 0

  16. Active Transforming Growth Factor-beta2 in the Aqueous Humor of Posterior Polymorphous Corneal Dystrophy Patients

    Czech Academy of Sciences Publication Activity Database

    Stádníková, A.; Ďuďáková, L.; Skalická, P.; Valenta, Zdeněk; Filipec, M.; Jirsová, K.

    2017-01-01

    Roč. 12, č. 4 (2017), č. článku e0175509. E-ISSN 1932-6203 Grant - others:GA ČR(CZ) GA17-12355S; GA MŠk(CZ) 7F14156 Institutional support: RVO:67985807 Keywords : transforming growth factor-beta2 * posterior polymorphous corneal dystrophy * corneal endothelial cells * general linear mixed-effect modelling * restricted maximum likelihood estimation Subject RIV: BB - Applied Statistics, Operational Research OBOR OECD: Statistics and probability Impact factor: 2.806, year: 2016

  17. Transcription Factor KLF5 Binds a Cyclin E1 Polymorphic Intronic Enhancer to Confer Increased Bladder Cancer Risk

    Science.gov (United States)

    Pattison, Jillian M.; Posternak, Valeriya; Cole, Michael D.

    2016-01-01

    It is well established that environmental toxins, such as exposure to arsenic, are risk factors in the development of urinary bladder cancer, yet recent genome-wide association studies (GWAS) provide compelling evidence that there is a strong genetic component associated with disease predisposition. A single nucleotide polymorphism (SNP), rs8102137, was identified on chromosome 19q12, residing 6 kb upstream of the important cell cycle regulator and proto-oncogene, Cyclin E1 (CCNE1). However, the functional role of this variant in bladder cancer predisposition has been unclear since it lies within a non-coding region of the genome. Here, it is demonstrated that bladder cancer cells heterozygous for this SNP exhibit biased allelic expression of CCNE1 with 1.5-fold more transcription occurring from the risk allele. Furthermore, using chromatin immunoprecipitation assays, a novel enhancer element was identified within the first intron of CCNE1 that binds Kruppel-like Factor 5 (KLF5), a known transcriptional activator in bladder cancer. Moreover, the data reveal that the presence of rs200996365, a SNP in high linkage disequilibrium with rs8102137 residing in the center of a KLF5 motif, alters KLF5 binding to this genomic region. Through luciferase assays and CRISPR-Cas9 genome editing, a novel polymorphic intronic regulatory element controlling CCNE1 transcription is characterized. These studies uncover how a cancer-associated polymorphism mechanistically contributes to an increased predisposition for bladder cancer development. Implications A polymorphic KLF5 binding site near the CCNE1 gene explains genetic risk identified through genome wide association studies. PMID:27514407

  18. Evidence of associations between brain-derived neurotrophic factor (BDNF serum levels and gene polymorphisms with tinnitus

    Directory of Open Access Journals (Sweden)

    Aysun Coskunoglu

    2017-01-01

    Full Text Available Background: Brain-derived neurotrophic factor (BDNF gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. Materials and Methods: In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. Results: Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. Conclusions: This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results.

  19. Evidence of associations between brain-derived neurotrophic factor (BDNF) serum levels and gene polymorphisms with tinnitus.

    Science.gov (United States)

    Coskunoglu, Aysun; Orenay-Boyacioglu, Seda; Deveci, Artuner; Bayam, Mustafa; Onur, Ece; Onan, Arzu; Cam, Fethi S

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA) samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results.

  20. Unraveling 14-3-3 proteins in C4 panicoids with emphasis on model plant Setaria italica reveals phosphorylation-dependent subcellular localization of RS splicing factor.

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    Karunesh Kumar

    Full Text Available 14-3-3 proteins are a large multigenic family of regulatory proteins ubiquitously found in eukaryotes. In plants, 14-3-3 proteins are reported to play significant role in both development and response to stress stimuli. Therefore, considering their importance, genome-wide analyses have been performed in many plants including Arabidopsis, rice and soybean. But, till date, no comprehensive investigation has been conducted in any C4 panicoid crops. In view of this, the present study was performed to identify 8, 5 and 26 potential 14-3-3 gene family members in foxtail millet (Si14-3-3, sorghum (Sb14-3-3 and maize (Zm14-3-3, respectively. In silico characterization revealed large variations in their gene structures; segmental and tandem duplications have played a major role in expansion of these genes in foxtail millet and maize. Gene ontology annotation showed the participation of 14-3-3 proteins in diverse biological processes and molecular functions, and in silico expression profiling indicated their higher expression in all the investigated tissues. Comparative mapping was performed to derive the orthologous relationships between 14-3-3 genes of foxtail millet and other Poaceae members, which showed a higher, as well as similar percentage of orthology among these crops. Expression profiling of Si14-3-3 genes during different time-points of abiotic stress and hormonal treatments showed a differential expression pattern of these genes, and sub-cellular localization studies revealed the site of action of Si14-3-3 proteins within the cells. Further downstream characterization indicated the interaction of Si14-3-3 with a nucleocytoplasmic shuttling phosphoprotein (SiRSZ21A in a phosphorylation-dependent manner, and this demonstrates that Si14-3-3 might regulate the splicing events by binding with phosphorylated SiRSZ21A. Taken together, the present study is a comprehensive analysis of 14-3-3 gene family members in foxtail millet, sorghum and maize

  1. Unraveling 14-3-3 proteins in C4 panicoids with emphasis on model plant Setaria italica reveals phosphorylation-dependent subcellular localization of RS splicing factor.

    Science.gov (United States)

    Kumar, Karunesh; Muthamilarasan, Mehanathan; Bonthala, Venkata Suresh; Roy, Riti; Prasad, Manoj

    2015-01-01

    14-3-3 proteins are a large multigenic family of regulatory proteins ubiquitously found in eukaryotes. In plants, 14-3-3 proteins are reported to play significant role in both development and response to stress stimuli. Therefore, considering their importance, genome-wide analyses have been performed in many plants including Arabidopsis, rice and soybean. But, till date, no comprehensive investigation has been conducted in any C4 panicoid crops. In view of this, the present study was performed to identify 8, 5 and 26 potential 14-3-3 gene family members in foxtail millet (Si14-3-3), sorghum (Sb14-3-3) and maize (Zm14-3-3), respectively. In silico characterization revealed large variations in their gene structures; segmental and tandem duplications have played a major role in expansion of these genes in foxtail millet and maize. Gene ontology annotation showed the participation of 14-3-3 proteins in diverse biological processes and molecular functions, and in silico expression profiling indicated their higher expression in all the investigated tissues. Comparative mapping was performed to derive the orthologous relationships between 14-3-3 genes of foxtail millet and other Poaceae members, which showed a higher, as well as similar percentage of orthology among these crops. Expression profiling of Si14-3-3 genes during different time-points of abiotic stress and hormonal treatments showed a differential expression pattern of these genes, and sub-cellular localization studies revealed the site of action of Si14-3-3 proteins within the cells. Further downstream characterization indicated the interaction of Si14-3-3 with a nucleocytoplasmic shuttling phosphoprotein (SiRSZ21A) in a phosphorylation-dependent manner, and this demonstrates that Si14-3-3 might regulate the splicing events by binding with phosphorylated SiRSZ21A. Taken together, the present study is a comprehensive analysis of 14-3-3 gene family members in foxtail millet, sorghum and maize, which provides

  2. Evaluation of insulin-like growth factor-I gene polymorphism in ...

    African Journals Online (AJOL)

    This study aimed to detect the genetic polymorphism of IGF-1 in different Egyptian sheep and goat breeds. The amplified fragments at 320-bp were digested with HaeIII endonuclease and the results show the presence of three different genotypes: CC (15.71%), CG (29.29%) and GG (55.0%). The nucleotide sequence ...

  3. The T309G MDM2 gene polymorphism is a novel risk factor for proliferative vitreoretinopathy

    NARCIS (Netherlands)

    S. Pastor-Idoate (Salvador); I. Rodriguez-Hernández (Irene); J. Rojas (Jimena); I. Fernandez (Itziar); M.T. García-Gutierrez (María Teresa); J.M. Ruiz-Moreno (Jose María); A. Rocha-Sousa (Amandio); Y. Ramkissoon (Yashin); S. Harsum (Steven); R.E. MacLaren (Robert ); D. Charteris (David); J.C. Vanmeurs (Jan C.); R. González-Sarmiento (Rogelio); J.C. Pastor (Jose Carlos)

    2013-01-01

    textabstractProliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism

  4. Association of the macrophage activating factor (MAF) precursor activity with polymorphism in vitamin D-binding protein.

    Science.gov (United States)

    Nagasawa, Hideko; Sasaki, Hideyuki; Uto, Yoshihiro; Kubo, Shinichi; Hori, Hitoshi

    2004-01-01

    Serum vitamin D-binding protein (Gc protein or DBP) is a highly expressed polymorphic protein, which is a precursor of the inflammation-primed macrophage activating factor, GcMAF, by a cascade of carbohydrate processing reactions. In order to elucidate the relationship between Gc polymorphism and GcMAF precursor activity, we estimated the phagocytic ability of three homotypes of Gc protein, Gc1F-1F, Gc1S-1S and Gc2-2, through processing of their carbohydrate moiety. We performed Gc typing of human serum samples by isoelectric focusing (IEF). Gc protein from human serum was purified by affinity chromatography with 25-hydroxyvitamin D3-sepharose. A phagocytosis assay of Gc proteins, modified using beta-glycosidase and sialidase, was carried out. The Gc1F-1F phenotype was revealed to possess Galbeta1-4GalNAc linkage by the analysis of GcMAF precursor activity using beta1-4 linkage-specific galactosidase from jack bean. The GcMAF precursor activity of the Gc1F-1F phenotype was highest among three Gc homotypes. The Gc polymorphism and carbohydrate diversity of Gc protein are significant for its pleiotropic effects.

  5. The nematode eukaryotic translation initiation factor 4E/G complex works with a trans-spliced leader stem-loop to enable efficient translation of trimethylguanosine-capped RNAs.

    Science.gov (United States)

    Wallace, Adam; Filbin, Megan E; Veo, Bethany; McFarland, Craig; Stepinski, Janusz; Jankowska-Anyszka, Marzena; Darzynkiewicz, Edward; Davis, Richard E

    2010-04-01

    Eukaryotic mRNA translation begins with recruitment of the 40S ribosome complex to the mRNA 5' end through the eIF4F initiation complex binding to the 5' m(7)G-mRNA cap. Spliced leader (SL) RNA trans splicing adds a trimethylguanosine (TMG) cap and a sequence, the SL, to the 5' end of mRNAs. Efficient translation of TMG-capped mRNAs in nematodes requires the SL sequence. Here we define a core set of nucleotides and a stem-loop within the 22-nucleotide nematode SL that stimulate translation of mRNAs with a TMG cap. The structure and core nucleotides are conserved in other nematode SLs and correspond to regions of SL1 required for early Caenorhabditis elegans development. These SL elements do not facilitate translation of m(7)G-capped RNAs in nematodes or TMG-capped mRNAs in mammalian or plant translation systems. Similar stem-loop structures in phylogenetically diverse SLs are predicted. We show that the nematode eukaryotic translation initiation factor 4E/G (eIF4E/G) complex enables efficient translation of the TMG-SL RNAs in diverse in vitro translation systems. TMG-capped mRNA translation is determined by eIF4E/G interaction with the cap and the SL RNA, although the SL does not increase the affinity of eIF4E/G for capped RNA. These results suggest that the mRNA 5' untranslated region (UTR) can play a positive and novel role in translation initiation through interaction with the eIF4E/G complex in nematodes and raise the issue of whether eIF4E/G-RNA interactions play a role in the translation of other eukaryotic mRNAs.

  6. The Nematode Eukaryotic Translation Initiation Factor 4E/G Complex Works with a trans-Spliced Leader Stem-Loop To Enable Efficient Translation of Trimethylguanosine-Capped RNAs ▿ †

    Science.gov (United States)

    Wallace, Adam; Filbin, Megan E.; Veo, Bethany; McFarland, Craig; Stepinski, Janusz; Jankowska-Anyszka, Marzena; Darzynkiewicz, Edward; Davis, Richard E.

    2010-01-01

    Eukaryotic mRNA translation begins with recruitment of the 40S ribosome complex to the mRNA 5′ end through the eIF4F initiation complex binding to the 5′ m7G-mRNA cap. Spliced leader (SL) RNA trans splicing adds a trimethylguanosine (TMG) cap and a sequence, the SL, to the 5′ end of mRNAs. Efficient translation of TMG-capped mRNAs in nematodes requires the SL sequence. Here we define a core set of nucleotides and a stem-loop within the 22-nucleotide nematode SL that stimulate translation of mRNAs with a TMG cap. The structure and core nucleotides are conserved in other nematode SLs and correspond to regions of SL1 required for early Caenorhabditis elegans development. These SL elements do not facilitate translation of m7G-capped RNAs in nematodes or TMG-capped mRNAs in mammalian or plant translation systems. Similar stem-loop structures in phylogenetically diverse SLs are predicted. We show that the nematode eukaryotic translation initiation factor 4E/G (eIF4E/G) complex enables efficient translation of the TMG-SL RNAs in diverse in vitro translation systems. TMG-capped mRNA translation is determined by eIF4E/G interaction with the cap and the SL RNA, although the SL does not increase the affinity of eIF4E/G for capped RNA. These results suggest that the mRNA 5′ untranslated region (UTR) can play a positive and novel role in translation initiation through interaction with the eIF4E/G complex in nematodes and raise the issue of whether eIF4E/G-RNA interactions play a role in the translation of other eukaryotic mRNAs. PMID:20154140

  7. The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Muhammad Rauzan

    Full Text Available Chronic myeloid leukemia (CML treatment has been improved by tyrosine kinase inhibitors (TKIs such as imatinib mesylate (IM but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance.

  8. A case presenting concurrence of Marfan syndrome, Basedow's disease and Arg353Gln polymorphism-related factor VII deficiency.

    Science.gov (United States)

    Tanaka, Kotoko; Seino, Yoshihiko; Inokuchi, Koiti; Ohmura, Kazuko; Kobayashi, Yoshinori; Takano, Teruo

    2005-02-15

    We report the case of a 48-year-old Japanese man who suffered from Marfan syndrome with severe aortic regurgitation, mitral regurgitation and rapid atrial fibrillation, which were aggravated by hyperdynamic circulatory conditions associated with coexistent Basedow's disease. Furthermore, concurrence of Arg353Gln polymorphism-related factor VII deficiency was discovered at the preoperative assessments. Both of his two brothers suffered from Marfan syndrome; however they had no findings of Arg353Glu polymorphism-related factor VII deficiency or Basedow's disease. After normalization of thyroid function, he had successfully the operations of Bentall procedure: a composite prosthetic graft: replacement of both the ascending aorta and aortic valve, and mitral valve annuloplasty. No specific therapy such as fresh frozen plasma or factor VII replacement therapy was required. He completely returned to his business work 6 weeks after the operation. Concurrence of Marfan syndrome and factor VII deficiency induced by two-hit genomic abnormalities and furthermore Basedow's disease, which significantly compromised the pathophysiological condition of Marfan syndrome, is extremely rare.

  9. Study on association between genetic polymorphisms of haem oxygenase-1, tumour necrosis factor, cadmium exposure and malaria pathogenicity and severity

    Directory of Open Access Journals (Sweden)

    Ruangweerayut Ronnatrai

    2010-09-01

    Full Text Available Abstract Background Malaria is the most important public health problems in tropical and sub-tropical countries. Haem oxygenase (HO enzyme and the pro-inflammatory cytokine tumour necrosis factor (TNF have been proposed as one of the factors that may play significant role in pathogenicity/severity of malaria infection. HO is the enzyme of the microsomal haem degradation pathway that yields biliverdin, carbon monoxide, and iron. In this study, the association between malaria disease pathogenicity/severity and (GTn repeat polymorphism in the promoter region of the inducible HO-1 including the effect of cadmium exposure (potent inducer of HO-1 transcription as well as polymorphism of TNF were investigated. Methods Blood samples were collected from 329 cases non-severe malaria with acute uncomplicated Plasmodium falciparum malaria (UM and 80 cases with Plasmodium vivax malaria (VM, and 77 cases with severe or cerebral malaria (SM for analysis of genetic polymorphisms of HO-1 and TNF and cadmium levels. These patients consisted of 123 (25.3% Thai, 243 (50.0% Burmese and 120 (24.7% Karen who were present at Mae Sot General Hospital, Mae Sot, Tak Province, Thailand. Results The number of (GTn repeats of the HO-1 gene in all patients varied between 16 and 39 and categorized to short (S, medium (M and long (L GTn repeats. The genotype of (GTn repeat of HO-1 was found to be significantly different among the three ethnic groups of patients. Significantly higher frequency of S/L genotype was found in Burmese compared with Thai patients, while significantly lower frequencies of S/S and M/L but higher frequency of M/M genotype was observed in Burmese compared with Karen patients. No significant association between HO-1 and TNF polymorphisms including the inducing effect of cadmium and malaria pathogenicity/severity was observed. Conclusions Difference in the expression of HO-1 genotype in different ethnic groups may contribute to different severity of malaria

  10. Susceptibility to invasive meningococcal disease: polymorphism of complement system genes and Neisseria meningitidis factor H binding protein.

    Directory of Open Access Journals (Sweden)

    Declan T Bradley

    Full Text Available Neisseria meningitidis can cause severe infection in humans. Polymorphism of Complement Factor H (CFH is associated with altered risk of invasive meningococcal disease (IMD. We aimed to find whether polymorphism of other complement genes altered risk and whether variation of N. meningitidis factor H binding protein (fHBP affected the risk association.We undertook a case-control study with 309 European cases and 5,200 1958 Birth Cohort and National Blood Service cohort controls. We used additive model logistic regression, accepting P<0.05 as significant after correction for multiple testing. The effects of fHBP subfamily on the age at infection and severity of disease was tested using the independent samples median test and Student's T test. The effect of CFH polymorphism on the N. meningitidis fHBP subfamily was investigated by logistic regression and Chi squared test.Rs12085435 A in C8B was associated with odds ratio (OR of IMD (0.35 [95% CI 0.19-0.67]; P = 0.03 after correction. A CFH haplotype tagged by rs3753396 G was associated with IMD (OR 0.56 [95% CI 0.42-0.76], P = 1.6x10⁻⁴. There was no bacterial load (CtrA cycle threshold difference associated with carriage of this haplotype. Host CFH haplotype and meningococcal fHBP subfamily were not associated. Individuals infected with meningococci expressing subfamily A fHBP were younger than those with subfamily B fHBP meningococci (median 1 vs 2 years; P = 0.025.The protective CFH haplotype alters odds of IMD without affecting bacterial load for affected heterozygotes. CFH haplotype did not affect the likelihood of infecting meningococci having either fHBP subfamily. The association between C8B rs12085435 and IMD requires independent replication. The CFH association is of interest because it is independent of known functional polymorphisms in CFH. As fHBP-containing vaccines are now in use, relationships between CFH polymorphism and vaccine effectiveness and side-effects may become

  11. The determinants of alternative RNA splicing in human cells.

    Science.gov (United States)

    Ramanouskaya, Tatsiana V; Grinev, Vasily V

    2017-12-01

    Alternative splicing represents an important level of the regulation of gene function in eukaryotic organisms. It plays a critical role in virtually every biological process within an organism, including regulation of cell division and cell death, differentiation of tissues in the embryo and the adult organism, as well as in cellular response to diverse environmental factors. In turn, studies of the last decade have shown that alternative splicing itself is controlled by different mechanisms. Unfortunately, there is no clear understanding of how these diverse mechanisms, or determinants, regulate and constrain the set of alternative RNA species produced from any particular gene in every cell of the human body. Here, we provide a consolidated overview of alternative splicing determinants including RNA-protein interactions, epigenetic regulation via chromatin remodeling, coupling of transcription-to-alternative splicing, effect of secondary structures in pre-RNA, and function of the RNA quality control systems. We also extensively and critically discuss some mechanistic insights on coordinated inclusion/exclusion of exons during the formation of mature RNA molecules. We conclude that the final structure of RNA is pre-determined by a complex interplay between cis- and trans-acting factors. Altogether, currently available empirical data significantly expand our understanding of the functioning of the alternative splicing machinery of cells in normal and pathological conditions. On the other hand, there are still many blind spots that require further deep investigations.

  12. The N363S polymorphism of the glucocorticoid receptor and metabolic syndrome factors in men

    DEFF Research Database (Denmark)

    Buemann, Benjamin; Black, Eva; Holst, Claus

    2005-01-01

    with the obese men (n = 299; age, 50 +/- 7 years). The subjects were genotyped for the N363S polymorphism by polymerase chain reaction-restriction fragment length polymorphism. Body composition was measured by DXA. Glucose metabolism was evaluated by an oral glucose tolerance test, and the Matsudas index...... was calculated as a proxy for insulin sensitivity. Serum triglycerides and total and high-density lipoprotein-cholesterol were measured in the fasting state. RESULTS: Among the men with juvenile-onset obesity, carriers (n = 17) of the 363S allele had a lower whole body fat percentage, after accounting...... for differences in BMI and higher Matsudas index, compared with the noncarriers. The difference in Matsudas index lost statistical significance after the difference in body fat was accounted for. In the randomly sampled men, these variables did not relate to genotype. No relationship between carriers...

  13. Polymorphisms in the hypoxia-inducible factor 1 alpha gene in Mexican patients with preeclampsia: A case-control study

    Directory of Open Access Journals (Sweden)

    Nava-Salazar Sonia

    2011-03-01

    Full Text Available Abstract Background Although the etiology of preeclampsia is still unclear, recent work suggests that changes in circulating angiogenic factors play a key role in its pathogenesis. In the trophoblast of women with preeclampsia, hypoxia-inducible factor 1 alpha (HIF-1α is over-expressed, and induces the expression of non-angiogenic factors and inhibitors of trophoblast differentiation. This observation prompted the study of HIF-1α and its relation to preeclampsia. It has been described that the C1772T (P582S and G1790A (A588T polymorphisms of the HIF1A gene have significantly greater transcriptional activity, correlated with an increased expression of their proteins, than the wild-type sequence. In this work, we studied whether either or both HIF1A variants contribute to preeclampsia susceptibility. Results Genomic DNA was isolated from 150 preeclamptic and 105 healthy pregnant women. Exon 12 of the HIF1A gene was amplified by PCR, and the genotypes of HIF1A were determined by DNA sequencing. In preeclamptic women and controls, the frequencies of the T allele for C1772T were 4.3 vs. 4.8%, and the frequencies of the A allele for G1790A were 0.0 vs. 0.5%, respectively. No significant differences were found between groups. Conclusion The frequency of the C1772T and G1790A polymorphisms of the HIF1A gene is very low, and neither polymorphism is associated with the development of preeclampsia in the Mexican population.

  14. Single nucleotide polymorphism in Egyptian cattle insulin-like growth factor binding protein-3 gene

    Directory of Open Access Journals (Sweden)

    Othman E. Othman

    2014-12-01

    It is concluded that the IGFBP-3/HaeIII polymorphism may be utilized as a good marker for genetic differentiation between cattle animals for different body functions such as growth, metabolism, reproduction, immunity and energy balance. The nucleotide sequences of Egyptian cattle IGFBP-3 A and C alleles were submitted to GenBank with the accession numbers KF899893 and KF899894, respectively.

  15. The role of polypyrimidine tract-binding proteins and other hnRNP proteins in plant splicing regulation

    Directory of Open Access Journals (Sweden)

    Andreas eWachter

    2012-05-01

    Full Text Available Alternative precursor mRNA splicing is a widespread phenomenon in multicellular eukaryotes and represents a major means for functional expansion of the transcriptome. While several recent studies have revealed an important link between splicing regulation and fundamental biological processes in plants, many important aspects, such as the underlying splicing regulatory mechanisms, are so far not well understood. Splicing decisions are in general based on a splicing code that is determined by the dynamic interplay of splicing-controlling factors and cis-regulatory elements. Several members of the group of heterogeneous nuclear ribonucleoprotein (hnRNP proteins are well-known regulators of splicing in animals and the comparatively few reports on some of their plant homologues revealed similar functions. This also applies to polypyrimidine tract-binding proteins (PTBs, a thoroughly investigated class of hnRNP proteins with splicing regulatory functions in both animals and plants. Further examples from plants are auto- and cross-regulatory splicing circuits of glycine-rich RNA-binding proteins (GRPs and splicing enhancement by oligouridylatebinding proteins. Besides their role in defining splice site choice, hnRNP proteins are also involved in multiple other steps of nucleic acid metabolism, highlighting the functional versatility of this group of proteins in higher eukaryotes.

  16. The role of IL6 and ESR1 gene polymorphisms as immunological factors of pregnancy maintenance

    Directory of Open Access Journals (Sweden)

    Kucherenko A. M.

    2013-09-01

    Full Text Available Aim. The study is aimed at the evaluation of the association of IL6 gene -174G/C polymorphism and ESR1 gene -397C/T polymorphism with recurrent pregnancy loss (RPL pathogenesis and at the investigation of the ESR1 gene -397C/T variant regulatory significance for the IL6 gene function. Methods. A case group of 75 women with RPL history and a control group of 106 unrelated healthy women, who have given birth to at least one child conceived in natural way, were genotyped by a PCR based restriction fragment length polymorphism assay. Results. There was no significant difference in IL6 -174G/C or ESR1 -397C/T genotype and allele frequencies between the case and control groups. Combined genotype distribution analysis showed significantly (p < 0.05 lower frequency of individuals homozygous for both IL6 -174G and ESR1 -397C alleles in case group (0.026 comparing to control (0.094. Conclusions. Genotype comprising IL6 -174G and ESR1 -397C alleles in homozygous state may be considered as a genetic marker of successful pregnancy maintenance during gestation early stages.

  17. [Interaction between HLA-DRB1 gene polymorphism and environmental risk factors in the development of gestational diabetes mellitus].

    Science.gov (United States)

    Wang, Ming; Zhang, Li; Liu, Xinghui

    2014-04-01

    To explore the interactions between human leukocyte antigen (HLA) -DRB1 gene polymorphism and environmental risk factors in gestational diabetes mellitus (GDM) pathogenesis. Pregnant women who had prenatal cares in Obstetric Department, West China Second Hospital of Sichuan University were recruited from January 1(st) to December 31(st) in 2011. A prospective cohort study was conducted in the women who had a glucose challenge test (GCT) or 75 g oral glucose tolerance test (OGTT) during 24-28 gestational weeks. A total of 104 women diagnosed with GDM were randomly included in GDM group while another 103 normal women fell into the control group. The HLA-DRB1 polymorphism was detected by Polymerase Chain Reaction - Sequence Specific Primers (PCR-SSP) method in both groups. The interactions between HLA-DRB1 polymorphism and environmental risk factors were analyzed based on the simple-case-study method. (1) There were 712 pregnant women with complete perinatal information during January 1(st) to December 31(st) , 2011, among whom 175 (24.6%) women were diagnosed with GDM. A logistic regression analysis showed that advanced maternal age (OR = 1.081, 95%CI: 1.027- 1.138), imbalanced diet (OR = 3.329, 95%CI: 2.167-5.116), high body mass index (BMI ≥ 24.0 kg/m(2)) before pregnancy (OR = 1.095, 95%CI:1.008-1.190), HBsAg carrier status (OR = 3.173, 95%CI: 1.387-7.260) and family history of diabetes mellitus (DM) (OR = 1.798, 95%CI: 1.063-3.041) were risk factors of GDM. (2) There were 49 HLA-DRB1 genotypes and 51 HLA-DRB1 genotypes in GDM group and the control group, respectively. We further compared the genotypes that occurred in over 3 cases in either group and found that HLA-DRB1*12, 16 was only detected in 5 cases (5/103, 4.9%) in control group, and the difference was significant between the two groups (P = 0.029). HLA-DRB1*11, 16 and HLA-DRB1*09,09 were only detected in 4 cases (3.8%, 4/104) and 5 cases (4.8%, 5/104) in GDM group respectively, but without significant

  18. Investigating the CFH Gene Polymorphisms as a Risk Factor for Age-related Macular Degeneration in an Iranian Population.

    Science.gov (United States)

    Babanejad, Mojgan; Moein, Hamidreza; Akbari, Mohammad R; Badiei, Azadeh; Yaseri, Mehdi; Soheilian, Masoud; Najmabadi, Hossein

    2016-06-01

    Age-related macular degeneration (AMD) is a complex disorder which results in irreversible vision loss and progressive impairment of central vision. Disease susceptibility is influenced by multiple genetic and environmental factors. Single nucleotide polymorphisms (SNP) in the complement factor H gene are the most important genetic risk factors. We conducted a case-control study to investigate the association four SNPs (dbSNP ID: rs800292, rs1061170, rs2274700 and rs3753395) of CFH gene with AMD in the Iranian population. We recruited 100 AMD patients and 100 age- and sex-matched normal controls. Direct sequencing for three SNPs (rs800292, rs2274700 and rs3753395) and restriction fragment length polymorphism utilized for rs1061170. Allele and genotype frequencies of SNPs were calculated and tested for departure from Hardy-Weinberg equilibrium using the Chi-square test. An allelic and genotypic association was compared by logistic regression analysis using the SNPassoc. According to our results, the frequencies of risk allele for all SNPs (G, G, A, and C alleles of rs800292, rs2274700, rs3753395 and rs1061170, respectively) were significantly higher in AMD patients (p value prevention and treatment of AMD.

  19. Human Splicing Finder: an online bioinformatics tool to predict splicing signals

    OpenAIRE

    Desmet, Francois-Olivier; Hamroun, Dalil; Lalande, Marine; Collod-Beroud, Gwenaelle; Claustres, Mireille; Beroud, Christophe

    2009-01-01

    International audience; Thousands of mutations are identified yearly. Although many directly affect protein expression, an increasing proportion of mutations is now believed to influence mRNA splicing. They mostly affect existing splice sites, but synonymous, non-synonymous or nonsense mutations can also create or disrupt splice sites or auxiliary cis-splicing sequences. To facilitate the analysis of the different mutations, we designed Human Splicing Finder (HSF), a tool to predict the effec...

  20. Diverse alternative back-splicing and alternative splicing landscape of circular RNAs

    Science.gov (United States)

    Zhang, Xiao-Ou; Dong, Rui; Zhang, Yang; Zhang, Jia-Lin; Luo, Zheng; Zhang, Jun; Chen, Ling-Ling; Yang, Li

    2016-01-01

    Circular RNAs (circRNAs) derived from back-spliced exons have been widely identified as being co-expressed with their linear counterparts. A single gene locus can produce multiple circRNAs through alternative back-splice site selection and/or alternative splice site selection; however, a detailed map of alternative back-splicing/splicing in circRNAs is lacking. Here, with the upgraded CIRCexplorer2 pipeline, we systematically annotated different types of alternative back-splicing and alternative splicing events in circRNAs from various cell lines. Compared with their linear cognate RNAs, circRNAs exhibited distinct patterns of alternative back-splicing and alternative splicing. Alternative back-splice site selection was correlated with the competition of putative RNA pairs across introns that bracket alternative back-splice sites. In addition, all four basic types of alternative splicing that have been identified in the (linear) mRNA process were found within circRNAs, and many exons were predominantly spliced in circRNAs. Unexpectedly, thousands of previously unannotated exons were detected in circRNAs from the examined cell lines. Although these novel exons had similar splice site strength, they were much less conserved than known exons in sequences. Finally, both alternative back-splicing and circRNA-predominant alternative splicing were highly diverse among the examined cell lines. All of the identified alternative back-splicing and alternative splicing in circRNAs are available in the CIRCpedia database (http://www.picb.ac.cn/rnomics/circpedia). Collectively, the annotation of alternative back-splicing and alternative splicing in circRNAs provides a valuable resource for depicting the complexity of circRNA biogenesis and for studying the potential functions of circRNAs in different cells. PMID:27365365

  1. Effect of tension lap splice on the behavior of high strength concrete (HSC beams

    Directory of Open Access Journals (Sweden)

    Ahmed El-Azab

    2014-12-01

    Full Text Available In the recent years, many research efforts have been carried out on the bond strength between normal strength concrete (NSC and reinforcing bars spliced in tension zones in beams. Many codes gave a minimum splice length for tension and compression reinforcement as a factor of the bar diameter depending on many parameters such as concrete strength, steel yield stress, shape of bar end, shape of bar surface and also bar location. Also, codes gave another restriction about the percentage of total reinforcement to be spliced at the same time. Comparatively limited attention has been directed toward the bond between high strength concrete (HSC and reinforcing bars spliced in tension zones in beams. HSC has high modulus of elasticity, high density and long-term durability. This research presents an experimental study on the bond between high strength concrete (HSC and reinforcing bars spliced in tension zones in beams. It reports the influence of several parameters on bond in splices. The parameters covered are casting position, splice length as a factor of bar diameter, bar diameter and reinforcement ratio. The research involved tests on sixteen simply-supported beams of 1800 mm span, 200 mm width and 400 mm thickness made of HSC. In each beam, the total tensile steel bars were spliced in the constant moment zone. Crack pattern, crack propagation, cracking load, failure load and mi span deflection were recorded and analyzed to study the mentioned parameters effect.

  2. BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT.

    Science.gov (United States)

    Piras, Ignazio Stefano; Angius, Andrea; Andreani, Marco; Testi, Manuela; Lucarelli, Guido; Floris, Matteo; Marktel, Sarah; Ciceri, Fabio; La Nasa, Giorgio; Fleischhauer, Katharina; Roncarolo, Maria Grazia; Bulfone, Alessandro; Gregori, Silvia; Bacchetta, Rosa

    2014-11-01

    The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic SCT (allo-HSCT). We applied whole-genome analysis to investigate genetic variants-other than HLA class I and II-associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single-nucleotide polymorphisms (SNPs) in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong linkage disequilibrium between each other (R(2)=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P<0.00001 for BAT2 SNP rs11538264, and P<0.0001 for BAT3 SNP rs10484558), whereas the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs 2.6%, nominal P=1.15 × 10(-8); and adjusted P=0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT.

  3. Epigenetic and epistatic interactions between serotonin transporter and brain-derived neurotrophic factor genetic polymorphism: insights in depression.

    Science.gov (United States)

    Ignácio, Z M; Réus, G Z; Abelaira, H M; Quevedo, J

    2014-09-05

    Epidemiological studies have shown significant results in the interaction between the functions of brain-derived neurotrophic factor (BDNF) and 5-HT in mood disorders, such as major depressive disorder (MDD). The latest research has provided convincing evidence that gene transcription of these molecules is a target for epigenetic changes, triggered by stressful stimuli that starts in early childhood and continues throughout life, which are subsequently translated into structural and functional phenotypes culminating in depressive disorders. The short variants of 5-HTTLPR and BDNF-Met are seen as forms which are predisposed to epigenetic aberrations, which leads individuals to a susceptibility to environmental adversities, especially when subjected to stress in early life. Moreover, the polymorphic variants also feature epistatic interactions in directing the functional mechanisms elicited by stress and underlying the onset of depressive disorders. Also emphasized are works which show some mediators between stress and epigenetic changes of the 5-HTT and BDNF genes, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cAMP response element-binding protein (CREB), which is a cellular transcription factor. Both the HPA axis and CREB are also involved in epistatic interactions between polymorphic variants of 5-HTTLPR and Val66Met. This review highlights some research studying changes in the epigenetic patterns intrinsic to genes of 5-HTT and BDNF, which are related to lifelong environmental adversities, which in turn increases the risks of developing MDD. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Association Study of Tumor Necrosis Factor Receptor 1 (TNFR1 Gene Polymorphisms with Schizophrenia in the Polish Population

    Directory of Open Access Journals (Sweden)

    Renata Suchanek-Raif

    2017-01-01

    Full Text Available Schizophrenia is a devastating mental disorder with undetermined aetiology. Previous research has suggested that dysregulation of proinflammatory cytokines and their receptors plays a role in developing schizophrenia. We examined the association of the three single nucleotide polymorphisms (SNPs; rs4149576, rs4149577, and rs1860545 in the tumor necrosis factor receptor 1 (TNFR1 gene with the development and psychopathology of paranoid schizophrenia in the Polish Caucasian sample consisting of 388 patients and 657 control subjects. The psychopathology was assessed using a five-factor model of the Positive and Negative Syndrome Scale (PANSS. SNPs were genotyped using the TaqMan 5′-exonuclease allelic discrimination assay. The SNPs tested were not associated with a predisposition to paranoid schizophrenia in either the entire sample or after stratification according to gender. However, rs4149577 and rs1860545 SNPs were associated with the intensity of the PANSS excitement symptoms in men, which may contribute to the risk of violent behavior. Polymorphisms in the TNFR1 gene may have an impact on the symptomatology of schizophrenia in men.

  5. Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism is not a risk factor for hypertension in SLE nephritis.

    Science.gov (United States)

    Negi, Vir S; Devaraju, Panneer; Gulati, Reena

    2015-09-01

    SLE is a systemic autoimmune disease with high prevalence of hypertension. Around 40-75 % of SLE patients develop nephritis, a major cause of hypertension and mortality. Angiotensin-converting enzyme (ACE) maintains the blood pressure and blood volume homeostasis. An insertion/deletion (I/D) polymorphism in intron 16 of ACE gene was reported to influence the development of hypertension, nephritis, and cardiovascular diseases in different ethnic populations. Despite compelling evidence for the high prevalence of hypertension in individuals with SLE, underlying factors for its development are not well studied. With this background, we analyzed the influence of ACE insertion/deletion polymorphism on susceptibility to SLE, development of nephritis and hypertension, other clinical features and autoantibody phenotype in South Indian SLE patients. Three hundred patients with SLE and 460 age and sex similar ethnicity matched individuals were included as patients and healthy controls, respectively. The ACE gene insertion/deletion polymorphism was analyzed by PCR. Insertion (I) and deletion (D) alleles were observed to be equally distributed among patients (57 and 43 %) and controls (59 and 41 %), respectively. The mutant (D) allele did not confer significant risk for SLE (II vs. ID: p = 0.4, OR 1.15, 95 % CI 0.8-1.6; II vs. DD: p = 0.34, OR 1.22, 95 % CI 0.8-1.85). There was no association of the ACE genotype or the allele with development of lupus nephritis (II vs. ID: p = 0.19, OR 1.41, 95 % CI 0.84-2.36; II vs. DD: p = 0.41, OR 0.74, 95 % CI 0.38-1.41) or hypertension (II vs. ID: p = 0.85, OR 0.9, 95 % CI 0.43-1.8; II vs. DD: p = 0.66, OR 1.217, 95 % CI 0.5-2.8). The presence of mutant allele (D) was not found to influence any clinical features or autoantibody phenotype. The insertion/deletion polymorphism of the ACE gene is not a genetic risk factor for SLE and does not influence development of hypertension or lupus nephritis in South Indian

  6. A retrospective comparative exploratory study on two Methylentetrahydrofolate Reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients

    International Nuclear Information System (INIS)

    Blank, Susanne; Kumar, Rajiv; Ott, Katja; Rachakonda, Sivaramakrishna; Keller, Gisela; Weichert, Wilko; Lordick, Florian; Langer, Rupert; Springfeld, Christoph; Bruckner, Thomas; Becker, Karen

    2014-01-01

    Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas. 569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression). Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6 th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7 th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact. The MTHFR A1298C polymorphisms was an independent prognostic factor in patients

  7. Single Nucleotide Polymorphism in Gene Encoding Transcription Factor Prep1 Is Associated with HIV-1-Associated Dementia

    Science.gov (United States)

    van Manen, Daniëlle; Bunnik, Evelien M.; van Sighem, Ard I.; Sieberer, Margit; Boeser-Nunnink, Brigitte; de Wolf, Frank; Schuitemaker, Hanneke; Portegies, Peter; Kootstra, Neeltje A.; van 't Wout, Angélique B.

    2012-01-01

    Background Infection with HIV-1 may result in severe cognitive and motor impairment, referred to as HIV-1-associated dementia (HAD). While its prevalence has dropped significantly in the era of combination antiretroviral therapy, milder neurocognitive disorders persist with a high prevalence. To identify additional therapeutic targets for treating HIV-associated neurocognitive disorders, several candidate gene polymorphisms have been evaluated, but few have been replicated across multiple studies. Methods We here tested 7 candidate gene polymorphisms for association with HAD in a case-control study consisting of 86 HAD cases and 246 non-HAD AIDS patients as controls. Since infected monocytes and macrophages are thought to play an important role in the infection of the brain, 5 recently identified single nucleotide polymorphisms (SNPs) affecting HIV-1 replication in macrophages in vitro were also tested. Results The CCR5 wt/Δ32 genotype was only associated with HAD in individuals who developed AIDS prior to 1991, in agreement with the observed fading effect of this genotype on viral load set point. A significant difference in genotype distribution among all cases and controls irrespective of year of AIDS diagnosis was found only for a SNP in candidate gene PREP1 (p = 1.2×10−5). Prep1 has recently been identified as a transcription factor preferentially binding the −2,518 G allele in the promoter of the gene encoding MCP-1, a protein with a well established role in the etiology of HAD. Conclusion These results support previous findings suggesting an important role for MCP-1 in the onset of HIV-1-associated neurocognitive disorders. PMID:22347417

  8. Single nucleotide polymorphism in gene encoding transcription factor Prep1 is associated with HIV-1-associated dementia.

    Directory of Open Access Journals (Sweden)

    Sebastiaan M Bol

    Full Text Available BACKGROUND: Infection with HIV-1 may result in severe cognitive and motor impairment, referred to as HIV-1-associated dementia (HAD. While its prevalence has dropped significantly in the era of combination antiretroviral therapy, milder neurocognitive disorders persist with a high prevalence. To identify additional therapeutic targets for treating HIV-associated neurocognitive disorders, several candidate gene polymorphisms have been evaluated, but few have been replicated across multiple studies. METHODS: We here tested 7 candidate gene polymorphisms for association with HAD in a case-control study consisting of 86 HAD cases and 246 non-HAD AIDS patients as controls. Since infected monocytes and macrophages are thought to play an important role in the infection of the brain, 5 recently identified single nucleotide polymorphisms (SNPs affecting HIV-1 replication in macrophages in vitro were also tested. RESULTS: The CCR5 wt/Δ32 genotype was only associated with HAD in individuals who developed AIDS prior to 1991, in agreement with the observed fading effect of this genotype on viral load set point. A significant difference in genotype distribution among all cases and controls irrespective of year of AIDS diagnosis was found only for a SNP in candidate gene PREP1 (p = 1.2 × 10(-5. Prep1 has recently been identified as a transcription factor preferentially binding the -2,518 G allele in the promoter of the gene encoding MCP-1, a protein with a well established role in the etiology of HAD. CONCLUSION: These results support previous findings suggesting an important role for MCP-1 in the onset of HIV-1-associated neurocognitive disorders.

  9. Genetic polymorphisms within tumor necrosis factor gene promoter region: a role for susceptibility to ventilator-associated pneumonia.

    Science.gov (United States)

    Kotsaki, Antigoni; Raftogiannis, Maria; Routsi, Christina; Baziaka, Fotini; Kotanidou, Anastasia; Antonopoulou, Anastasia; Orfanos, Stylianos E; Katsenos, Chrisostomos; Koutoukas, Pantelis; Plachouras, Diamantis; Mandragos, Konstantinos; Giamarellos-Bourboulis, Evangelos J

    2012-08-01

    Debatable findings exist among various studies regarding the impact of single nucleotide polymorphisms (SNPs) within the promoter region of the tumor necrosis factor (TNF) gene for susceptibility to infections. Their impact was investigated in a cohort of mechanically ventilated patients who developed ventilator-associated pneumonia (VAP). Two-hundred and thirteen mechanically ventilated patients who developed VAP were enrolled. Genomic DNA was extracted and SNPs at the -376, -308 and -238 position of the promoter region of the TNF gene were assessed by restriction fragment length polymorphisms. Monocytes were isolated from 47 patients when they developed sepsis and stimulated by bacterial endotoxin for the production of TNFα and of interleukin-6 (IL-6). Patients were divided into two groups; 166 patients bearing only wild-type alleles of all three studied polymorphisms; and 47 patients carrying at least one A allele of the three studied SNPs. Time between start of mechanical ventilation and advent of VAP was significantly shorter in the second group than in the first group (log-rank: 4.416, p: 0.041). When VAP supervened, disease severity did not differ between groups. Stimulation of TNFα and of IL-6 was much greater by monocytes for patients carrying A alleles. Carriage of at least one A allele of the three studied SNPs at the promoter region of the TNF-gene is associated with shorter time to development of VAP but it is not associated with disease severity. Findings may be related with a role of the studied SNPs in the production of pro-inflammatory cytokines. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. The association of factor V G1961A (factor V Leiden), prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G polymorphisms with recurrent pregnancy loss in Bosnian women.

    Science.gov (United States)

    Jusić, Amela; Balić, Devleta; Avdić, Aldijana; Pođanin, Maja; Balić, Adem

    2018-08-01

    Aim To investigate association of factor V Leiden, prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G polymorphisms with recurrent pregnancy loss in Bosnian women. Methods A total of 60 women with two or more consecutive miscarriages before 20 weeks of gestation with the same partners and without history of known causes or recurrent pregnancy loss were included. A control group included 80 healthy women who had one or more successful pregnancies without history of any complication which could be associated with miscarriages. Genotyping of factor V Leiden, prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G polymorphisms were performed by polymerase chain reaction/restriction fragments length polymorphism method (PCR/RFLP). Results Both factor V Leiden and MTHFR C677T polymorphisms were significantly associated with recurrent pregnancy loss (RPL) in Bosnian women while prothrombin G20210A and PAI-1 4G/5G polymorphisms did not show strongly significant association. Conclusion The presence of thrombophilic polymorphisms may predispose women to recurrent pregnancy loss. Future investigation should be addressed in order to find when carriers of those mutations, polymorphisms should be treated with anticoagulant therapy. Copyright© by the Medical Assotiation of Zenica-Doboj Canton.

  11. GC content around splice sites affects splicing through pre-mRNA secondary structures

    Directory of Open Access Journals (Sweden)

    Chen Liang

    2011-01-01

    Full Text Available Abstract Background Alternative splicing increases protein diversity by generating multiple transcript isoforms from a single gene through different combinations of exons or through different selections of splice sites. It has been reported that RNA secondary structures are involved in alternative splicing. Here we perform a genomic study of RNA secondary structures around splice sites in humans (Homo sapiens, mice (Mus musculus, fruit flies (Drosophila melanogaster, and nematodes (Caenorhabditis elegans to further investigate this phenomenon. Results We observe that GC content around splice sites is closely associated with the splice site usage in multiple species. RNA secondary structure is the possible explanation, because the structural stability difference among alternative splice sites, constitutive splice sites, and skipped splice sites can be explained by the GC content difference. Alternative splice sites tend to be GC-enriched and exhibit more stable RNA secondary structures in all of the considered species. In humans and mice, splice sites of first exons and long exons tend to be GC-enriched and hence form more stable structures, indicating the special role of RNA secondary structures in promoter proximal splicing events and the splicing of long exons. In addition, GC-enriched exon-intron junctions tend to be overrepresented in tissue-specific alternative splice sites, indicating the functional consequence of the GC effect. Compared with regions far from splice sites and decoy splice sites, real splice sites are GC-enriched. We also found that the GC-content effect is much stronger than the nucleotide-order effect to form stable secondary structures. Conclusion All of these results indicate that GC content is related to splice site usage and it may mediate the splicing process through RNA secondary structures.

  12. Cyclin D1 gene polymorphism as a risk factor for squamous cell carcinoma of the upper aerodigestive system in non-alcoholics

    DEFF Research Database (Denmark)

    Nishimoto, Ines Nobuko; Pinheiro, Nidia Alice; Rogatto, Silvia Regina

    2004-01-01

    Squamous cell carcinoma of the upper aerodigestive tract (UADT) is associated with environmental factors, especially tobacco and alcohol consumption. Genetic factors, including cyclin D1 (CCND1) polymorphism have been suggested to play an important role in tumorigenesis and progression of UADT...

  13. TP53 genetic polymorphisms, interactions with lifestyle factors and lung cancer risk: a case control study in a Chinese population

    International Nuclear Information System (INIS)

    Li, Yanli; Su, Jia; Cai, Lin; Yu, Shunzhang; Zhang, Zuo-Feng; Mu, Lina; Chang, Shen-Chih; Niu, Rungui; Liu, Li; Crabtree-Ide, Christina R; Zhao, Baoxing; Shi, Jianping; Han, Xiaoyou; Li, Jiawei

    2013-01-01

    A pathway-based genotyping analysis suggested rs2078486 was a novel TP53 SNP, but very few studies replicate this association. TP53 rs1042522 is the most commonly studied SNP, but very few studies examined its potential interaction with environmental factors in relation to lung cancer risk. This study aims to examine associations between two TP53 single-nucleotide polymorphisms (SNPs) (rs2078486, rs1042522), their potential interaction with environmental factors and risk of lung cancer. A case–control study was conducted in Taiyuan, China. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Multiplicative and additive interactions between TP53 SNPs and lifestyle factors were evaluated. Variant TP53 rs2078486 SNP was significantly associated with elevated lung cancer risk among smokers (OR: 1.70, 95% CI: 1.08 - 2.67) and individuals with high indoor air pollution exposure (OR: 1.51, 95% CI: 1.00-2.30). Significant or borderline significant multiplicative and additive interactions were found between TP53 rs2078486 polymorphism with smoking and indoor air pollution exposure. The variant genotype of TP53 SNP rs1042522 significantly increased lung cancer risk in the total population (OR: 1.57, 95% CI: 1.11-2.21), but there was no evidence of heterogeneity among individuals with different lifestyle factors. This study confirmed that TP53 rs2078486 SNP is potentially a novel TP53 SNP that may affect lung cancer risk. Our study also suggested potential synergetic effects of TP53 rs2078486 SNP with smoking and indoor air pollution exposure on lung cancer risk

  14. Spliced RNA of woodchuck hepatitis virus.

    Science.gov (United States)

    Ogston, C W; Razman, D G

    1992-07-01

    Polymerase chain reaction was used to investigate RNA splicing in liver of woodchucks infected with woodchuck hepatitis virus (WHV). Two spliced species were detected, and the splice junctions were sequenced. The larger spliced RNA has an intron of 1300 nucleotides, and the smaller spliced sequence shows an additional downstream intron of 1104 nucleotides. We did not detect singly spliced sequences from which the smaller intron alone was removed. Control experiments showed that spliced sequences are present in both RNA and DNA in infected liver, showing that the viral reverse transcriptase can use spliced RNA as template. Spliced sequences were detected also in virion DNA prepared from serum. The upstream intron produces a reading frame that fuses the core to the polymerase polypeptide, while the downstream intron causes an inframe deletion in the polymerase open reading frame. Whereas the splicing patterns in WHV are superficially similar to those reported recently in hepatitis B virus, we detected no obvious homology in the coding capacity of spliced RNAs from these two viruses.

  15. The Role of Alternative Splicing in the Control of Immune Homeostasis and Cellular Differentiation.

    Science.gov (United States)

    Yabas, Mehmet; Elliott, Hannah; Hoyne, Gerard F

    2015-12-22

    Alternative splicing of pre-mRNA helps to enhance the genetic diversity within mammalian cells by increasing the number of protein isoforms that can be generated from one gene product. This provides a great deal of flexibility to the host cell to alter protein function, but when dysregulation in splicing occurs this can have important impact on health and disease. Alternative splicing is widely used in the mammalian immune system to control the development and function of antigen specific lymphocytes. In this review we will examine the splicing of pre-mRNAs yielding key proteins in the immune system that regulate apoptosis, lymphocyte differentiation, activation and homeostasis, and discuss how defects in splicing can contribute to diseases. We will describe how disruption to trans-acting factors, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), can impact on cell survival and differentiation in the immune system.

  16. FOX-2 Dependent Splicing of Ataxin-2 Transcript Is Affected by Ataxin-1 Overexpression

    Science.gov (United States)

    Welzel, Franziska; Kaehler, Christian; Isau, Melanie; Hallen, Linda; Lehrach, Hans; Krobitsch, Sylvia

    2012-01-01

    Alternative splicing is a fundamental posttranscriptional mechanism for controlling gene expression, and splicing defects have been linked to various human disorders. The splicing factor FOX-2 is part of a main protein interaction hub in a network related to human inherited ataxias, however, its impact remains to be elucidated. Here, we focused on the reported interaction between FOX-2 and ataxin-1, the disease-causing protein in spinocerebellar ataxia type 1. In this line, we further evaluated this interaction by yeast-2-hybrid analyses and co-immunoprecipitation experiments in mammalian cells. Interestingly, we discovered that FOX-2 localization and splicing activity is affected in the presence of nuclear ataxin-1 inclusions. Moreover, we observed that FOX-2 directly interacts with ataxin-2, a protein modulating spinocerebellar ataxia type 1 pathogenesis. Finally, we provide evidence that splicing of pre-mRNA of ataxin-2 depends on FOX-2 activity, since reduction of FOX-2 levels led to increased skipping of exon 18 in ataxin-2 transcripts. Most striking, we observed that ataxin-1 overexpression has an effect on this splicing event as well. Thus, our results demonstrate that FOX-2 is involved in splicing of ataxin-2 transcripts and that this splicing event is altered by overexpression of ataxin-1. PMID:22666429

  17. An alternative to the search for single polymorphisms: toward molecular personality scales for the five-factor model.

    Science.gov (United States)

    McCrae, Robert R; Scally, Matthew; Terracciano, Antonio; Abecasis, Gonçalo R; Costa, Paul T

    2010-12-01

    There is growing evidence that personality traits are affected by many genes, all of which have very small effects. As an alternative to the largely unsuccessful search for individual polymorphisms associated with personality traits, the authors identified large sets of potentially related single nucleotide polymorphisms (SNPs) and summed them to form molecular personality scales (MPSs) with from 4 to 2,497 SNPs. Scales were derived from two thirds of a large (N = 3,972) sample of individuals from Sardinia who completed the Revised NEO Personality Inventory (P. T. Costa, Jr., & R. R. McCrae, 1992) and were assessed in a genomewide association scan. When MPSs were correlated with the phenotype in the remaining one third of the sample, very small but significant associations were found for 4 of the 5e personality factors when the longest scales were examined. These data suggest that MPSs for Neuroticism, Openness to Experience, Agreeableness, and Conscientiousness (but not Extraversion) contain genetic information that can be refined in future studies, and the procedures described here should be applicable to other quantitative traits. PsycINFO Database Record (c) 2010 APA, all rights reserved.

  18. Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients.

    Science.gov (United States)

    Schüle, Cornelius; Zill, Peter; Baghai, Thomas C; Eser, Daniela; Zwanzger, Peter; Wenig, Nadine; Rupprecht, Rainer; Bondy, Brigitta

    2006-09-01

    Data suggest that both neurotrophic and hypothalamic-pituitary-adrenocortical (HPA) systems are involved in the pathophysiology of depression. The aim of the present study was to investigate whether the non-conservative brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has an impact on HPA axis activity in depressed patients. At admission, the dexamethasone/CRH (DEX/CRH) test was performed in 187 drug-free in-patients suffering from major depression or depressed state of bipolar disorder (DSM-IV criteria). Moreover, genotyping of BDNF Val66Met polymorphism was carried out using the fluorescence resonance energy transfer method (FRET). Homozygous carriers of the Met/Met genotype showed a significantly higher HPA axis activity during the DEX/CRH test than patients carrying the Val/Val or Val/Met genotype (ACTH, cortisol). Our results further contribute to the hypothesized association between HPA axis dysregulation and reduced neuroplasticity in depression and are consistent with the assumption that BDNF is a stress-responsive intercellular messenger modifying HPA axis activity.

  19. Analysis of von Willebrand factor A domain-related protein (WARP polymorphism in temperate and tropical Plasmodium vivax field isolates

    Directory of Open Access Journals (Sweden)

    Zakeri Sedigheh

    2009-06-01

    Full Text Available Abstract Background The identification of key molecules is crucial for designing transmission-blocking vaccines (TBVs, among those ookinete micronemal proteins are candidate as a general class of malaria transmission-blocking targets. Here, the sequence analysis of an extra-cellular malaria protein expressed in ookinetes, named von Willebrand factor A domain-related protein (WARP, is reported in 91 Plasmodium vivax isolates circulating in different regions of Iran. Methods Clinical isolates were collected from north temperate and southern tropical regions in Iran. Primers have been designed based on P. vivax sequence (ctg_6991 which amplified a fragment of about 1044 bp with no size variation. Direct sequencing of PCR products was used to determine polymorphism and further bioinformatics analysis in P. vivax sexual stage antigen, pvwarp. Results Amplified pvwarp gene showed 886 bp in size, with no intron. BLAST analysis showed a similarity of 98–100% to P. vivax Sal-I strain; however, Iranian isolates had 2 bp mismatches in 247 and 531 positions that were non-synonymous substitution [T (ACT to A (GCT and R (AGA to S (AGT] in comparison with the Sal-I sequence. Conclusion This study presents the first large-scale survey on pvwarp polymorphism in the world, which provides baseline data for developing WARP-based TBV against both temperate and tropical P. vivax isolates.

  20. Bg1II polymorphism of the epidermal growth factor receptor (EGF-R) gene

    Energy Technology Data Exchange (ETDEWEB)

    Biunno, I; Pozzi, M R; Radice, P; Mondini, P; Pierotti, M A; Porta, G D [Istituto Nazionale Tumori, Milan (Italy); Haley, J; Waterfield, M D [Ludwig Institute for Cancer Research, London (England)

    1988-08-11

    A 770 bp cDNA fragment was derived from the cytoplasmic portion of the EGF-R (ref. Libermann et al., 1985). Bg1II identifies 4 invariant bands of 7.0, 5.0, 3.5 and 1.2 kb and a two allele polymorphism with a band of either 10.6 kb (lane 1) or 9.4 kb (lane 3). An heterozygote individual is represented. The frequency was analyzed in 78 unrelated European Caucasians. Its chromosomal location was determined. Co-dominant segregation was demonstrated in three families of 12 individuals. A rare variant of 8.3 kb was seen in one chromosome out of the 144 examined. This allelic form has not yet been fully characterized.

  1. Polymorphisms of the oxytocin receptor gene and overeating: the intermediary role of endophenotypic risk factors.

    Science.gov (United States)

    Davis, C; Patte, K; Zai, C; Kennedy, J L

    2017-05-22

    Oxytocin (OXT) is an evolutionarily ancient neuropeptide with strong links to affiliative and prosocial behaviors, and the management of stress. Increases in OXT also tend to decrease food intake, especially of sweet carbohydrates. The social correlates of low OXT levels mesh with the social deficits and stress proneness identified in interpersonal models of overeating, as well as the increased appetite for highly palatable foods typically seen in chronic overeaters. The objectives of this study were to investigate links between polymorphisms of the oxytocin receptor (OXTR) gene and overeating, and to examine OXTR links with relevant endophenotypes of overeating related to reward and stress sensitivity, and to food preferences. The sample comprised 460 adults between the ages of 25 and 50 years recruited from the community, and representing a broad range of body weights. Overeating, reward and punishment sensitivity, and food preferences, were quantified as composite variables using well-validated questionnaires. In addition, seven single-nucleotide polymorphisms (rs237878, rs237885, rs2268493, rs2268494, rs2254298, rs53576, rs2268498) of the OXTR gene were genotyped. Analyses identified a four-marker haplotype that was significantly related to food preferences. Individual genotype analyses also found that at least one of the markers was related to each of the phenotypic variables. In addition, an empirically derived structural equation model linking genetic and phenotype variables produced a good fit to the data. The results of this preliminary study have demonstrated that OXTR variation is associated with overeating, and with endophenotypic traits such as sweet and fatty food preferences, and reward and punishment sensitivity. In general, the genetic findings also favor the view that overeating may be associated with relatively low basal OXT levels.

  2. IFNG polymorphism (+874 T>A is not a risk factor for cervical cancer

    Directory of Open Access Journals (Sweden)

    Ani Melani Maskoen

    2013-04-01

    Full Text Available Introduction Cervical cancer cases are rising and many women are infected with human papillomavirus (HPV. Interferon gamma (IFN-ã is one of the key regulatory cytokines that influence the HPV clearance. The production and the function of IFN-ã may impaired by the defect of the IFNG gene leading to the cervical malignant progression. This study aimed to examine the association between IFNG+874 T>A polymorphism and cervical cancer in women Methods In a case-control study design, consecutive untreated women with cervical cancer who showed for the first time in Hasan Sadikin Hospital Bandung were enrolled (n=98 and for controls women who came for PAP smear (n = 81. Controls were not matched in ages and ethnicities. DNA extracted from blood was amplified by amplification refractory mutation system - polymerase chain reaction method (ARMS – PCR to detect IFNG+874 T>A polymorphism. Results The distribution of IFNG genotypes TT, TA and AA for women with cervical cancer who met the inclusion criteria (n= 64 and with negative intraepithelial lesion or malignancy (n=42 were 14.1%, 50.0%, 35.9% and 7.1%, 52.4%, 40.5%, respectively. No significant differences could be observed between both groups (p=0.64. Stratifying the cervical cancer women into a group of squamous cell carcinoma (n = 54 revealed no statistical different. Conclusion IFNG +874 T>A polymorphismseems not to contribute in susceptibility to cervical cancer. Identification of other variants in IFNG gene signaling and its role in the development of cervical cancer diseases need to be further examined.

  3. A novel CDX2 isoform regulates alternative splicing.

    Directory of Open Access Journals (Sweden)

    Matthew E Witek

    Full Text Available Gene expression is a dynamic and coordinated process coupling transcription with pre-mRNA processing. This regulation enables tissue-specific transcription factors to induce expression of specific transcripts that are subsequently amplified by alternative splicing allowing for increased proteome complexity and functional diversity. The intestine-specific transcription factor CDX2 regulates development and maintenance of the intestinal epithelium by inducing expression of genes characteristic of the mature enterocyte phenotype. Here, sequence analysis of CDX2 mRNA from colonic mucosa-derived tissues revealed an alternatively spliced transcript (CDX2/AS that encodes a protein with a truncated homeodomain and a novel carboxy-terminal domain enriched in serine and arginine residues (RS domain. CDX2 and CDX2/AS exhibited distinct nuclear expression patterns with minimal areas of co-localization. CDX2/AS did not activate the CDX2-dependent promoter of guanylyl cyclase C nor inhibit transcriptional activity of CDX2. Unlike CDX2, CDX2/AS co-localized with the putative splicing factors ASF/SF2 and SC35. CDX2/AS altered splicing patterns of CD44v5 and Tra2-β1 minigenes in Lovo colon cancer cells independent of CDX2 expression. These data demonstrate unique dual functions of the CDX2 gene enabling it to regulate gene expression through both transcription (CDX2 and pre-mRNA processing (CDX2/AS.

  4. Cell-cycle-dependent three-dimensional redistribution of nuclear proteins, P 120, pKi-67, and SC 35 splicing factor, in the presence of the topoisomerase I inhibitor camptothecin.

    Science.gov (United States)

    Elias, Emmanuel; Lalun, Nathalie; Lorenzato, Marianne; Blache, Laurent; Chelidze, Pavel; O'Donohue, Marie-Françoise; Ploton, Dominique; Bobichon, Hélène

    2003-11-15

    Topoisomerase I (Topo I) is mostly known for its role in DNA relaxation, which is required for duplication and transcription. Topo I acts as a protein kinase mainly directed to the mRNA splicing factor SC35. Camptothecin is one of the specific Topo I inhibitors and is effective on the two functions of the enzyme. In this study we demonstrated that treatment of KB cells with camptothecin for only 30 min induced the 3D reorganization and redistribution of three proteins involved in the nucleus machinery, P 120, pKi-67, and SC 35, and this occurred in a cell cycle-dependent manner. Our data were obtained from confocal microscopic studies after immunolabeling, 3D reconstruction, and measurement of the nuclear components volumes. In the presence of camptothecin, P 120, which occupied the nucleolar volume, lost its reticulation and pKi-67 was redistributed within the nucleoplasm and even into the cytoplasm. Finally, for SC 35 the fusion of its dots into bigger volumes was observed specifically during the G1 phase. Variations of volumes were also observed for the nucleolus and for the nucleus. These results pointed out that, depending on the cell cycle phase, Topo I functions were selective toward the three different proteins.

  5. Complement Factor H Y402H and LOC387715 A69S Polymorphisms in Association with Age-Related Macular Degeneration in Iran.

    Science.gov (United States)

    Nazari Khanamiri, Hossein; Ghasemi Falavarjani, Khalil; Sanati, Mohammad Hossein; Aryan, Hajar; Irani, Alireza; Hashemi, Masih; Modarres, Mehdi; Parvaresh, Mohammad Mehdi; Nikeghbali, Aminollah

    2014-04-01

    To determine the frequency of complement factor H (Y402H) and age related macular degeneration susceptibility gene 2 (A69S) single nucleotide polymorphisms in patients with age-related macular degeneration (AMD) and in matched non-AMD controls in an Iranian population. Seventy patients with AMD and 86 age- and sex-matched controls were recruited and examined. Peripheral blood sample was obtained from all subjects for DNA extraction and direct sequencing of Y402H and A69S genes. Odds ratios (ORs) with 95% confidence intervals (CIs) for the association of Y402H and A69S polymorphisms with AMD were determined. The frequencies of both homozygous and heterozygous genotypes were significantly higher in cases than controls for both Y402H and A69S polymorphisms. In comparison to the wild genotypes, OR for AMD associated with Y402H and A69S polymorphisms were 1.9 (95% CI, 1.1-3.2) and 2.2 (95%CI, 1.6-3.1), respectively. Joint risk analysis considering both genes revealed a higher risk of AMD when polymorphisms were present for both genes. Y402H and A69S polymorphisms were strongly associated with AMD in this Iranian population.

  6. Complement Factor H Y402H and LOC387715 A69S Polymorphisms in Association with Age-Related Macular Degeneration in Iran

    Directory of Open Access Journals (Sweden)

    Hossein Nazari Khanamiri

    2014-01-01

    Full Text Available Purpose: To determine the frequency of complement factor H (Y402H and age related macular degeneration susceptibility gene 2 (A69S single nucleotide polymorphisms in patients with age-related macular degeneration (AMD and in matched non-AMD controls in an Iranian population. Methods: Seventy patients with AMD and 86 age- and sex-matched controls were recruited and examined. Peripheral blood sample was obtained from all subjects for DNA extraction and direct sequencing of Y402H and A69S genes. Odds ratios (ORs with 95% confidence intervals (CIs for the association of Y402H and A69S polymorphisms with AMD were determined. Results: The frequencies of both homozygous and heterozygous genotypes were significantly higher in cases than controls for both Y402H and A69S polymorphisms. In comparison to the wild genotypes, OR for AMD associated with Y402H and A69S polymorphisms were 1.9 (95% CI, 1.1-3.2 and 2.2 (95%CI, 1.6-3.1, respectively. Joint risk analysis considering both genes revealed a higher risk of AMD when polymorphisms were present for both genes. Conclusion: Y402H and A69S polymorphisms were strongly associated with AMD in this Iranian population.

  7. Analysis of the Association Between Apolipoprotein E Polymorphism and Cardiovascular Risk Factors in an Elderly Population with Longevity

    Directory of Open Access Journals (Sweden)

    Schwanke Carla Helena Augustin

    2002-01-01

    Full Text Available OBJECTIVE: To establish the allelic and genotypic frequencies related to apolipoprotein E (ApoE polymorphism and association of the genotypes with risk factors and cardiovascular morbidity in an elderly population with longevity. METHODS: We analyzed 70 elderly patients aged 80 years or more who were part of the Projeto Veranópolis. We used the gene amplification technique through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and cleavage with the restriction enzyme Hha I to identify the ApoE genotypes. The most frequent genotypes were compared considering biological variables and cardiovascular risks and morbidity. RESULTS: The frequencies of the E2, E3, and E4 alleles were 0.05, 0.84, and 0.11, respectively, and of the genotypes were as follows: E3E3 (0.70, E3E4 (0.22, E2E3 (0.06, and E2E2 (0.02. Individuals with the E3E4 had a mean age greater than those with the E3E3. No association was observed between the genotypes and the variables analyzed, except for obesity, which was associated with the E3E3 genotype. Individuals with the E3E4 genotype had high levels of LDL-cholesterol and fibrinogen as compared with those with the E3E3 genotype. CONCLUSION: The results suggest that the E4E4 genotype may be associated with early mortality. A balance between the protective or neutral factors and the cardiovascular risk factors may occur among the individuals with different genotypes, attenuating the negative effects of the E4 allele.

  8. The role of genetic (PON1 polymorphism and environmental factors, especially physical activity, in antioxidant function of paraoxonase*

    Directory of Open Access Journals (Sweden)

    Aneta Otocka-Kmiecik

    2009-12-01

    Full Text Available Paraoxonase 1 ([i]PON1[/i] is a member of a three-gene family ([i]PON1, PON2[/i], and [i]PON3[/i]. PON1 activity dominates in human plasma. It is secreted from hepatic cells and is found in the circulation bound to high-density lipoproteins (HDLs. For many years it has been known only for its ability to hydrolyze organophosphate derivatives. More recently, PON1’s antioxidant activity draws attention as the enzyme was described to prevent oxidation of lipoproteins by reactive oxygen species formed during oxidative stress. PON1 was also shown to hydrolyze atherogenic products of oxidative lipid modification such as phospholipid peroxides and cholesterol ester hydroperoxides. Some studies indicate that the enzyme presents a lipolactonase activity and hydrolyzes homocysteine thiolactone (HCTL. There is growing evidence as to PON1’s protective role in atherosclerosis. Genetic (PON1 polymorphism and environmental factors and lifestyle may influence PON1 blood concentration and biological activity. Among the many recognized factors accounting for lifestyle, physical activity plays an important role. Various, often opposite, effects on PON1 status are observed in regular training and single physical activities. The results of different studies are often contradictory. It may depend on the time, intensity, and frequency of physical activity. Additionally, it seems that the effects of physical activity on [i]PON1[/i] blood concentration and activity are modified by environmental and lifestyle factors as well as [i]PON1[/i] polymorphism.

  9. Catechol-O-Methyltransferase (COMT) Gene (Val158Met) and Brain-Derived Neurotropic Factor (BDNF) (Val66Met) Genes Polymorphism in Schizophrenia: A Case-Control Study

    OpenAIRE

    Saravani, Ramin; Galavi, Hamid Reza; Lotfian Sargazi, Marzieh

    2017-01-01

    Objective: Several studies have shown that some polymorphisms of genes encoding catechol-O-methyltransferase (COMT), the key enzyme in degrading dopamine, and norepinephrine and the human brain-derived neurotropic factor (BDNF), a nerve growth factor, are strong candidates for risk of schizophrenia (SCZ). In the present study, we aimed at examining the effects of COMT Val158Met (G>A) and BDNF Val66Met (G>A) polymorphisms on SCZ risk in a sample of Iranian population. Method: This case- contro...

  10. A comprehensive study of tumor necrosis factor-alpha genetic polymorphisms, its expression in skin and relation to histopathological features in psoriasis

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    Nikhil N Moorchung

    2015-01-01

    Full Text Available Background: Tumor necrosis factor-alpha (TNFα is an important inflammatory mediator in psoriasis and several genetic polymorphisms of this cytokine have been reported. Majority of studies have focused on the increased G- A polymorphism at the -308 position in psoriasis. There has been no comprehensive study evaluating the genetic polymorphisms, TNFα expression in the skin and histopathology. We are undertaking this study to outline TNFα genetic polymorphisms, its skin expression and histopathological correlation to help determine its role at the genetic and protein level. Materials and Methods : 112 patients of psoriasis and 243 healthy controls were included in this prospective study. 5 ml of peripheral blood was collected to study the TNFα genetic polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. Histopathological analysis of biopsies from the 112 patients were done using visual analogue scale and correlated with the findings. 61 of these cases were analyzed for TNFα expression by immunohistochemistry. The results of study were statistically analyzed using SPSS 13.0 statistical package program. Results: A strong association of TNFα -308 G/A polymorphism in psoriasis cases was detected. The A allele of the TNFα -308 G/A polymorphism occurs rarely in the Indian population, however there is an over representation of this allele in psoriatic patients. There was no association seen between TNFα genotype and histopathological severity of psoriasis. Conclusion: The study emphasized the central role of TNFα in the pathogenesis of psoriasis. TNFα genotyping may be helpful in identifying subjects in whom anti-TNFα therapeutic strategies may be tried.

  11. Characterization of a splicing mutation in group A xeroderma pigmentosum

    International Nuclear Information System (INIS)

    Satokata, Ichiro; Tanaka, Kiyoji; Miura, Naoyuki; Miyamoto, Iwai; Okada, Yoshio; Satoh, Yoshiaki; Kondo, Seiji

    1990-01-01

    The molecular basis of group A xeroderma pigmentosum (WP) was investigated by comparison of the nucleotide sequences of multiple clones of the XP group A complementing gene (XPAC) from a patient with group A XP with that of a normal gene. The clones showed a G → C substitution at the 3' splice acceptor site of intron 3, which altered the obligatory AG acceptor dinucleotide to AC. Nucleotide sequencing of cDNAs amplified by the polymerase chain reaction revealed that this single base substitution abolishes the canonical 3' splice site, thus creating two abnormally spliced mRNA forms. The larger form is identical with normal mRNA except for a dinucleotide deletion at the 5' end of exon 4. This deletion results in a frameshift with premature translation termination in exon 4. The smaller form has a deletion of the entire exon 3 and the dinucleotide at the 5' end of exon 4. The result of a transfection study provided additional evidence that this single base substitution is the disease-causing mutation. This single base substitution creates a new cleavage site for the restriction nuclease AlwNI. Analysis of AlwNI restriction fragment length polymorphism showed a high frequency of this mutation in Japanese patients with group A XP: 16 of 21 unrelated Japanese patients were homozygous and 4 were heterozygous for this mutation. However, 11 Caucasians and 2 Blacks with group A XP did not have this mutant allele. The polymorphic AlwNI restriction fragments are concluded to be useful for diagnosis of group A XP in Japanese subjects, including prenatal cases and carriers

  12. Modulation of splicing of the preceding intron by antisense oligonucleotide complementary to intra-exon sequence deleted in dystrophin Kobe

    Energy Technology Data Exchange (ETDEWEB)

    Takeshima, Y.; Matuso, M.; Sakamoto, H.; Nishio, H. [Kobe Univ. School of Medicine and Science (Japan)

    1994-09-01

    Molecular analysis of dystrophin Kobe showed that exon 19 of the dystrophin gene bearing a 52 bp deletion was skipped during splicing, although the known consensus sequences at the 5{prime} and 3{prime} splice site of exon 19 were maintained. These data suggest that the deleted sequence of exon 19 may function as a cis-acting factor for exact splicing for the upstream intron. To investigate this potential role, an in vitro splicing system using dystrophin precursors was established. A two-exon precursor containing exon 18, truncated intron 18, and exon 19 was accurately spliced. However, splicing of intron 18 was dramatically inhibited when wild exon 19 was replaced with mutated exon 19. Even though the length of exon 19 was restored to normal by replacing the deleted sequence with other sequence, splicing of intron 18 was not fully reactivated. Characteristically, splicing of intron 18 was inactivated more markedly when the replaced sequence contained less polypurine stretches. These data suggested that modification of the exon sequence would result in a splicing abnormality. Antisense 31 mer 2`-O-methyl ribonucleotide was targeted against 5{prime} end of deleted region of exon 19 to modulate splicing of the mRNA precursor. Splicing of intron 18 was inhibited in a dose- and time-dependent manner. This is the first in vitro evidence to show splicing of dystrophin pre-mRNA can be managed by antisense oligonucleotides. These experiments represent an approach in which antisense oligonucleotides are used to restore the function of a defective dystrophin gene in Duchenne muscular dystrophy by inducing skipping of certain exons during splicing.

  13. Acute Endoplasmic Reticulum Stress-Independent Unconventional Splicing of XBP1 mRNA in the Nucleus of Mammalian Cells

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    Yuanyuan Wang

    2015-06-01

    Full Text Available The regulation of expression of X-box-binding protein-1 (XBP1, a transcriptional factor, involves an unconventional mRNA splicing that removes the 26 nucleotides intron. In contrast to the conventional splicing that exclusively takes place in the nucleus, determining the location of unconventional splicing still remains controversial. This study was designed to examine whether the unconventional spicing of XBP1 mRNA could occur in the nucleus and its possible biological relevance. We use RT-PCR reverse transcription system and the expand high fidelity PCR system to detect spliced XBP1 mRNA, and fraction cells to determine the location of the unconventional splicing of XBP1 mRNA. We employ reporter constructs to show the presence of unconventional splicing machinery in mammal cells independently of acute endoplasmic reticulum (ER stress. Our results reveal the presence of basal unconventional splicing of XBP1 mRNA in the nucleus that also requires inositol-requiring transmembrane kinase and endonuclease 1α (IRE1α and can occur independently of acute ER stress. Furthermore, we confirm that acute ER stress induces the splicing of XBP1 mRNA predominantly occurring in the cytoplasm, but it also promotes the splicing in the nucleus. The deletion of 5′-nucleotides in XBP1 mRNA significantly increases its basal unconventional splicing, suggesting that the secondary structure of XBP1 mRNA may determine the location of unconventional splicing. These results suggest that the unconventional splicing of XBP1 mRNA can take place in the nucleus and/or cytoplasm, which possibly depends on the elaborate regulation. The acute ER stress-independent unconventional splicing in the nucleus is most likely required for the maintaining of day-to-day folding protein homeostasis.

  14. Functional and prognostic influence of receptor polymorphisms in the vascular endothelial growth factor system in colorectal cancer

    DEFF Research Database (Denmark)

    Hansen, T; Spindler, K G; Aalund Olsen, Dorte

    2009-01-01

    was significantly higher than the median protein concentration of the CC genotype, p = 0.005. The CC genotype held prognostic information compared to CT and TT genotypes for both SNP's, pinfluence on the VEGFR-2 protein level, and the -604 T/C SNP...... on the gene expression level in CRC patients. The results furthermore indicate a prognostic influence of both SNP's on progression-free survival. No significant financial relationships to disclose.......e15032 Background: The vascular endothelial growth factor (VEGF) system plays a key role in the angiogenic process ensuring a sufficient blood supply to the growth of malignant tumours. The clinical importance of single nucleotide polymorphisms (SNP's) in the VEGF receptors is still unknown...

  15. Genetic polymorphisms of hemostatic factors and thrombotic risk in non BCR-ABL myeloproliferative neoplasms: A pilot study

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    Dambrauskienė R

    2017-06-01

    Full Text Available The most important complications of Philadelphianegagive (non BCR-ABL myeloproliferative neoplasms (MPNs are vascular events. Our aim was to evaluate the effects of single nucleotide polymorphisms (SNPs, platelet glycoproteins (GPs (Ia/IIa, Ibα, IIb/IIIa and VI, von Willebrand factor (vWF, coagulation factor VII (FVII, β-fibrinogen, and the risk of thrombosis in patients with non BCR-ABL MPNs at the Lithuanian University of Health Sciences. Kaunas, Lithuania. Genotyping was done for 108 patients. The TT genotype of the GP Ia/IIa c.807C>T polymorphism was more frequently found in the group of MPN patients with arterial thrombosis compared to MPN patients who were thrombosis-free [26.5 vs. 11.5%, p = 0.049; odds ratio (OR 2.68; 95% confidence interval (95% CI 1.01-7.38]. The CT genotype of the β-fibrinogen c.-148C>T polymorphism occurred more frequently in MPN patients with arterial, and total thrombosis compared to the wild or homozygous genotype (57.7 vs. 40.0 vs. 12.5%; p = 0.027, (64.7 vs. 44.4 vs. 25%; p = 0.032, respectively. The carrier state for the c.-323P10 variant of FVII SNP (summation of P10/10 and P0/10 was more frequent in MPN patients with thrombosis compared to the wild-type genotype carriers (71.4 vs. 43.4%; p = 0.049; OR 3.26; 95% CI 1.01-11.31. The coexistence of heterozygous β-fibrinogen c.-148C>T and FVII c.-323P0/10 SNP, increased the risk of arterial thrombosis (21.1 vs. 3.7%, p = 0.008; OR 6.93; 95% CI 1.38-34.80. The TT genotype of GP Ia/IIa c.807C>T, the CT genotype of β-fibrinogen c.-148C>T and FVII c.-323P0/10 SNP could be associated with risk of thrombosis in MPN patients.

  16. cis-Acting and trans-acting modulation of equine infectious anemia virus alternative RNA splicing

    International Nuclear Information System (INIS)

    Liao, Huey-Jane; Baker, Carl C.; Princler, Gerald L.; Derse, David

    2004-01-01

    Equine infectious anemia virus (EIAV), a lentivirus distantly related to HIV-1, encodes regulatory proteins, EIAV Tat (ETat) and Rev (ERev), from a four-exon mRNA. Exon 3 of the tat/rev mRNA contains a 30-nucleotide purine-rich element (PRE) which binds both ERev and SF2/ASF, a member of the SR family of RNA splicing factors. To better understand the role of this element in the regulation of EIAV pre-mRNA splicing, we quantified the effects of mutation or deletion of the PRE on exon 3 splicing in vitro and on alternative splicing in vivo. We also determined the branch point elements upstream of exons 3 and 4. In vitro splicing of exon 3 to exon 4 was not affected by mutation of the PRE, and addition of purified SR proteins enhanced splicing independently of the PRE. In vitro splicing of exon 2 to exon 3 was dependent on the PRE; under conditions of excess SR proteins, either the PRE or the 5' splice site of exon 3 was sufficient to activate splicing. We applied isoform-specific primers in real-time RT-PCR reactions to quantitatively analyze alternative splicing in cells transfected with rev-minus EIAV provirus constructs. In the context of provirus with wild-type exon 3, greater than 80% of the viral mRNAs were multiply spliced, and of these, less than 1% excluded exon 3. Deletion of the PRE resulted in a decrease in the relative amount of multiply spliced mRNA to about 40% of the total and approximately 39% of the viral mRNA excluded exon 3. Ectopic expression of ERev caused a decrease in the relative amount of multiply spliced mRNA to approximately 50% of the total and increased mRNAs that excluded exon 3 to about 4%. Over-expression of SF2/ASF in cells transfected with wild-type provirus constructs inhibited splicing but did not significantly alter exon 3 skipping

  17. Association of the polymorphism 12109g>A from the REN gene as a risk factor for preterm birth

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    Irám P Rodríguez-Sánchez

    2016-11-01

    Full Text Available Introduction: Preterm birth is the most important cause of neonatal mortality and morbidity. It is a multifactorial disease with different etiologies, including genetic factors. Genetic variability is represented by single nucleotide polymorphisms (SNPs in genes of proteins involved in the contractile activity. We determine the association between SNP 12109G> A in REN associated with preterm birth and premature rupture of membrane. Materials and methods: A study of cases (N=112, 22–36 weeks of gestation; mean: 31, 95% confidence interval 30.7–32.2 and controls (N=66; 38–40 weeks of gestation from the last menstrual period; mean: 39.8, 95% confidence interval 38.9–39.4 was performed. Genomic DNA was isolated in all patients from peripheral blood. The SNP 12109G> A (Mbo I in REN was typified by PCR-restriction fragment length polymorphism. Results: A significant difference in the case group for the SNP 12109G>A was observed. The A allele was increased in women with preterm birth (81% cases vs. 15% control, p A has odds ratio 6.62 (95% confidence interval 3.14–14.15, which means a high risk of preterm birth/premature rupture of membrane in presence of allele A, both in homozygotes and in heterozygotes. Conclusion: Allelic frequency of A of SNP 12109G>A was higher in women with preterm birth than in women with normal vaginal delivery and could be considered a risk factor.

  18. Interactions among insulin resistance, inflammation factors, obesity-related gene polymorphisms, environmental risk factors, and diet in the development of gestational diabetes mellitus.

    Science.gov (United States)

    Feng, Yang; Jiang, Chen-Dong; Chang, Ai-Min; Shi, Ying; Gao, Junjun; Zhu, Linlin; Zhang, Zhan

    2018-03-08

    The aim of this study was to investigate the correlations and interactions between the polymorphisms of insulin resistance-related genes (ADIPOQ rs2241766), inflammation factors (TNF-α rs1800629, IL-6 rs1800795), obesity-related genes (GNB3 rs5443, ADRB rs1042714), and risk factors for gestational diabetes mellitus (GDM) such as diet structure in the development of GDM. This research was conducted among women who visited the third-affiliate hospital of Zhengzhou University for pregnancy checkups from 1 June 2014 to 30 December 2014. Based on the results of a 75-g glucose tolerance test (OGTT), 140 pregnant women with GDM were randomly selected as a part of the GDM group and140 healthy, pregnant women as part of the control group. Relevant clinical and laboratory data for the child and the mother including her pregnancy outcomes and the delivery mode were collected for the epidemiological survey. The results showed that risk factors for GDM are advanced age, the hepatitis B virus, family history of diabetes, high body mass index before pregnancy, and weight gain of ≥10 kg before 24-week gestation. We found that diet structures were severely unbalanced. The polymorphisms rs2241766 and rs5443 were found to potentially be associated with GDM; moreover, a positive interaction was demonstrated between rs2241766 and age, and a negative interaction was demonstrated with weight gain of ≥10 kg before 24-week gestation. Our findings demonstrate that both environmental risk factors and genetic background contribute to the development of GDM.

  19. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study.

    Science.gov (United States)

    Criado-García, Juan; Fuentes, Francisco; Cruz-Teno, Cristina; García-Rios, Antonio; Jiménez-Morales, Anabel; Delgado-Lista, Javier; Mata, Pedro; Alonso, Rodrigo; López-Miranda, José; Pérez-Jiménez, Francisco

    2011-04-09

    Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

  20. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study

    Directory of Open Access Journals (Sweden)

    Pérez-Jiménez Francisco

    2011-04-01

    Full Text Available Abstract Background Heterozygous Familial Hypercholesterolemia (FH is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. Results This case-control study comprised 720 patients (546 with FH and 174 controls. We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag and whether they could be predictive factors for cardiovascular risk. 75% (410 of the patients with FH were RR, 23% (127 RQ and 1.6% (9 QQ; in the control group 75.3% (131 were RR, 21.3% (37 RQ and 3.4% (6 QQ (p = 0.32. No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease, either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96. In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97. Conclusions Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

  1. Promoter polymorphisms in trefoil factor 2 and trefoil factor 3 genes and susceptibility to gastric cancer and atrophic gastritis among Chinese population.

    Science.gov (United States)

    Xu, Qian; Chen, Mo-Ye; He, Cai-Yun; Sun, Li-Ping; Yuan, Yuan

    2013-10-15

    The polymorphisms in trefoil factor (TFF) gene family that protect gastrointestinal epithelium might influence individual vulnerability to gastric cancer (GC) and atrophic gastritis. We used the Sequenom MassARRAY platform to identify the genotypes of TFF2 rs3814896 and TFF3 rs9981660 polymorphisms in 478 GC patients, 652 atrophic gastritis patients, and 724 controls. For the TFF2 rs3814896 polymorphism, in the subgroup aged ≤ 50 years, we found that AG+GG genotypes were associated with a 0.746-fold decreased risk of atrophic gastritis [p=0.023, 95% confidence interval (CI)=0.580-0.960], a 0.626-fold decreased risk of GC (p=0.005, 95% CI=0.451-0.868), and a 0.663-fold decreased risk of diffuse-type GC (p=0.034, 95% CI=0.452-0.970) compared with the common AA genotype. For the TFF3 rs9981660 polymorphism, in the male subgroup, individuals with variant AG+AA genotype were associated with a 0.761-fold decreased risk of diffuse-type GC compared with the common GG genotype (p=0.043, 95% CI=0.584-0.992). Additionally, we found that in subjects aged ≤ 50 years compared with common AA genotype, TFF2 rs3814896 AG+GG genotypes were associated with increased TFF2 mRNA levels in the total gastric cancer specimens and in the diffuse-type gastric cancer specimens; and in males aged ≤ 50 years compared with common GG genotype, TFF3 rs9981660 AA+AG genotypes were associated with TFF3 mRNA levels in diffuse-type gastric cancer tissues and their corresponding non-cancerous tissues. To our knowledge, this is the first report of an association between the TFF2 rs3814896 AG+GG genotypes and decreased risks of GC, diffuse-type GC, and atrophic gastritis in younger people aged ≤ 50 years, and an association between TFF3 rs9981660 AG+AA genotype and decreased risk of diffuse-type GC in men. Moreover, we found that TFF2 rs3814896 AG+GG genotypes in people aged ≤ 50 years and TFF3 rs9981660 AG+AA genotypes in younger males with diffuse-type GC were associated with higher levels of

  2. Factor VII R353Q genetic polymorphism is associated with altered warfarin sensitivity among CYP2C9 *1/*1 carriers.

    Science.gov (United States)

    Mlynarsky, Liat; Bejarano-Achache, Idit; Muszkat, Mordechai; Caraco, Yoseph

    2012-05-01

    Warfarin responsiveness is characterized by marked interindividual variability. A major portion of this variability is attributed to CYP2C9 and VKORC1 polymorphisms, but almost 50% is still unaccounted for. This paper reports the first prospective study on the association between factor VII R353Q polymorphism and warfarin responsiveness during induction. Genotyping for factor VII R353Q and 323D/I polymorphisms was performed in a cohort consisting of 374 patients (198 CYP2C9*1/*1) treated with warfarin who were prospectively followed from warfarin initiation. Compared with *1/*1-R/R and *1/*1-R/Q genotype carriers, *1/*1-Q/Q homozygotes achieved higher International Normalized Ratio (INR) values while consuming lower warfarin doses. The greater sensitivity was illustrated by 82.1% higher Warfarin Sensitivity Index During Induction (WSIDI) (0.14 ± 0.11 vs. 0.08 ± 0.50 mg⁻¹ Mann-Whitney, P = 0.043). Multiple regression analysis consisting of both genetic and nongenetic factors explained 26% of WSIDI variability, with R353Q genetic polymorphism having a modest yet significant effect and accounting for 1.7% of the overall variability. Moreover, the incidence of overanticoagulation (i.e., INR > 4) was 6.94-fold higher among *1/*1-Q/Q vs. *1/*1-R/R&R/Q carriers during warfarin induction (Pearson chi-square, P = 0.005). These findings were not accounted for by a chance difference in the distribution of VKORC1 genotypes. Analysis of these parameters among the entire cohort, including CYP2C9*2 and CYP2C9*3 variant allele carriers, did not reach statistical significance. Warfarin responsiveness during induction was unrelated to factor VII 323D/I genetic polymorphism. The response to warfarin during induction is influenced by factor VII R353Q polymorphism. The prospective use of this polymorphism, along with CYP2C9 and VKORC1, may enhance the accuracy of warfarin loading. However, the impact of R353Q polymorphism on overall warfarin response is subtle, and it is therefore

  3. SplicePlot: a utility for visualizing splicing quantitative trait loci.

    Science.gov (United States)

    Wu, Eric; Nance, Tracy; Montgomery, Stephen B

    2014-04-01

    RNA sequencing has provided unprecedented resolution of alternative splicing and splicing quantitative trait loci (sQTL). However, there are few tools available for visualizing the genotype-dependent effects of splicing at a population level. SplicePlot is a simple command line utility that produces intuitive visualization of sQTLs and their effects. SplicePlot takes mapped RNA sequencing reads in BAM format and genotype data in VCF format as input and outputs publication-quality Sashimi plots, hive plots and structure plots, enabling better investigation and understanding of the role of genetics on alternative splicing and transcript structure. Source code and detailed documentation are available at http://montgomerylab.stanford.edu/spliceplot/index.html under Resources and at Github. SplicePlot is implemented in Python and is supported on Linux and Mac OS. A VirtualBox virtual machine running Ubuntu with SplicePlot already installed is also available.

  4. TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.

    Directory of Open Access Journals (Sweden)

    Pavan Kumar P

    2014-03-01

    Full Text Available TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

  5. TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.

    Science.gov (United States)

    Kumar P, Pavan; Franklin, Sarah; Emechebe, Uchenna; Hu, Hao; Moore, Barry; Lehman, Chris; Yandell, Mark; Moon, Anne M

    2014-03-01

    TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

  6. Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Francesco Parmeggiani

    2015-08-01

    Full Text Available Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD and pathologic myopia (PM, both of which are frequently complicated by subfoveal choroidal neovascularization (CNV. Photodynamic therapy with verteporfin (PDT-V is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985 has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1 total number of photodynamic treatments; and (2 change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype received a higher number of photodynamic treatments than patients without it (GG wild-type genotype (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively. Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively. The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of

  7. An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles

    NARCIS (Netherlands)

    Wilson, A. G.; de Vries, N. [=Niek; Pociot, F.; di Giovine, F. S.; van der Putte, L. B.; Duff, G. W.

    1993-01-01

    The tumor necrosis factor (TNF) alpha gene lies within the class III region of the major histocompatibility complex (MHC), telomeric to the class II and centromeric to the class I region. We have recently described the first polymorphism within the human TNF-alpha locus. This is biallelic and lies

  8. Capacity of columns with splice imperfections

    International Nuclear Information System (INIS)

    Popov, E.P.; Stephen, R.M.

    1977-01-01

    To study the behavior of spliced columns subjected to tensile forces simulating situations which may develop in an earthquake, all of the spliced specimens were tested to failure in tension after first having been subjected to large compressive loads. The results of these tests indicate that the lack of perfect contact at compression splices of columns may not be important, provided that the gaps are shimmed and welding is used to maintain the sections in alignment

  9. The connection between splicing and cancer

    OpenAIRE

    Srebrow, Anabella; Kornblihtt, Alberto Rodolfo

    2017-01-01

    Alternative splicing is a crucial mechanism for generating protein diversity. Different splice variants of a given protein can display different and even antagonistic biological functions. Therefore, appropriate control of their synthesis is required to assure the complex orchestration of cellular processes within multicellular organisms. Mutations in cisacting splicing elements or changes in the activity of regulatory proteins that compromise the accuracy of either constitutive or alternativ...

  10. Polymorphisms of transforming growth factor beta 1 (RS#1800468 and RS#1800471) and esophageal squamous cell carcinoma among Zhuangese population, China.

    Science.gov (United States)

    Tang, Ren-Guang; Huang, Yong-Zhi; Yao, Li-Min; Xiao, Jian; Lu, Chuan; Yu, Qian

    2013-01-01

    Epidemiological evidence has shown two polymorphisms (namely RS#1800468G>A and RS#1800471G>C) of transforming growth factor-beta 1 (TGF-β1) gene may be involved in the cancer development. However, their role in the carcinogenic process of esophageal squamous cell carcinoma (ESCC) has been less well elaborated. We conducted a hospital-based case-control study including 391 ESCC cases and 508 controls without any evidence of tumors to evaluate the association between these two polymorphisms and ESCC risk and prognosis for Zhuangese population by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system (ARMS)-PCR techniques. We found that individuals with the genotypes with RS#1800471 C allele (namely RS#1800471-GC or -CC) had an increased risk of ESCC than those without above genotypes (namely RS#1800471-GG, adjusted odds ratio 3.26 and 5.65, respectively). Further stratification analysis showed that this polymorphism was correlated with tumor histological grades and TNM (tumor, node, and metastasis) stage, and modified the serum levels of TGF-β1. Additionally, RS#1800471 polymorphism affected ESCC prognosis (hazard ratio, 3.40), especially under high serum levels of TGF-β1 conditions. However, RS#1800468 polymorphism was not significantly related to ESCC risk. These findings indicated that TGF-β1 RS#1800471G>C polymorphism may be a genetic modifier for developing ESCC in Zhuangese population. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way.

    Science.gov (United States)

    Chang, Chuan-Chia; Chang, Hsin-An; Chen, Tien-Yu; Fang, Wen-Hui; Huang, San-Yuan

    2014-09-01

    The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Large exon size does not limit splicing in vivo.

    Science.gov (United States)

    Chen, I T; Chasin, L A

    1994-03-01

    Exon sizes in vertebrate genes are, with a few exceptions, limited to less than 300 bases. It has been proposed that this limitation may derive from the exon definition model of splice site recognition. In this model, a downstream donor site enhances splicing at the upstream acceptor site of the same exon. This enhancement may require contact between factors bound to each end of the exon; an exon size limitation would promote such contact. To test the idea that proximity was required for exon definition, we inserted random DNA fragments from Escherichia coli into a central exon in a three-exon dihydrofolate reductase minigene and tested whether the expanded exons were efficiently spliced. DNA from a plasmid library of expanded minigenes was used to transfect a CHO cell deletion mutant lacking the dhfr locus. PCR analysis of DNA isolated from the pooled stable cotransfectant populations displayed a range of DNA insert sizes from 50 to 1,500 nucleotides. A parallel analysis of the RNA from this population by reverse transcription followed by PCR showed a similar size distribution. Central exons as large as 1,400 bases could be spliced into mRNA. We also tested individual plasmid clones containing exon inserts of defined sizes. The largest exon included in mRNA was 1,200 bases in length, well above the 300-base limit implied by the survey of naturally occurring exons. We conclude that a limitation in exon size is not part of the exon definition mechanism.

  13. Alanine repeats influence protein localization in splicing speckles and paraspeckles.

    Science.gov (United States)

    Chang, Shuo-Hsiu; Chang, Wei-Lun; Lu, Chia-Chen; Tarn, Woan-Yuh

    2014-12-16

    Mammalian splicing regulatory protein RNA-binding motif protein 4 (RBM4) has an alanine repeat-containing C-terminal domain (CAD) that confers both nuclear- and splicing speckle-targeting activities. Alanine-repeat expansion has pathological potential. Here we show that the alanine-repeat tracts influence the subnuclear targeting properties of the RBM4 CAD in cultured human cells. Notably, truncation of the alanine tracts redistributed a portion of RBM4 to paraspeckles. The alanine-deficient CAD was sufficient for paraspeckle targeting. On the other hand, alanine-repeat expansion reduced the mobility of RBM4 and impaired its splicing activity. We further took advantage of the putative coactivator activator (CoAA)-RBM4 conjoined splicing factor, CoAZ, to investigate the function of the CAD in subnuclear targeting. Transiently expressed CoAZ formed discrete nuclear foci that emerged and subsequently separated-fully or partially-from paraspeckles. Alanine-repeat expansion appeared to prevent CoAZ separation from paraspeckles, resulting in their complete colocalization. CoAZ foci were dynamic but, unlike paraspeckles, were resistant to RNase treatment. Our results indicate that the alanine-rich CAD, in conjunction with its conjoined RNA-binding domain(s), differentially influences the subnuclear localization and biogenesis of RBM4 and CoAZ. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Association of protein Z and factor VII gene polymorphisms with risk ...

    Indian Academy of Sciences (India)

    Protein Z (PZ) and factor (F) VII are two important factors in the clotting pathway ..... found in NCBI (http://www.ncbi.nlm.nih.gov/projects/SNP), chosen from the largest population .... power of this population-based case–control study was lim-.

  15. The role of tumor necrosis factor-alpha -308 G/A and transforming growth factor-beta 1 -915 G/C polymorphisms in childhood idiopathic thrombocytopenic purpura

    Directory of Open Access Journals (Sweden)

    Emel Okulu

    2011-09-01

    Full Text Available Objective: To increase our understanding of the etiology of idiopathic thrombocytopenic purpura (ITP some cytokine gene polymorphisms were analyzed for susceptibility to the disease. The aim of this study was to investigate the role of tumor necrosis factor-alpha (TNF-α -308 G/A and transforming growth factor-beta 1 (TGF-β1 –915 G/C polymorphisms in the development and clinical progression of childhood ITP.Materials and Methods: In all, 50 pediatric patients with ITP (25 with acute ITP and 25 with chronic ITP and 48 healthy controls were investigated via LightCycler® PCR analysis for TNF-α -308 G/A and TGF-β1 -915 G/C polymorphisms.Results: The frequency of TNF-α -308 G/A polymorphism was 20%, 16%, and 22.9% in the acute ITP patients, chronic ITP patients, and controls, respectively (p>0.05. The frequency of TGF-β1 -915 G/C polymorphism was 16%, 8%, and 8.3% in the acute ITP patients, chronic ITP patients, and controls, respectively (p>0.05. The risk of developing ITP and clinical progression were not associated with TNF-α -308 G/A (OR: 0.738, 95% CI: 0.275-1.981, and OR: 0.762, 95% CI: 0.179-3.249 or TGF-β1 -915 G/C (OR: 1.5, 95% CI: 0.396-5.685, and OR: 0.457, 95% CI: 0.076-2.755 polymorphisms. Conclusion: The frequency of TNF-α -308 G/A and TGF-β1 -915 G/C polymorphisms did not differ between pediatric ITP patients and healthy controls, and these polymorphisms were not associated with susceptibility to the development and clinical progression of the disease.

  16. Effect of the Gas6 c.834+7G>A polymorphism and the interaction of known risk factors on AMD pathogenesis in Hungarian patients.

    Directory of Open Access Journals (Sweden)

    Gergely Losonczy

    Full Text Available Age-related macular degeneration (AMD is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26-0.97, p = 0.04. Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30-393.02, p = 0.0033, respectively, but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98-12.25, p = 0.0006. Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the

  17. Association between polymorphisms in the coagulation factor VII gene and coronary heart disease risk in different ethnicities: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Mo Xingbo

    2011-08-01

    Full Text Available Abstract Background Previous studies have examined the association between polymorphisms in the coagulation factor VII gene and the risk of coronary heart disease (CHD, but those studies have been inconclusive. This study was conducted to assess the associations between these polymorphisms and CHD and evaluated the associations in different ethnicities. Methods Literature-based searching was conducted to collect data and two methods, namely fixed-effects and random-effects, were performed to pool the odds ratio (OR, together with the 95% confidence interval (CI. Publication bias and between-study heterogeneity were also examined. Results Thirty-nine case-control studies of the three polymorphisms, R353Q (rs6046, HVR4 and -323Ins10 (rs36208070 in factor VII gene and CHD were enrolled in this meta-analysis, including 9,151 cases of CHD and 14,099 controls for R353Q, 2,863 cases and 2,727 controls for HVR4, and 2,862 cases and 4,240 controls for -323Ins10. Significant association was only found in Asian population for R353Q (Q vs R, with pooled OR of 0.70(95%CI: 0.55, 0.90. For the -323Ins10 polymorphism (10 vs 0, we found significant associations in both Asian and European populations, with pooled ORs of 0.74(95%CI: 0.61, 0.88 and 0.63(95%CI: 0.53, 0.74, respectively. Marginal significant association was found between HVR4 (H7 vs H5+H6 and CHD (OR = 0.88, 95% CI: 0.78, 1.00. There was no evidence of publication bias, but between-study heterogeneity was found in the analyses. Conclusions The -323Ins10 polymorphism in factor VII gene is significantly associated with CHD in both Asian and European populations, while R353Q polymorphism showed trend for association with CHD in Asians. Lack of association was found for HVR4 polymorphism. Further studies are needed to confirm the association, especially for -323Ins10 polymorphism.

  18. Polymorphisms in NFKB1 and TLR4 and Interaction with Dietary and Life Style Factors in Relation to Colorectal Cancer in a Danish Prospective Case-Cohort Study

    DEFF Research Database (Denmark)

    Kopp, Tine Iskov; Andersen, Vibeke; Tjoøneland, Anne

    2015-01-01

    Maintenance of a balance between commensal bacteria and the mucosal immune system is crucial and intestinal dysbiosis may be a key event in the pathogenesis of colorectal cancer (CRC). The toll-like receptor 4 (TLR4) is an important pattern-recognition receptor that regulates inflammation...... and barrier function in the gut by a mechanism that involves activation of the nuclear factor-kappa B (NF-kappa B) transcription factor. Dietary and life style factors may impact these functions. We therefore used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants...... from the Danish Diet, Cancer and Health cohort to investigate three polymorphisms in NFKB1 and TLR4 and their possible interactions with diet and life style factors in relation to risk of CRC. Homozygous carriage of the variant allele of the TLR4/rs5030728 polymorphism was associated with increased...

  19. SplicingTypesAnno: annotating and quantifying alternative splicing events for RNA-Seq data.

    Science.gov (United States)

    Sun, Xiaoyong; Zuo, Fenghua; Ru, Yuanbin; Guo, Jiqiang; Yan, Xiaoyan; Sablok, Gaurav

    2015-04-01

    Alternative splicing plays a key role in the regulation of the central dogma. Four major types of alternative splicing have been classified as intron retention, exon skipping, alternative 5 splice sites or alternative donor sites, and alternative 3 splice sites or alternative acceptor sites. A few algorithms have been developed to detect splice junctions from RNA-Seq reads. However, there are few tools targeting at the major alternative splicing types at the exon/intron level. This type of analysis may reveal subtle, yet important events of alternative splicing, and thus help gain deeper understanding of the mechanism of alternative splicing. This paper describes a user-friendly R package, extracting, annotating and analyzing alternative splicing types for sequence alignment files from RNA-Seq. SplicingTypesAnno can: (1) provide annotation for major alternative splicing at exon/intron level. By comparing the annotation from GTF/GFF file, it identifies the novel alternative splicing sites; (2) offer a convenient two-level analysis: genome-scale annotation for users with high performance computing environment, and gene-scale annotation for users with personal computers; (3) generate a user-friendly web report and additional BED files for IGV visualization. SplicingTypesAnno is a user-friendly R package for extracting, annotating and analyzing alternative splicing types at exon/intron level for sequence alignment files from RNA-Seq. It is publically available at https://sourceforge.net/projects/splicingtypes/files/ or http://genome.sdau.edu.cn/research/software/SplicingTypesAnno.html. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. A Systems-Level Analysis Reveals Circadian Regulation of Splicing in Colorectal Cancer.

    Science.gov (United States)

    El-Athman, Rukeia; Fuhr, Luise; Relógio, Angela

    2018-06-20

    Accumulating evidence points to a significant role of the circadian clock in the regulation of splicing in various organisms, including mammals. Both dysregulated circadian rhythms and aberrant pre-mRNA splicing are frequently implicated in human disease, in particular in cancer. To investigate the role of the circadian clock in the regulation of splicing in a cancer progression context at the systems-level, we conducted a genome-wide analysis and compared the rhythmic transcriptional profiles of colon carcinoma cell lines SW480 and SW620, derived from primary and metastatic sites of the same patient, respectively. We identified spliceosome components and splicing factors with cell-specific circadian expression patterns including SRSF1, HNRNPLL, ESRP1, and RBM 8A, as well as altered alternative splicing events and circadian alternative splicing patterns of output genes (e.g., VEGFA, NCAM1, FGFR2, CD44) in our cellular model. Our data reveals a remarkable interplay between the circadian clock and pre-mRNA splicing with putative consequences in tumor progression and metastasis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.

    Directory of Open Access Journals (Sweden)

    Ronghui Li

    2016-06-01

    Full Text Available Mutations in the human MECP2 gene cause Rett syndrome (RTT, a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies.

  2. Association between Interleukin-10-1082 G/A and Tumor Necrosis Factor-α 308 G/A Gene Polymorphisms and Respiratory Distress Syndrome in Iranian Preterm Infants

    OpenAIRE

    Khoshdel, Abolfazl; Kheiri, Soleiman; Omidvari, Peyman; Moradi, Fahimeh; Hamidi, Majid; Teimori, Hossein

    2017-01-01

    Cytokine polymorphisms may contribute to the prevalence of respiratory distress syndrome. The present study was done to investigate the frequency of interleukin- (IL-) 10 and tumor necrosis factor- (TNF-) ? gene polymorphisms and their association with the risk of RDS in preterm infants. One-hundred and nineteen patients with RDS and 119 healthy preterm infants were enrolled. PCR restriction fragment length polymorphism was used to determine the frequency of IL-10 and TNF-? genotypes at -1082...

  3. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

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    Claire Jackson

    2013-01-01

    Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

  4. Gene polymorphisms as risk factors for predicting the cardiovascular manifestations in Marfan syndrome. Role of folic acid metabolism enzyme gene polymorphisms in Marfan syndrome.

    Science.gov (United States)

    Benke, Kálmán; Ágg, Bence; Mátyás, Gábor; Szokolai, Viola; Harsányi, Gergely; Szilveszter, Bálint; Odler, Balázs; Pólos, Miklós; Maurovich-Horvat, Pál; Radovits, Tamás; Merkely, Béla; Nagy, Zsolt B; Szabolcs, Zoltán

    2015-10-01

    Folic acid metabolism enzyme polymorphisms are believed to be responsible for the elevation of homocysteine (HCY) concentration in the blood plasma, correlating with the pathogenesis of aortic aneurysms and aortic dissection. We studied 71 Marfan patients divided into groups based on the severity of cardiovascular involvement: no intervention required (n=27, Group A); mild involvement requiring intervention (n=17, Group B); severe involvement (n=27, Group C) subdivided into aortic dilatation (n=14, Group C1) and aortic dissection (n=13, Group C2), as well as 117 control subjects. We evaluated HCY, folate, vitamin B12 and the polymorphisms of methylenetetrahydrofolate reductase (MTHFR;c.665C>T and c.1286A>C), methionine synthase (MTR;c.2756A>G) and methionine synthase reductase (MTRR;c.66A>G). Multiple comparisons showed significantly higher levels of HCY in Group C2 compared to Groups A, B, C1 and control group (pMarfan patients, and especially aortic dissection, is associated with higher HCY plasma levels and prevalence of homozygous genotypes of folic acid metabolism enzymes than mild or no cardiovascular involvement. These results suggest that impaired folic acid metabolism has an important role in the development and remodelling of the extracellular matrix of the aorta.

  5. Association and Interaction Effect of AGTR1 and AGTR2 Gene Polymorphisms with Dietary Pattern on Metabolic Risk Factors of Cardiovascular Disease in Malaysian Adults

    OpenAIRE

    Yap, Roseline Wai Kuan; Shidoji, Yoshihiro; Yap, Wai Sum; Masaki, Motofumi

    2017-01-01

    Gene-diet interaction using a multifactorial approach is preferred to study the multiple risk factors of cardiovascular disease (CVD). This study examined the association and gene-diet interaction effects of the angiotensin II type 1 receptor (AGTR1) gene (rs5186), and type 2 receptor (AGTR2) gene (rs1403543) polymorphisms on metabolic risk factors of CVD in Malaysian adults. CVD parameters (BMI, blood pressure, glycated hemoglobin, total cholesterol (TC), triglycerides, low-density lipoprote...

  6. Confounding factors and genetic polymorphism in the evaluation of individual steroid profiling

    Science.gov (United States)

    Kuuranne, Tiia; Saugy, Martial; Baume, Norbert

    2014-01-01

    In the fight against doping, steroid profiling is a powerful tool to detect drug misuse with endogenous anabolic androgenic steroids. To establish sensitive and reliable models, the factors influencing profiling should be recognised. We performed an extensive literature review of the multiple factors that could influence the quantitative levels and ratios of endogenous steroids in urine matrix. For a comprehensive and scientific evaluation of the urinary steroid profile, it is necessary to define the target analytes as well as testosterone metabolism. The two main confounding factors, that is, endogenous and exogenous factors, are detailed to show the complex process of quantifying the steroid profile within WADA-accredited laboratories. Technical aspects are also discussed as they could have a significant impact on the steroid profile, and thus the steroid module of the athlete biological passport (ABP). The different factors impacting the major components of the steroid profile must be understood to ensure scientifically sound interpretation through the Bayesian model of the ABP. Not only should the statistical data be considered but also the experts in the field must be consulted for successful implementation of the steroidal module. PMID:24764553

  7. Disease associated clinical factors and FTO polymorphism: effect on body mass in children with type 1 diabetes mellitus.

    Science.gov (United States)

    Łuczyński, Włodzimierz; Szypowska, Agnieszka; Głowińska-Olszewska, Barbara; Szadkowska, Agnieszka; Bossowski, Artur

    2014-08-01

    One of the consequences of excessive weight gain during insulin therapy in type 1 diabetes mellitus (T1DM) is an increased predisposition to cardiovascular diseases (CVD). Not only clinical but also genetic factors may play a role in the pathogenesis of this phenomenon. The aim of this study was to evaluate the prevalence of cardiovascular disease risk factors as well as the fat mass and obesity associated (FTO) gene rs9939609 variant in a large group of children with T1DM of the same ethnic-Polish origin. A total of 1237 children with T1DM and 1015 controls were recruited. The proportions of patients with obesity, hypertension, and abnormal LDL-cholesterol levels among children with T1DM were significantly higher than those in the non-diabetic. There was a higher rate of overweight, central obesity, and abnormal LDL-cholesterol levels among girls in comparison to that in boys in the group of children with diabetes. Children with inadequate metabolic control were characterized by the presence of more CVD risk factors. Similar differences were observed in children treated with the use of pens versus those using insulin pumps. The FTO gene single nucleotide polymorphism (SNP) correlated with body mass index (BMI) in both control and diabetic children, but the effect was lesser in diabetics. In a regression model the current BMI-SDS value in diabetics was significantly affected by the baseline BMI, disease duration, metabolic control, and subject's sex, but not the FTO genotype. Clinical rather than genetic factors have a greater impact on the development of overweight and obesity in insulin-treated children

  8. Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk.

    Science.gov (United States)

    Olson, N C; Raffield, L M; Lange, L A; Lange, E M; Longstreth, W T; Chauhan, G; Debette, S; Seshadri, S; Reiner, A P; Tracy, R P

    2018-01-01

    Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = -25.9 mU mL -1 per minor allele; FVIIa-AT, β = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL -1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in

  9. Involvement of the catalytic subunit of protein kinase A and of HA95 in pre-mRNA splicing

    International Nuclear Information System (INIS)

    Kvissel, Anne-Katrine; Orstavik, Sigurd; Eikvar, Sissel; Brede, Gaute; Jahnsen, Tore; Collas, Philippe; Akusjaervi, Goeran; Skalhegg, Bjorn Steen

    2007-01-01

    Protein kinase A (PKA) is a holoenzyme consisting of two catalytic (C) subunits bound to a regulatory (R) subunit dimer. Stimulation by cAMP dissociates the holoenzyme and causes translocation to the nucleus of a fraction of the C subunit. Apart from transcription regulation, little is known about the function of the C subunit in the nucleus. In the present report, we show that both Cα and Cβ are localized to spots in the mammalian nucleus. Double immunofluorescence analysis of splicing factor SC35 with the C subunit indicated that these spots are splicing factor compartments (SFCs). Using the E1A in vivo splicing assay, we found that catalytically active C subunits regulate alternative splicing and phosphorylate several members of the SR-protein family of splicing factors in vitro. Furthermore, nuclear C subunits co-localize with the C subunit-binding protein homologous to AKAP95, HA95. HA95 also regulates E1A alternative splicing in vivo, apparently through its N-terminal domain. Localization of the C subunit to SFCs and the E1A splicing pattern were unaffected by cAMP stimulation. Our findings demonstrate that the nuclear PKA C subunit co-locates with HA95 in SFCs and regulates pre-mRNA splicing, possibly through a cAMP-independent mechanism

  10. Chinmo prevents transformer alternative splicing to maintain male sex identity.

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    Lydia Grmai

    2018-02-01

    Full Text Available Reproduction in sexually dimorphic animals relies on successful gamete production, executed by the germline and aided by somatic support cells. Somatic sex identity in Drosophila is instructed by sex-specific isoforms of the DMRT1 ortholog Doublesex (Dsx. Female-specific expression of Sex-lethal (Sxl causes alternative splicing of transformer (tra to the female isoform traF. In turn, TraF alternatively splices dsx to the female isoform dsxF. Loss of the transcriptional repressor Chinmo in male somatic stem cells (CySCs of the testis causes them to "feminize", resembling female somatic stem cells in the ovary. This somatic sex transformation causes a collapse of germline differentiation and male infertility. We demonstrate this feminization occurs by transcriptional and post-transcriptional regulation of traF. We find that chinmo-deficient CySCs upregulate tra mRNA as well as transcripts encoding tra-splice factors Virilizer (Vir and Female lethal (2d (Fl(2d. traF splicing in chinmo-deficient CySCs leads to the production of DsxF at the expense of the male isoform DsxM, and both TraF and DsxF are required for CySC sex transformation. Surprisingly, CySC feminization upon loss of chinmo does not require Sxl but does require Vir and Fl(2d. Consistent with this, we show that both Vir and Fl(2d are required for tra alternative splicing in the female somatic gonad. Our work reveals the need for transcriptional regulation of tra in adult male stem cells and highlights a previously unobserved Sxl-independent mechanism of traF production in vivo. In sum, transcriptional control of the sex determination hierarchy by Chinmo is critical for sex maintenance in sexually dimorphic tissues and is vital in the preservation of fertility.

  11. Chinmo prevents transformer alternative splicing to maintain male sex identity.

    Science.gov (United States)

    Grmai, Lydia; Hudry, Bruno; Miguel-Aliaga, Irene; Bach, Erika A

    2018-02-01

    Reproduction in sexually dimorphic animals relies on successful gamete production, executed by the germline and aided by somatic support cells. Somatic sex identity in Drosophila is instructed by sex-specific isoforms of the DMRT1 ortholog Doublesex (Dsx). Female-specific expression of Sex-lethal (Sxl) causes alternative splicing of transformer (tra) to the female isoform traF. In turn, TraF alternatively splices dsx to the female isoform dsxF. Loss of the transcriptional repressor Chinmo in male somatic stem cells (CySCs) of the testis causes them to "feminize", resembling female somatic stem cells in the ovary. This somatic sex transformation causes a collapse of germline differentiation and male infertility. We demonstrate this feminization occurs by transcriptional and post-transcriptional regulation of traF. We find that chinmo-deficient CySCs upregulate tra mRNA as well as transcripts encoding tra-splice factors Virilizer (Vir) and Female lethal (2)d (Fl(2)d). traF splicing in chinmo-deficient CySCs leads to the production of DsxF at the expense of the male isoform DsxM, and both TraF and DsxF are required for CySC sex transformation. Surprisingly, CySC feminization upon loss of chinmo does not require Sxl but does require Vir and Fl(2)d. Consistent with this, we show that both Vir and Fl(2)d are required for tra alternative splicing in the female somatic gonad. Our work reveals the need for transcriptional regulation of tra in adult male stem cells and highlights a previously unobserved Sxl-independent mechanism of traF production in vivo. In sum, transcriptional control of the sex determination hierarchy by Chinmo is critical for sex maintenance in sexually dimorphic tissues and is vital in the preservation of fertility.

  12. Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS

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    Annika Dötsch

    2017-06-01

    Full Text Available Hypoxia-inducible-factor-2α (HIF-2α and HIF-2 degrading prolyl-hydroxylases (PHD are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS. Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP [ch2:46441523(hg18] and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902 are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs’ prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1 common, and (2 independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay and HIF-2α-polymorphism (restriction digest + agarose-gel visualization, and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%, 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%, and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%. PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09–10.22; p = 0.034 within 30-days, whereas the other SNPs had no significant impact (p = ns. The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS.

  13. Tumor necrosis factor alpha polymorphism correlates with deleterious effects of ultraviolet B light on cutaneous immunity

    NARCIS (Netherlands)

    Vincek, V.; Kurimoto, I.; Medema, J. P.; Prieto, E.; Streilein, J. W.

    1993-01-01

    Intradermally injected tumor necrosis factor alpha (TNF-alpha) mimics the effects of UV B light (UVB) radiation and neutralizing anti-TNF-alpha antibodies abolish the deleterious effects of UVB on induction of contact hypersensitivity suggesting that TNF-alpha is the major mediator of UVB effects on

  14. Vascular endothelial growth factor gene polymorphisms in patients with colorectal cancer Polimorfismos del gen del factor de crecimiento vascular endotelial en pacientes con cáncer colorrectal

    Directory of Open Access Journals (Sweden)

    M. Vidaurreta

    2010-01-01

    Full Text Available Background: angiogenesis plays an important role in tumor progression. The vascular endothelial growth factor (VEGF is an important regulator of angiogenesis. In the present study we evaluated single nucleotide polymorphisms (SNPs -2578C > A, -1154G > A, and +936C > T in the VEGF gene, and their prognostic value for patients operated on for colorectal cancer (CRC. Patients and method: VEGF polymorphisms have been analyzed in 177 patients who had undergone surgical resection at Hospital Clínico San Carlos. The analysis of these polymorphisms was performed with specific probes for each nucleotide in a multiplex reaction using real-time PCR. Results: we only found a statistically significant relationship for one of these three polymorphisms, +936C > T, with gender and tumor location; 10.7% of patients heterozygotes for this SNP had tumors located in proximal colon, 35.2% in distal segment and 54.1% in rectum (p = 0.03. Patients with the +936T/T genotype had 100% overall survival (OS. Conclusion: patients with a +936T/T genotype showed increased survival, therefore the +936C > T SNP could be a useful marker in the follow-up and clinical management of patients with colorectal cancer.Introducción: la angiogénesis juega un papel importante en la progresión de los tumores. El factor de crecimiento endotelial vascular (VEGF es un importante regulador de la angiogénesis. En este trabajo se han analizado los polimorfismos de único nucleó-tido (SNP -2578C > A, -1154G > A y +936C > T del gen VEGF en pacientes intervenidos de carcinoma colorrectal, así como su posible implicación pronóstica. Pacientes y método: el estudio de estos SNP se ha realizado en 177 pacientes intervenidos quirúrgicamente de carcinoma colorrectal (CCR en el Hospital Clínico San Carlos. El análisis de los polimorfismos se realizó con sondas específicas para cada nucleótido y se determinó mediante una reacción multiplex mediante real time PCR. Resultados: de los 3

  15. Influence of The -202 A/C insulin-like growth factor-binding protein-3 promoter polymorphism on individual variation in height in Korean girls

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    Min Ju Yi

    2017-03-01

    Full Text Available PurposeThe most common single nucleotide polymorphism in the IGFBP3 promoter region occurs at position -202. This polymorphic variation occurs frequently and may influence growth hormone responsiveness and somatic growth. However, the effects of IGFBP3 promoter polymorphism on growth in children are unknown.MethodsRestriction fragment length polymorphism-based genotyping of the -202 single nucleotide polymorphism was performed in 146 Korean girls aged between 15 and 16 years, who were selected randomly from the Seoul School Health Promotion Center. The participants were divided into 3 groups (tall, medium, and short according to the height percentile established from normal reference values for Korean children. The serum levels of insulin-like growth factor I (IGF-I and IGF-binding protein-3 (IGFBP-3 were then compared according to genotype.ResultsThe genotype distribution in the participants was 79 AA (54.1%, 60 AC (41.1%, and 7 CC (4.8%. The C allele frequency at the -202 IGFBP3 position was 25.4% in this group. The mean serum IGFBP-3 concentration in girls with the AA genotype was higher than that in girls with the AC genotype in the medium (P=0.047 and short (P=0.035 groups, respectively. There was no difference in the IGF-I to IGFBP-3 molar ratio between the AA and AC genotype groups (P=0.161.ConclusionIn conclusion, the -202 polymorphism in the IGFBP3 promoter region is assumed to affect the serum concentration of IGFBP-3 in children as well as in adults. However, it is unclear whether this affects physical development according to the concentration of IGFBP-3.

  16. Computational Analysis of an Evolutionarily Conserved VertebrateMuscle Alternative Splicing Program

    Energy Technology Data Exchange (ETDEWEB)

    Das, Debopriya; Clark, Tyson A.; Schweitzer, Anthony; Marr,Henry; Yamamoto, Miki L.; Parra, Marilyn K.; Arribere, Josh; Minovitsky,Simon; Dubchak, Inna; Blume, John E.; Conboy, John G.

    2006-06-15

    A novel exon microarray format that probes gene expression with single exon resolution was employed to elucidate critical features of a vertebrate muscle alternative splicing program. A dataset of 56 microarray-defined, muscle-enriched exons and their flanking introns were examined computationally in order to investigate coordination of the muscle splicing program. Candidate intron regulatory motifs were required to meet several stringent criteria: significant over-representation near muscle-enriched exons, correlation with muscle expression, and phylogenetic conservation among genomes of several vertebrate orders. Three classes of regulatory motifs were identified in the proximal downstream intron, within 200nt of the target exons: UGCAUG, a specific binding site for Fox-1 related splicing factors; ACUAAC, a novel branchpoint-like element; and UG-/UGC-rich elements characteristic of binding sites for CELF splicing factors. UGCAUG was remarkably enriched, being present in nearly one-half of all cases. These studies suggest that Fox and CELF splicing factors play a major role in enforcing the muscle-specific alternative splicing program, facilitating expression of a set of unique isoforms of cytoskeletal proteins that are critical to muscle cell differentiation. Supplementary materials: There are four supplementary tables and one supplementary figure. The tables provide additional detailed information concerning the muscle-enriched datasets, and about over-represented oligonucleotide sequences in the flanking introns. The supplementary figure shows RT-PCR data confirming the muscle-enriched expression of exons predicted from the microarray analysis.

  17. The Effect of PAI-1 4G/5G Polymorphism and Clinical Factors on Coronary Artery Occlusion in Myocardial Infarction

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    Tajinder Kumar Parpugga

    2015-01-01

    Full Text Available Objective. Data on the impact of PAI-1-675 4G/5G genotype for fibrinolysis during myocardial infarction are inconsistent. The aim of our study was to evaluate the association of clinical and genetic (PAI-1-675 4G/5G polymorphism factors with coronary artery occlusion in patients with myocardial infarction. Materials and Methods. PAI-1-675 4G/5G detection was achieved by using Sanger sequencing in a sample of patients hospitalized for stent implantation due to myocardial infarction. We categorized the patients into two groups: patients with coronary artery occlusion and patients without coronary artery occlusion according to angiographic evaluation. Results. We identified n=122 (32.4% 4G/4G, n=186 (49.5% 4G/5G, and n=68 (18.1% 5G/5G PAI-1 genotype carriers. Univariate and multivariate analysis showed that only the 4G/5G genotype was associated with coronary artery occlusion (OR: 1.656 and 95% CI: 1.009–2.718, p=0.046. Conclusions. Our results showed that carriers of PAI-1 4G/5G genotype with myocardial infarction have increased odds of coronary artery occlusion more than 1.6 times in comparison to the carriers of homozygous genotypes.

  18. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism interacts with gender to influence cortisol responses to mental stress.

    Science.gov (United States)

    Jiang, Rong; Babyak, Michael A; Brummett, Beverly H; Siegler, Ilene C; Kuhn, Cynthia M; Williams, Redford B

    2017-05-01

    Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with cortisol responses to stress with gender differences reported, although the findings are not entirely consistent. To evaluate the role of Val66Met genotype and gender on cortisol responses to stress, we conducted a 45-min mental stress protocol including four tasks and four rest periods. Blood cortisol was collected for assay immediately before and after each task and rest period. A significant two-way interaction of Val66Met genotype×gender (P=0.022) was observed on the total area under the curve (AUC), a total cortisol response over time, such that the Val/Val genotype was associated with a larger cortisol response to stress as compared to the Met group in women but not in men. Further contrast analyses between the Val/Val and Met group for each stress task showed a similar increased cortisol pattern among women Val/Val genotype but not among men. The present findings indicate the gender differences in the effect of Val66Met genotype on the cortisol responses to stress protocol, and extend the evidence for the importance of gender and the role of Val66Met in the modulation of stress reactivity and subsequent depression prevalence. Further studies and the underlying mechanism need to be investigated, which may provide an insight for prevention, intervention, and treatment strategies that target those at high risk. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. The brain-derived neurotrophic factor Val66Met polymorphism is associated with age-related change in reasoning skills.

    Science.gov (United States)

    Harris, S E; Fox, H; Wright, A F; Hayward, C; Starr, J M; Whalley, L J; Deary, I J

    2006-05-01

    A polymorphism (Val66Met) in the gene encoding brain-derived neurotrophic factor (BDNF) has previously been associated with impaired hippocampal function and scores on the Logical Memory subtest of the Wechsler Memory Scale-Revised (WMS-R). Despite its widespread expression in the brain, there have been few studies examining the role of BDNF on cognitive domains, other than memory. We examined the association between BDNF Val66Met genotype and non-verbal reasoning, as measured by Raven's standard progressive matrices (Raven), in two cohorts of relatively healthy older people, one aged 79 (LBC1921) and the other aged 64 (ABC1936) years. LBC1921 and ABC1936 subjects had reasoning measured at age 11 years, using the Moray House Test (MHT), in the Scottish Mental Surveys of 1932 and 1947, respectively. BDNF genotype was significantly associated with later life Raven scores, controlling for sex, age 11 MHT score and cohort (P = 0.001). MHT, Verbal Fluency and Logical Memory scores were available, in later life, for LBC1921 only. BDNF genotype was significantly associated with age 79 MHT score, controlling for sex and age 11 MHT score (P = 0.016). In both significant associations, Met homozygotes scored significantly higher than heterozygotes and Val homozygotes. This study indicates that BDNF genotype contributes to age-related changes in reasoning skills, which are closely related to general intelligence.

  20. The Effect of PAI-1 4G/5G Polymorphism and Clinical Factors on Coronary Artery Occlusion in Myocardial Infarction.

    Science.gov (United States)

    Parpugga, Tajinder Kumar; Tatarunas, Vacis; Skipskis, Vilius; Kupstyte, Nora; Zaliaduonyte-Peksiene, Diana; Lesauskaite, Vaiva

    2015-01-01

    Data on the impact of PAI-1-675 4G/5G genotype for fibrinolysis during myocardial infarction are inconsistent. The aim of our study was to evaluate the association of clinical and genetic (PAI-1-675 4G/5G polymorphism) factors with coronary artery occlusion in patients with myocardial infarction. PAI-1-675 4G/5G detection was achieved by using Sanger sequencing in a sample of patients hospitalized for stent implantation due to myocardial infarction. We categorized the patients into two groups: patients with coronary artery occlusion and patients without coronary artery occlusion according to angiographic evaluation. We identified n = 122 (32.4%) 4G/4G, n = 186 (49.5%) 4G/5G, and n = 68 (18.1%) 5G/5G PAI-1 genotype carriers. Univariate and multivariate analysis showed that only the 4G/5G genotype was associated with coronary artery occlusion (OR: 1.656 and 95% CI: 1.009-2.718, p = 0.046). Our results showed that carriers of PAI-1 4G/5G genotype with myocardial infarction have increased odds of coronary artery occlusion more than 1.6 times in comparison to the carriers of homozygous genotypes.

  1. Complement factor H polymorphisms in Japanese population with age-related macular degeneration.

    Science.gov (United States)

    Okamoto, Haru; Umeda, Shinsuke; Obazawa, Minoru; Minami, Masayoshi; Noda, Toru; Mizota, Atsushi; Honda, Miki; Tanaka, Minoru; Koyama, Risa; Takagi, Ikue; Sakamoto, Yoshihiro; Saito, Yoshihiro; Miyake, Yozo; Iwata, Takeshi

    2006-03-06

    To study the frequency of five haplotypes previously reported in the complement factor H (CFH) gene for Japanese patients with age-related macular degeneration (AMD). Genomic DNA was isolated from peripheral blood samples taken from 96 Japanese AMD patients and 89 age-matched controls. All patients were diagnosed as having exudative (wet-type) AMD. The amplified polymerase chain reaction (PCR) products of CFH exons 2, 9, and 13, and intron 6 were analyzed by temperature gradient capillary electrophoresis (TGCE) and by direct sequencing. The haplotypes were identified, and their frequencies were calculated and compared with reported results. Five haplotypes were identified in the Japanese population including four already reported in the American population. The frequencies of these haplotypes were significantly different between Japanese and American in both control and case groups. The haplotype containing Y402H, which was previously reported to be associated with AMD, was only 4% in the control and case population, with a p value of 0.802. However, two other haplotypes were found as risk factors, which gave an increased likelihood of AMD of 1.9 and 2.5 fold (95% CI 1.12-3.69 and 1.42-6.38). One protective haplotype that decreased the likelihood of AMD by 1.6 fold (95% CI 0.26-0.67) was identified. The frequencies for five haplotypes previously identified were analyzed in a Japanese population with AMD. Four previously found haplotypes were identified and one additional haplotype was found. The frequencies of each haplotype were significantly different from that in found Americans affected with AMD. Two of the haplotypes were identified as risk factors and one was considered protective.

  2. Transcription factor 7-like 2 polymorphism and context-specific risk of metabolic syndrome, type 2 diabetes, and dyslipidemia

    Directory of Open Access Journals (Sweden)

    Abbasali Palizban

    2017-01-01

    Full Text Available Background: The transcription factor 7-like 2 gene (TCF7L2 is an element of the Wnt signaling pathway. There is lack of evidence if TCF7L2 has a functional role in lipid metabolism and regulation of the components constitutes the metabolic syndrome (MetSyn. The aims of this study were to evaluate whether the risk allele of TCF7L2 gene polymorphism is associated with dyslipidemia and MetSyn. Materials and Methods: The MetSyn subjects were participated only based on the National Cholesterol Education Program – Third Adult Treatment Panel criteria. In this case–control study, the DNA from MetSyn patients without (n = 90 and with type 2 diabetes (T2D (n = 94 were genotyped. Results: The results show that the genotype-phenotype for CC, CT/TT of TCF7L2 gene polymorphism correlated with body mass index and waist circumference in MetSyn and MetSyn + T2D subjects (r = −0.949 and r = −0.963, respectively. The subjects that only possess MetSyn but are not diabetics show the 2 h postprandial glucose and fasting blood glucose, glycated hemoglobin significantly lower (P < 0.05 than those subjects have both abnormality. The level of triglyceride in CT/TT carriers in MetSyn was higher than CC carriers (P = 0.025. A comparison with the controls subjects, the frequencies of the T allele in the groups of MetSyn (46.66% and MetSyn + T2D (47.34% show significantly different (P < 0.05. The odds ratios for T allele in (MetSyn/(normal, (MetSyn + T2D/(normal, and in (MetSyn + T2D/(MetSyn were 3.59 (95% confidence interval [CI], 1.33–9.67, P = 0.0093, 3.76 (95% CI, 1.40–10.07, P = 0.0068, and 1.08 (95% CI: 0.55– 2.11, P = 0.834, respectively. Conclusion: The results revealed the important insights essential for the role of TCF7L2 that the T allele of TCF7L2 plays a significant role in the susceptibility to dyslipidemia, MetSyn, and T2D.

  3. Vitamins B2 and B6 and Genetic Polymorphisms Related to One-Carbon Metabolism as Risk Factors for Gastric Adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition

    NARCIS (Netherlands)

    Eussen, Simone J. P. M.; Vollset, Stein Emil; Hustad, Steinar; Midttun, Oivind; Meyer, Klaus; Fredriksen, Ase; Ueland, Per Magne; Jenab, Mazda; Slimani, Nadia; Ferrari, Pietro; Agudo, Antonio; Sala, Nuria; Capella, Gabriel; Del Giudice, Giuseppe; Palli, Domenico; Boeing, Heiner; Weikert, Cornelia; Bueno-de-Mesquita, H. Bas; Buechner, Frederike L.; Carneiro, Fatima; Berrino, Franco; Vineis, Paolo; Tumino, Rosario; Panico, Salvatore; Berglund, Goran; Manjer, Jonas; Stenling, Roger; Hallmans, Goeran; Martinez, Carmen; Arrizola, Larraitz; Barricarte, Aurelio; Navarro, Carmen; Rodriguez, Laudina; Bingham, Sheila; Linseisen, Jakob; Kaaks, Rudolf; Overvad, Kim; Tjonneland, Anne; Peeters, Petra H. M.; Numans, Mattijs E.; Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Morois, Sophie; Trichopoulou, Antonia; Lund, Eiliv; Plebani, Mario; Riboli, Elio; Gonzalez, Carlos A.

    B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric

  4. Spliced

    DEFF Research Database (Denmark)

    Addison, Courtney Page

    2017-01-01

    Human gene therapy (HGT) aims to cure disease by inserting or editing the DNA of patients with genetic conditions. Since foundational genetic techniques came into use in the 1970s, the field has developed to the point that now three therapies have market approval, and over 1800 clinical trials have...

  5. Polymorphism in leptin receptor gene was associated with obesity in ...

    African Journals Online (AJOL)

    The mutation in leptin receptor (LEPR) gene causes splicing abnormality that resulted in truncated receptor, aberrant signal transduction, leptin resistance, and obesity. This study aims to determine the association of LEPR gene polymorphisms, rs1137100 and rs1137101, on phenotype and leptin level between obese and ...

  6. Position dependence of the rous sarcoma virus negative regulator of splicing element reflects proximity to a 5' splice site

    International Nuclear Information System (INIS)

    Wang Yuedi; McNally, Mark T.

    2003-01-01

    Rous sarcoma virus (RSV) requires incomplete splicing of its viral transcripts to maintain efficient replication. A splicing inhibitor element, the negative regulator of splicing (NRS), is located near the 5' end of the RNA but the significance of this positioning is not known. In a heterologous intron the NRS functions optimally when positioned close to the authentic 5' splice site. This observation led us to investigate the basis of the position dependence. Four explanations were put forth and stressed the role of three major elements involved in splicing, the 3' splice site, the 5' splice site, and the 5' end cap structure. NRS function was unrelated to its position relative to the 3' splice site or the cap structure and appeared to depend on its position relative to the authentic 5' splice site. We conclude that position dependence may reflect distance constraints necessary for competition of the NRS with the authentic 5' splice site for pairing with the 3' splice sites

  7. Tumor Necrosis Factor (TNF -308G>A, Nitric Oxide Synthase 3 (NOS3 +894G>T Polymorphisms and Migraine Risk: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Min Chen

    Full Text Available Conflicting data have been reported on the association between tumor necrosis factor (TNF -308G>A and nitric oxide synthase 3 (NOS3 +894G>T polymorphisms and migraine. We performed a meta-analysis of case-control studies to evaluate whether the TNF -308G>A and NOS3 +894G>T polymorphisms confer genetic susceptibility to migraine.We performed an updated meta-analysis for TNF -308G>A and a meta-analysis for NOS3 +894G>T based on studies published up to July 2014. We calculated study specific odds ratios (OR and 95% confidence intervals (95% CI assuming allele contrast, dominant model, recessive model, and co-dominant model as pooled effect estimates.Eleven studies in 6682 migraineurs and 22591 controls for TNF -308G>A and six studies in 1055 migraineurs and 877 controls for NOS3 +894G>T were included in the analysis. Neither indicated overall associations between gene polymorphisms and migraine risk. Subgroup analyses suggested that the "A" allele of the TNF -308G>A variant increases the risk of migraine among non-Caucasians (dominant model: pooled OR = 1.82; 95% CI 1.15 - 2.87. The risk of migraine with aura (MA was increased among both Caucasians and non-Caucasians. Subgroup analyses suggested that the "T" allele of the NOS3 +894G>T variant increases the risk of migraine among non-Caucasians (co-dominant model: pooled OR = 2.10; 95% CI 1.14 - 3.88.Our findings appear to support the hypothesis that the TNF -308G>A polymorphism may act as a genetic susceptibility factor for migraine among non-Caucasians and that the NOS3 +894G>T polymorphism may modulate the risk of migraine among non-Caucasians.

  8. Association of functional polymorphisms from brain-derived neurotrophic factor and serotonin-related genes with depressive symptoms after a medical stressor in older adults.

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    Kerri S Rawson

    Full Text Available Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val to methionine (Met polymorphism in brain-derived neurotrophic factor (BDNF, serotonin 1A receptor (5HT1a-rs6295 polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531 as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012. BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37. Unlike prior studies of stressful life events, the S' 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006. No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor.

  9. Polymorphisms in NFKB1 and TLR4 and interaction with dietary and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study.

    Science.gov (United States)

    Kopp, Tine Iskov; Andersen, Vibeke; Tjonneland, Anne; Vogel, Ulla

    2015-01-01

    Maintenance of a balance between commensal bacteria and the mucosal immune system is crucial and intestinal dysbiosis may be a key event in the pathogenesis of colorectal cancer (CRC). The toll-like receptor 4 (TLR4) is an important pattern-recognition receptor that regulates inflammation and barrier function in the gut by a mechanism that involves activation of the nuclear factor-κB (NF-κB) transcription factor. Dietary and life style factors may impact these functions. We therefore used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort to investigate three polymorphisms in NFKB1 and TLR4 and their possible interactions with diet and life style factors in relation to risk of CRC. Homozygous carriage of the variant allele of the TLR4/rs5030728 polymorphism was associated with increased risk of CRC (incidence rate ratio (IRR) = 1.30; 95% confidence interval (CI): 1.05-1.60; P = 0.02 (gene-dose model); IRR = 1.24; 95%CI: 1.01-1.51; P = 0.04 (recessive model)). Del-carriers of the NFKB1/rs28362491 polymorphism had a 17% (95%CI: 1.03-1.34; P = 0.02) increased risk of CRC compared to homozygous carriers of the ins-allele. However, none of these risk estimates withstood adjustment for multiple comparisons. We found no strong gene-environment interactions between the examined polymorphism and diet and life style factors in relation to CRC risk.

  10. Polymorphisms in NFKB1 and TLR4 and interaction with dietary and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study.

    Directory of Open Access Journals (Sweden)

    Tine Iskov Kopp

    Full Text Available Maintenance of a balance between commensal bacteria and the mucosal immune system is crucial and intestinal dysbiosis may be a key event in the pathogenesis of colorectal cancer (CRC. The toll-like receptor 4 (TLR4 is an important pattern-recognition receptor that regulates inflammation and barrier function in the gut by a mechanism that involves activation of the nuclear factor-κB (NF-κB transcription factor. Dietary and life style factors may impact these functions. We therefore used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort to investigate three polymorphisms in NFKB1 and TLR4 and their possible interactions with diet and life style factors in relation to risk of CRC. Homozygous carriage of the variant allele of the TLR4/rs5030728 polymorphism was associated with increased risk of CRC (incidence rate ratio (IRR = 1.30; 95% confidence interval (CI: 1.05-1.60; P = 0.02 (gene-dose model; IRR = 1.24; 95%CI: 1.01-1.51; P = 0.04 (recessive model. Del-carriers of the NFKB1/rs28362491 polymorphism had a 17% (95%CI: 1.03-1.34; P = 0.02 increased risk of CRC compared to homozygous carriers of the ins-allele. However, none of these risk estimates withstood adjustment for multiple comparisons. We found no strong gene-environment interactions between the examined polymorphism and diet and life style factors in relation to CRC risk.

  11. Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

    Science.gov (United States)

    Bahrami, A; Behzadi, Sh; Miraei-Ashtiani, S R; Roh, S-G; Katoh, K

    2013-09-15

    The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Apolipoprotein E Gene Polymorphism and Its Association with Cardiovascular Heart Disease Risk Factors in Type 2 Diabetes Mellitus

    OpenAIRE

    Amani Ashari; Julia Omar; Arif Hashim; Shahrul Hamid

    2016-01-01

    Apolipoprotein E (APOE) gene polymorphism has influence on serum lipids which relates to cardiovascular risk. The purpose of this study was to determine the frequency distribution of APOE alleles among Malaysian Type 2 Diabetes Mellitus (DM) patients with and without coronary artery disease (CAD) and their association with serum lipid profiles. A total of 115 patients were recruited in which 78 patients had Type 2 DM without CAD and 37 patients had Type 2 DM with CAD. The APOE polymorphism wa...

  13. The relationship in Japanese infants between a genetic polymorphism in the promoter region of the insulin-like growth factor I gene and the plasma level.

    Science.gov (United States)

    Kinoshita, Yumiko; Kizaki, Zenro; Ishihara, Yasunori; Nakajima, Hisakazu; Adachi, Shinsuke; Kosaka, Kitaro; Kinugasa, Akihiko; Sugimoto, Tohru

    2007-01-01

    Evidence is accumulating that the promoter region of the insulin-like growth factor I (IGF-I) gene polymorphism and low levels of IGF-I are associated with type 2 diabetes, cardiovascular disease and birth weight; however, the number of wild-type alleles is different in each country. This study aimed to examine the 737/738 marker, a cytosine-adenine repeat in the promoter region of the IGF-I gene polymorphism, and plasma IGF-I levels in Japanese infants and analyze the genetic background. Data were collected for 15 months in Kyoto Prefectural University of Medicine. The body composition parameters of all infants were determined at birth. At 5 days after birth, we took blood samples to measure the product size of the promoter region of the IGF-I gene polymorphism and plasma IGF-I. In a population-based sample of 160 subjects, 6 different alleles and 16 genotypes were identified in the promoter region of the IGF-I gene polymorphism. The existence of a 196-bp allele has proved to result in a low plasma IGF-I level, a small head and chest circumference (p body composition parameters in Japanese infants. Our results suggest genetical influence on prenatal growth and serum IGF-I levels.

  14. DNA Polymorphism of Insulin-like Growth Factor-binding Protein-3 Gene and Its Association with Cashmere Traits in Cashmere Goats

    Directory of Open Access Journals (Sweden)

    Haiying Liu

    2012-11-01

    Full Text Available Insulin-like growth factor binding protein-3 (IGFBP-3 gene is important for regulation of growth and development in mammals. The present investigation was carried out to study DNA polymorphism by PCR-RFLP of IGFBP-3 gene and its effect on fibre traits of Chinese Inner Mongolian cashmere goats. The fibre traits data investigated were cashmere fibre diameter, combed cashmere weight, cashmere fibre length and guard hair length. Four hundred and forty-four animals were used to detect polymorphisms in the hircine IGFBP-3 gene. A 316-bp fragment of the IGFBP-3 gene in exon 2 was amplified and digested with HaeIII restriction enzyme. Three patterns of restriction fragments were observed in the populations. The frequency of AA, AB and BB genotypes was 0.58, 0.33 and 0.09 respectively. The allelic frequency of the A and B allele was 0.75 and 0.25 respectively. Nucleotide sequencing revealed a C>G transition in the exon 2 region of the IGFBP-3 gene resulting in R158G change which caused the polymorphism. Least squares analysis revealed a significant effect of genotypes on cashmere weight (p0.05. The animals of AB and BB genotypes showed higher cashmere weight, cashmere fibre length and hair length than the animals possessing AA genotype. These results suggested that polymorphisms in the hircine IGFBP-3 gene might be a potential molecular marker for cashmere weight in cashmere goats.

  15. The brain-derived neurotrophic factor (BDNF val66met polymorphism differentially affects performance on subscales of the Wechsler memory scale – third edition (WMS-III

    Directory of Open Access Journals (Sweden)

    Yvette Nicole Lamb

    2015-08-01

    Full Text Available Single nucleotide polymorphisms in the brain-derived neurotrophic factor (BDNF gene and the catechol-O-methyltransferase (COMT gene influence brain structure and function, as well as cognitive abilities. They are most influential in the hippocampus and prefrontal cortex (PFC, respectively. Recall and recognition are forms of memory proposed to have different neural substrates, with recall having a greater dependence on the PFC and hippocampus. This study aimed to determine whether the BDNF val66met or COMT val158met polymorphisms differentially affect recall and recognition, and whether these polymorphisms interact. A sample of 100 healthy adults was assessed on recall and familiarity-based recognition using the Faces and Family Pictures subscales of the Wechsler Memory Scale – Third Edition (WMS-III. COMT genotype did not affect performance on either task. The BDNF polymorphism (i.e. met carriers relative to val homozygotes was associated with poorer recall ability, while not influencing recognition. Combining subscale scores in memory tests such as the WMS might obscure gene effects. Our results demonstrate the importance of distinguishing between recall and familiarity-based recognition in neurogenetics research.

  16. Homocysteine and the C677T Gene Polymorphism of Its Key Metabolic Enzyme MTHFR Are Risk Factors of Early Renal Damage in Hypertension in a Chinese Han Population.

    Science.gov (United States)

    Yun, Lin; Xu, Rui; Li, Guohua; Yao, Yucai; Li, Jiamin; Cong, Dehong; Xu, Xingshun; Zhang, Lihua

    2015-12-01

    The combined hyperhomocysteinemia condition is a feature of the Chinese hypertensive population. This study used the case-control method to investigate the association between plasma homocysteine and the C677T gene polymorphism of its key metabolic enzyme, 5, 10-methylenetetrahydrofolate reductase (MTHFR), and early renal damage in a hypertensive Chinese Han population.A total of 379 adult essential hypertensive patients were selected as the study subjects. The personal information, clinical indicators, and the C677T gene polymorphism of MTHFR were texted. This study used the urine microalbumin/urine creatinine ratio (UACR) as a grouping basis: the hypertension without renal damage group (NRD group) and the hypertension combined with early renal damage group (ERD group).Early renal damage in the Chinese hypertensive population was associated with body weight, systolic pressure, diastolic pressure, urea nitrogen, serum creatinine, cystatin C, uric acid, aldosterone, and glomerular filtration rate. The homocysteine level and the UACR in the TT genotype group were higher than those in the CC genotype group. The binary logistic regression analysis results showed that after sex and age were adjusted, the MTHFR C677T gene polymorphism was correlated with early renal damage in hypertension in both the recessive model and in the additive model.Plasma homocysteine and the C677T gene polymorphism of its key metabolic enzyme MTHFR might be independent risk factors of early renal damage in the hypertensive Chinese Han population.

  17. Shared polymorphisms and modifiable behavior factors for myocardial infarction and high cholesterol in a retrospective population study.

    Science.gov (United States)

    Liang, Yulan; Kelemen, Arpad

    2017-09-01

    Genetic and environmental (behavior, clinical, and demographic) factors are associated with increased risks of both myocardial infarction (MI) and high cholesterol (HC). It is known that HC is major risk factor that may cause MI. However, whether there are common single nucleotide polymorphism (SNPs) associated with both MI and HC is not firmly established, and whether there are modulate and modified effects (interactions of genetic and known environmental factors) on either HC or MI, and whether these joint effects improve the predictions of MI, is understudied.The purpose of this study is to identify novel shared SNPs and modifiable environmental factors on MI and HC. We assess whether SNPs from a metabolic pathway related to MI may relate to HC; whether there are moderate effects among SNPs, lifestyle (smoke and drinking), HC, and MI after controlling other factors [gender, body mass index (BMI), and hypertension (HTN)]; and evaluate prediction power of the joint and modulate genetic and environmental factors influencing the MI and HC.This is a retrospective study with residents of Erie and Niagara counties in New York with a history of MI or with no history of MI. The data set includes environmental variables (demographic, clinical, lifestyle). Thirty-one tagSNPs from a metabolic pathway related to MI are genotyped. Generalized linear models (GLMs) with imputation-based analysis are conducted for examining the common effects of tagSNPs and environmental exposures and their interactions on having a history of HC or MI.MI, BMI, and HTN are significant risk factors for HC. HC shows the strongest effect on risk of MI in addition to HTN; gender and smoking status while drinking status shows protective effect on MI. rs16944 (gene IL-1β) and rs17222772 (gene ALOX) increase the risks of HC, while rs17231896 (gene CETP) has protective effects on HC either with or without the clinical, behavioral, demographic factors with different effect sizes that may indicate the

  18. Association of epidermal growth factor and epidermal growth factor receptor polymorphisms with the risk of hepatitis B virus-related hepatocellular carcinoma in the population of North China.

    Science.gov (United States)

    Wu, Jia; Zhang, Wei; Xu, Aiqiang; Zhang, Li; Yan, Tao; Li, Zhuo; Wu, Xiaopan; Zhu, Xilin; Ma, Juan; Li, Ke; Li, Hui; Liu, Ying

    2013-08-01

    Hepatocellular carcinoma (HCC) is a common solid malignant tumor occurring worldwide that leads to the third largest cause of death compared to other cancers. Genetic and environmental factors are involved in the pathogenesis of HCC. Epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) can stimulate the proliferation of epidermal and epithelial cells. The EGF signal pathway has a relationship with the growth of the embryo, tissue repairing, and tumorigenesis. In this study, 416 patients with hepatitis B virus infection (HBV)-related HCC and 645 individuals who had never been infected with HBV of the Chinese Han population were enrolled. Eight single-nucleotide polymorphisms (SNPs), whose minor allele frequency >20% in the EGF and EGFR genes, were genotyped to examine their associations with hepatocarcinogenesis. Genotyping experiments were carried out using TaqMan. There were significant differences in genotype distributions (p=0.005) and allele frequencies (p=0.001, odds ratio [OR]=1.43, 95% confidence interval [CI]=1.15-1.79) of rs11569017 in the EGF gene between the HCC and control groups. After binary logistic regression to determine independent factors for susceptibility to HCC under an additive model, rs11569017 was still independently associated with the susceptibility to HCC (p=0.021, OR=1.48, 95% CI=1.06-2.07), but no significant differences in other SNPs were found. Additionally, the haplotype T-G constructed by rs11569017 and rs4444903 of the EGF gene might increase the risk of HBV-related HCC (p=0.002, OR=1.44, 95% CI=1.15-1.82). The rs11569017 T allele was associated with susceptibility to HBV-related HCC.

  19. Depolarization-mediated regulation of alternative splicing

    Directory of Open Access Journals (Sweden)

    Alok eSharma

    2011-12-01

    Full Text Available Alternative splicing in eukaryotes plays an important role in regulating gene expression by selectively including alternative exons. A wealth of information has been accumulated that explains how alternative exons are selected in a developmental stage- or tissue-specific fashion. However, our knowledge of how cells respond to environmental changes to alter alternative splicing is very limited. For example, although a number of alternative exons have been shown to be regulated by calcium level alterations, the underlying mechanisms are not well understood. As calcium signaling in neurons plays a crucial role in essential neuronal functions such as learning and memory formation, it is important to understand how this process is regulated at every level in gene expression. The significance of the dynamic control of alternative splicing in response to changes of calcium levels has been largely unappreciated. In this communication, we will summarize the recent advances in calcium signaling-mediated alternative splicing that have provided some insights into the important regulatory mechanisms. In addition to describing the cis-acting RNA elements on the pre-mRNA molecules that respond to changes of intracellular calcium levels, we will summarize how splicing regulators change and affect alternative splicing in this process. We will also discuss a novel mode of calcium-mediated splicing regulation at the level of chromatin structure and transcription.

  20. Impact of vascular endothelial growth factor (VEGF and vascular endothelial growth factor receptor (VEGFR single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms.

    Directory of Open Access Journals (Sweden)

    Rossana Berardi

    Full Text Available Angiogenesis represents a key event in cancer development, leading to local invasion e metastatization, and might be considered a basic feature in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs with a high expression of angiogenic molecules. We aimed to analyze the prognostic and predictive role of angiogenic factors in GEP-NENs through the analysis of single nucleotide polymorphisms (SNPs of VEGF-A, VEGFR2 and VEGFR3. The genomic DNA of 58 consecutive patients with GEP-NENs treated at our Institution was extracted from peripheral blood. Two SNPs were identified respectively in VEGF-A (rs2010963G>C, rs699947A>C, VEGFR-2 (rs2305948C>T, rs1870377T>A, and VEGFR-3 (rs307821T>C, rs307826C>A gene. Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Median age was 57 years (range 24-79 years; 32 patients were male and 77.5% of NENs were localized in the pancreas. The allele frequency of VEGFR-2 rs2305948T and of VEGF-A rs2010963C showed a trend of higher frequency than in general population (12.1% vs. 8.0% and 34.5% vs. 31.2%, respectively. Three out SNPs (VEGF-A rs699947C, VEGF-A rs2010963GC and VEGFR-3 rs307821C showed a correlation with an increased risk of disease relapse. Moreover median PFS changes according to the presence of 0-1 SNPs (20.7% of cases; 61.9 months, 2 SNPs (25.9%; 49.2 months and 3 SNPs (53.4%; 27.8 months (p = 0.034. Results suggest, for the first time, that specific SNPs in VEGF-A and VEGFR-3 correlate with poor prognosis in GEP-NENs. The identification of this new prognostic factor might be helpful in order to optimize the management of these heterogeneous neoplasms.

  1. FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Chiung-Mei Chen

    Full Text Available Mutations in the F-box only protein 7 gene (FBXO7, the substrate-specifying subunit of SCF E3 ubiquitin ligase complex, cause Parkinson's disease (PD-15 (PARK15. To identify new variants, we sequenced FBXO7 cDNA in 80 Taiwanese early onset PD patients (age at onset ≤ 50 and only two known variants, Y52C (c.155A>G and M115I (c.345G>A, were found. To assess the association of Y52C and M115I with the risk of PD, we conducted a case-control study in a cohort of PD and ethnically matched controls. There was a nominal difference in the Y52C G allele frequency between PD and controls (p = 0.045. After combining data from China [1], significant difference in the Y52C G allele frequency between PD and controls (p = 0.012 and significant association of G allele with decreased PD risk (p = 0.017 can be demonstrated. Upon expressing EGFP-tagged Cys52 FBXO7 in cells, a significantly reduced rate of FBXO7 protein decay was observed when compared with cells expressing Tyr52 FBXO7. In silico modeling of Cys52 exhibited a more stable feature than Tyr52. In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2 was significantly reduced. Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination, which may be responsible for the reduced TRAF2 expression in Cys52 cells. After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth. We therefore hypothesize that Cys52 variant of FBXO7 may contribute to reduced PD susceptibility in Chinese.

  2. Fibroblast growth factor 23 (FGF23) gene polymorphisms are associated with essential hypertension risk and blood pressure levels in Chinese Han population.

    Science.gov (United States)

    Cai, Peng; Peng, Yan; Li, Li; Chu, Wei; Wang, Xukai

    2018-01-16

    In this case-control study, 246 EH patients and 157 healthy controls were selected from Chinese Han population to explore the associations between the fibroblast growth factor 23 (FGF23) gene polymorphisms and essential hypertension (EH).The SequenomMassarray system was used for the genotyping of three FGF23 gene Tag single-nucleotide polymorphisms, namely rs7955866, rs13312756, and rs3812822. The primers were designed by Assay Designer 3.1 software, and then the samples were added to a 384-well plate for the polymerase chain reaction amplification, shrimp alkaline phosphatase reaction, and desalting after extension. The distributions of the alleles, genotypes, and haplotypes were compared between the two groups. Confounding factors (sex, age, BMI, smoking, and drinking) were adjusted in the non-logistic regression, and the results showed that rs7955866 and rs3812822 polymorphisms were independently associated with the risk of developing EH (P control group showed that carrying rs7955866 A allele (P = 0.031) and rs3812822 C allele (P = 0.025) was associated with the increase of systolic blood pressure (SBP). The insulin (INS) level in the peripheral blood was significantly different between the case and control groups (P = 0.014). After confounding factors were excluded, the results showed that the serum INS level was also an independent risk factor of developing EH (P = 0.044; OR = 1.604, 95%CI: 1.014-2.539). In summary, our results suggest that FGF23 gene polymorphisms are associated with the risk of developing EH in Chinese Han population.

  3. RAGE splicing variants in mammals.

    Science.gov (United States)

    Sterenczak, Katharina Anna; Nolte, Ingo; Murua Escobar, Hugo

    2013-01-01

    The receptor for advanced glycation end products (RAGE) is a multiligand receptor of environmental stressors which plays key roles in pathophysiological processes, including immune/inflammatory disorders, Alzheimer's disease, diabetic arteriosclerosis, tumorigenesis, and metastasis. Besides the full-length RAGE protein in humans nearly 20 natural occurring RAGE splicing variants were described on mRNA and protein level. These naturally occurring isoforms are characterized by either N-terminally or C-terminally truncations and are discussed as possible regulators of the full-length RAGE receptor either by competitive ligand binding or by displacing the full-length protein in the membrane. Accordingly, expression deregulations of the naturally occurring isoforms were supposed to have significant effect on RAGE-mediated disorders. Thereby the soluble C-truncated RAGE isoforms present in plasma and tissues are the mostly focused isoforms in research and clinics. Deregulations of the circulating levels of soluble RAGE forms were reported in several RAGE-associated pathological disorders including for example atherosclerosis, diabetes, renal failure, Alzheimer's disease, and several cancer types. Regarding other mammalian species, the canine RAGE gene showed high similarities to the corresponding human structures indicating RAGE to be evolutionary highly conserved between both species. Similar to humans the canine RAGE showed a complex and extensive splicing activity leading to a manifold pattern of RAGE isoforms. Due to the similarities seen in several canine and human diseases-including cancer-comparative structural and functional analyses allow the development of RAGE and ligand-specific therapeutic approaches beneficial for human and veterinary medicine.

  4. Splicing pattern - ASTRA | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available List Contact us ASTRA Splicing pattern Data detail Data name Splicing pattern DOI 10.18908/lsdba.nbdc00371-0...04 Description of data contents The patterns of alternative splicing/transcriptional initiation Data file Fi...le name: astra_splicing_pattern.zip File URL: ftp://ftp.biosciencedbc.jp/archive/astra/LATEST/astra_splicing_patt...ogodb/view/astra_splicing_pattern#en Data acquisition method For the five organisms (H. sapiens, M. musculus...apping data into bit arrays, detection of splicing patterns and distribution to t

  5. The Role of the Val66Met Polymorphism of the Brain Derived Neurotrophic Factor Gene in Coping Strategies Relevant to Depressive Symptoms.

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    Warren Caldwell

    Full Text Available Disturbances of brain derived neurotrophic factor (BDNF signalling have been implicated in the evolution of depression, which likely arises, in part, as a result of diminished synaptic plasticity. Predictably, given stressor involvement in depression, BDNF is affected by recent stressors as well as stressors such as neglect experienced in early life. The effects of early life maltreatment in altering BDNF signalling may be particularly apparent among those individuals with specific BDNF polymorphisms. We examined whether polymorphisms of the Val66Met genotype might be influential in moderating how early-life events play out with respect to later coping styles, cognitive flexibility and depressive features. Among male and female undergraduate students (N = 124, childhood neglect was highly related to subsequent depressive symptoms. This outcome was moderated by the BDNF polymorphism in the sense that depressive symptoms appeared higher in Met carriers who reported low levels of neglect than in those with the Val/Val allele. However, under conditions of high neglect depressive symptoms only increased in the Val/Val individuals. In effect, the Met polymorphism was associated with depressive features, but did not interact with early life neglect in predicting later depressive features. It was further observed that among the Val/Val individuals, the relationship between neglect and depression was mediated by emotion-focused styles and diminished perceived control, whereas this mediation was not apparent in Met carriers. In contrast to the more typical view regarding this polymorphism, the data are consistent with the perspective that in the presence of synaptic plasticity presumably associated with the Val/Val genotype, neglect allows for the emergence of specific appraisal and coping styles, which are tied to depression. In the case of the reduced degree of neuroplasticity expected in the Met carriers, early life adverse experiences are not tied

  6. Control of HIV-1 env RNA splicing and transport: investigating the role of hnRNP A1 in exon splicing silencer (ESS3a) function

    International Nuclear Information System (INIS)

    Asai, Kengo; Platt, Craig; Cochrane, Alan

    2003-01-01

    The control of HIV-1 viral RNA splicing and transport plays an important role in the successful replication of the virus. Previous studies have identified both an exon splicing enhancer (ESE) and a bipartite exon splicing silencer (ESS3a and ESS3b) within the terminal exon of HIV-1 that are involved in modulating both splicing and Rev-mediated export of viral RNA. To define the mechanism of ESS3a function, experiments were carried out to better define the cis and trans components required for ESS3a activity. Mutations throughout the 30-nt element resulted in partial loss of ESS function. Combining mutations was found to have an additive effect, suggesting the presence of multiple binding sites. Analysis of interacting factors identified hnRNP A1 as one component of the complex that modulates ESS3a activity. However, subsequent binding analyses determined that hnRNP A1 interacts with only one portion of ESS3a, suggesting the involvement of another host factor. Parallel analysis of the effect of the mutations on Rev-mediated export determined that there is not a direct correlation between the effect of the mutations on splicing and RNA transport. Consistent with this hypothesis, replacement of ESS3a with consensus hnRNP A1 binding sites was found to be insufficient to block Rev-mediated RNA export

  7. LOW MOLECULAR MASS POLYPEPTIDE AND TRANSPORTER ANTIGEN PEPTIDE GENES POLYMORPHISM AS THE RISK FACTORS OF CERVICAL CANCER WHICH CAUSED BY HUMAN PAPILLOMAVIRUS TYPE-16 INFECTION IN BALI

    Directory of Open Access Journals (Sweden)

    I N. B. Mahendra

    2015-12-01

    Full Text Available Background: Until recently, cervical cancer is one of the major problem in women’s health issue related to its high incidence and mortality rate. The etiology of cervical cancer is the high risk oncogenic group of Human Papillomavirus (HPV, especially HPV-16 and 18 and its phylogenies. Meanwhile in Bali, more than 50% of infection are caused by HPV-16 infection. The main objective of this study was to investigate the role of LMP-2, LMP-7, TAP-1 and TAP-2 gene polymorphism as the risk factor in the cervical cancer carcinogenesis that is caused by HPV-16 infection. Method: A nested non-paired case-control study was conducted at Obstetric and Gynecologic Department Sanglah General Hospital, Bali-Indonesia from March 1 until August 31, 2013. Laboratory testing was carried out at Laboratory of Histopathology Leiden University Medical Centre, Netherlands,. Results: A total of 40 samples were collected, consist of 20epithelial cervical cancer patients with positive HPV-16 infection as the case group and 20 non-cervical cancer patients with positive HPV-16 infection as the control group. Women infected by HPV-16 with LMP-7 gene polymorphism had a higher risk (OR=7.36, CI 95%=1.38-40.55, p=0.013 to be diagnosed with cervical cancer. Balinese women who were infected by HPV-16 with TAP-2 gene polymorphism had a higher risk (OR= 9.33, CI 95%=2.18-39.96, p=0.001 to be diagnosed with cervical cancer. Meanwhile, Balinese women who were infected by HPV-16 with LMP-7 and TAP-2 genes polymorphism had a higher risk (OR=12.67, CI 95%=1.40-114.42, p=0.020 to be diagnosed with cervical cancer. As the result, it was shown that both of this gene polymorphism was working synergistically. Conclusion: TAP-2 and LMP-7 genes polymorphism play a role in the carcinogenesis mechanism of cervical cancer that is caused by HPV-16 infection in Bali. Meanwhile, LMP-2 and TAP-1 genes polymorphism were not found to play a role in the immunology pathway of cervical cancer that is

  8. Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder.

    Science.gov (United States)

    Nassan, Malik; Croarkin, Paul E; Luby, Joan L; Veldic, Marin; Joshi, Paramjit T; McElroy, Susan L; Post, Robert M; Walkup, John T; Cercy, Kelly; Geske, Jennifer R; Wagner, Karen D; Cuellar-Barboza, Alfredo B; Casuto, Leah; Lavebratt, Catharina; Schalling, Martin; Jensen, Peter S; Biernacka, Joanna M; Frye, Mark A

    2015-09-01

    Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association. DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult-onset cases at age >19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early-onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects. Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04). These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Associations of tumor necrosis factor-α-308 polymorphism with dengue infection: A systematic review and meta-analysis.

    Science.gov (United States)

    Pabalan, Noel; Chaisri, Suwit; Tabunhan, Sompong; Tarasuk, Mayuri; Jarjanazi, Hamdi; Steiner, Theodore

    2017-09-01

    Inconsistency of reported associations between the tumor necrosis factor-alpha-308 (TNFα-308) polymorphism (rs1800629) and dengue virus infection prompted a meta-analysis, to obtain more precise estimates. A literature search yielded 14 case-control studies. We calculated pooled odds ratios (OR) and 95% confidence intervals in three groups according to severity, dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue (DEN) using standard genetic models. Pooled ORs were subjected to modifier treatment where re-analysis was confined to Hardy-Weinberg compliant (HWC) studies. Heterogeneity of outcomes warranted examining their sources with outlier treatment. In subgroup analysis, we compared Asian and South/Central American (SCA)/Brazilian effects. Overall pooled outcomes yielded no significant effects (OR 0.66-1.44, P=0.08-0.96). In the dominant-codominant model, pooled effects were heterogeneous (I 2 =47%-71%) which was lost/reduced (I 2 =0%-43%) when outlier treatment was applied. This also yielded significant associations (OR 0.68-0.77, P=0.02-0.05). Our results are best seen in the Asian subgroup, which in itself already yielded significant effects in DEN (OR 0.62-0.67, P=0.01-0.02). These reduced risk findings were significant from the tests of interaction (P=0.001-0.02) which highlights the protective effects of TNFα-308 among Asians. TNFα-308 effects on dengue are based on significance and non-heterogeneity of the post-outlier outcomes in the dominant and codominant models. Here, pooled effects may also be ethnic specific, where Asians are protected but not SCA. Both modified and Asian effects are up to 38% protective. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus

    Science.gov (United States)

    Elek, Zsuzsanna; Németh, Nóra; Nagy, Géza; Németh, Helga; Somogyi, Anikó; Hosszufalusi, Nóra; Sasvári-Székely, Mária; Rónai, Zsolt

    2015-01-01

    The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ 2-test in combination with correction for multiple testing. For functional analysis, the entire 3’ UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3’ UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function. PMID:26426397

  11. Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus.

    Directory of Open Access Journals (Sweden)

    Zsuzsanna Elek

    Full Text Available The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ2-test in combination with correction for multiple testing. For functional analysis, the entire 3' UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.

  12. Genetic polymorphisms of the IL6 and NOD2 genes are risk factors for inflammatory reactions in leprosy.

    Science.gov (United States)

    Sales-Marques, Carolinne; Cardoso, Cynthia Chester; Alvarado-Arnez, Lucia Elena; Illaramendi, Ximena; Sales, Anna Maria; Hacker, Mariana de Andréa; Barbosa, Mayara Garcia de Mattos; Nery, José Augusto da Costa; Pinheiro, Roberta Olmo; Sarno, Euzenir Nunes; Pacheco, Antonio Guilherme; Moraes, Milton Ozório

    2017-07-01

    The pathways that trigger exacerbated immune reactions in leprosy could be determined by genetic variations. Here, in a prospective approach, both genetic and non-genetic variables influencing the amount of time before the development of reactional episodes were studied using Kaplan-Meier survival curves, and the genetic effect was estimated by the Cox proportional-hazards regression model. In a sample including 447 leprosy patients, we confirmed that gender (male), and high bacillary clinical forms are risk factors for leprosy reactions. From the 15 single nucleotide polymorphisms (SNPs) at the 8 candidate genes genotyped (TNF/LTA, IFNG, IL10, TLR1, NOD2, SOD2, and IL6) we observed statistically different survival curves for rs751271 at the NOD2 and rs2069845 at the IL6 genes (log-rank p-values = 0.002 and 0.023, respectively), suggesting an influence on the amount of time before developing leprosy reactions. Cox models showed associations between the SNPs rs751271 at NOD2 and rs2069845 at IL6 with leprosy reactions (HRGT = 0.45, p = 0.002; HRAG = 1.88, p = 0.0008, respectively). Finally, IL-6 and IFN-γ levels were confirmed as high, while IL-10 titers were low in the sera of reactional patients. Rs751271-GT genotype-bearing individuals correlated (p = 0.05) with lower levels of IL-6 in sera samples, corroborating the genetic results. Although the experimental size may be considered a limitation of the study, the findings confirm the association of classical variables such as sex and clinical forms with leprosy, demonstrating the consistency of the results. From the results, we conclude that SNPs at the NOD2 and IL6 genes are associated with leprosy reactions as an outcome. NOD2 also has a clear functional pro-inflammatory link that is coherent with the exacerbated responses observed in these patients.

  13. The effect of interaction between Melanocortin-4 receptor polymorphism and dietary factors on the risk of metabolic syndrome.

    Science.gov (United States)

    Koochakpoor, Gelareh; Daneshpour, Maryam S; Mirmiran, Parvin; Hosseini, Seyed Ahmad; Hosseini-Esfahani, Firoozeh; Sedaghatikhayat, Bahareh; Azizi, Fereidoun

    2016-01-01

    Controversial data is available on the effect of the Melanocortin-4 receptor (MC4R) gene variation on metabolic syndrome (MetS) and ineffectiveness of diet in managing MetS. Effects of the interaction between MC4R polymorphism and dietary factors on MetS were investigated in this study. Subjects of this nested case-control study were selected from among participants of Tehran Lipid and Glucose Study. Each case (n = 815) was pair matched randomly with a control by age (±5 years) and sex from among those who had not developed ≥1 MetS components at the time that the corresponding case developed MetS. Dietary patterns were determined using factor analysis on 25 foods groups using a valid and reliable, 168-item semi-quantitative food frequency questionnaire (FFQ). MC4R rs12970134 were genotyped by Tetra-Primer ARMS-polymerase chain reaction analysis. Adjusted conditional logistic regression was used to estimate the interactions of SNP with quartiles of dietary factors in relation to MetS. MetS was defined by the modified National Cholesterol Education Program/Adult Treatment panel III. Two dietary patterns were extracted. The healthy dietary pattern was loaded heavily on vegetables, legumes, low fat dairy, whole grains, liquid oils and fruits; the western dietary pattern consisted of a high intake of soft drinks, fast foods, sweets, solid oils, red meats, salty snacks, refined grains, high fat dairy, tea and coffee, eggs and poultry. Among A allele carriers, being in the highest quartiles of western dietary pattern score and saturated fatty acid intake had an increased risk of MetS, compared to those in the lowest quartile (P trend = 0.007). Saturated fatty acid intake could modulate the association of A allele carriers of MC4R with MetS (P interaction = 0.03). A significant interaction was observed between rs12970134 with total fat and iron intake on the risk of abdominal obesity (P interaction < 0.05). Our findings suggest an interaction between rs

  14. A single nucleotide polymorphism uncovers a novel function for the transcription factor Ace2 during Candida albicans hyphal development.

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    Diana M Calderón-Noreña

    2015-04-01

    Full Text Available Candida albicans is a major invasive fungal pathogen in humans. An important virulence factor is its ability to switch between the yeast and hyphal forms, and these filamentous forms are important in tissue penetration and invasion. A common feature for filamentous growth is the ability to inhibit cell separation after cytokinesis, although it is poorly understood how this process is regulated developmentally. In C. albicans, the formation of filaments during hyphal growth requires changes in septin ring dynamics. In this work, we studied the functional relationship between septins and the transcription factor Ace2, which controls the expression of enzymes that catalyze septum degradation. We found that alternative translation initiation produces two Ace2 isoforms. While full-length Ace2, Ace2L, influences septin dynamics in a transcription-independent manner in hyphal cells but not in yeast cells, the use of methionine-55 as the initiation codon gives rise to Ace2S, which functions as the nuclear transcription factor required for the expression of cell separation genes. Genetic evidence indicates that Ace2L influences the incorporation of the Sep7 septin to hyphal septin rings in order to avoid inappropriate activation of cell separation during filamentous growth. Interestingly, a natural single nucleotide polymorphism (SNP present in the C. albicans WO-1 background and other C. albicans commensal and clinical isolates generates a stop codon in the ninth codon of Ace2L that mimics the phenotype of cells lacking Ace2L. Finally, we report that Ace2L and Ace2S interact with the NDR kinase Cbk1 and that impairing activity of this kinase results in a defect in septin dynamics similar to that of hyphal cells lacking Ace2L. Together, our findings identify Ace2L and the NDR kinase Cbk1 as new elements of the signaling system that modify septin ring dynamics in hyphae to allow cell-chain formation, a feature that appears to have evolved in specific C

  15. Family Polymorphism

    DEFF Research Database (Denmark)

    Ernst, Erik

    2001-01-01

    safety and flexibility at the level of multi-object systems. We are granted the flexibility of using different families of kinds of objects, and we are guaranteed the safety of the combination. This paper highlights the inability of traditional polymorphism to handle multiple objects, and presents family...... polymorphism as a way to overcome this problem. Family polymorphism has been implemented in the programming language gbeta, a generalized version of Beta, and the source code of this implementation is available under GPL....

  16. Human Splicing Finder: an online bioinformatics tool to predict splicing signals.

    Science.gov (United States)

    Desmet, François-Olivier; Hamroun, Dalil; Lalande, Marine; Collod-Béroud, Gwenaëlle; Claustres, Mireille; Béroud, Christophe

    2009-05-01

    Thousands of mutations are identified yearly. Although many directly affect protein expression, an increasing proportion of mutations is now believed to influence mRNA splicing. They mostly affect existing splice sites, but synonymous, non-synonymous or nonsense mutations can also create or disrupt splice sites or auxiliary cis-splicing sequences. To facilitate the analysis of the different mutations, we designed Human Splicing Finder (HSF), a tool to predict the effects of mutations on splicing signals or to identify splicing motifs in any human sequence. It contains all available matrices for auxiliary sequence prediction as well as new ones for binding sites of the 9G8 and Tra2-beta Serine-Arginine proteins and the hnRNP A1 ribonucleoprotein. We also developed new Position Weight Matrices to assess the strength of 5' and 3' splice sites and branch points. We evaluated HSF efficiency using a set of 83 intronic and 35 exonic mutations known to result in splicing defects. We showed that the mutation effect was correctly predicted in almost all cases. HSF could thus represent a valuable resource for research, diagnostic and therapeutic (e.g. therapeutic exon skipping) purposes as well as for global studies, such as the GEN2PHEN European Project or the Human Variome Project.

  17. Spliceman2: a computational web server that predicts defects in pre-mRNA splicing.

    Science.gov (United States)

    Cygan, Kamil Jan; Sanford, Clayton Hendrick; Fairbrother, William Guy

    2017-09-15

    Most pre-mRNA transcripts in eukaryotic cells must undergo splicing to remove introns and join exons, and splicing elements present a large mutational target for disease-causing mutations. Splicing elements are strongly position dependent with respect to the transcript annotations. In 2012, we presented Spliceman, an online tool that used positional dependence to predict how likely distant mutations around annotated splice sites were to disrupt splicing. Here, we present an improved version of the previous tool that will be more useful for predicting the likelihood of splicing mutations. We have added industry-standard input options (i.e. Spliceman now accepts variant call format files), which allow much larger inputs than previously available. The tool also can visualize the locations-within exons and introns-of sequence variants to be analyzed and the predicted effects on splicing of the pre-mRNA transcript. In addition, Spliceman2 integrates with RNAcompete motif libraries to provide a prediction of which trans -acting factors binding sites are disrupted/created and links out to the UCSC genome browser. In summary, the new features in Spliceman2 will allow scientists and physicians to better understand the effects of single nucleotide variations on splicing. Freely available on the web at http://fairbrother.biomed.brown.edu/spliceman2 . Website implemented in PHP framework-Laravel 5, PostgreSQL, Apache, and Perl, with all major browsers supported. william_fairbrother@brown.edu. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  18. ZmbZIP60 mRNA is spliced in maize in response to ER stress

    Directory of Open Access Journals (Sweden)

    Li Yanjie

    2012-03-01

    Full Text Available Abstract Background Adverse environmental conditions produce ER stress and elicit the unfolded protein response (UPR in plants. Plants are reported to have two "arms" of the ER stress signaling pathway-one arm involving membrane-bound transcription factors and the other involving a membrane-associated RNA splicing factor, IRE1. IRE1 in yeast to mammals recognizes a conserved twin loop structure in the target RNA. Results A segment of the mRNA encoding ZmbZIP60 in maize can be folded into a twin loop structure, and in response to ER stress this mRNA is spliced, excising a 20b intron. Splicing converts the predicted protein from a membrane-associated transcription factor to one that is targeted to the nucleus. Splicing of ZmbZIP60 can be elicited in maize seedlings by ER stress agents such as dithiothreitol (DTT or tunicamycin (TM or by heat treatment. Younger, rather than older seedlings display a more robust splicing response as do younger parts of leaf, along a developmental gradient in a leaf. The molecular signature of an ER stress response in plants includes the upregulation of Binding Protein (BIP genes. Maize has numerous BIP-like genes, and ER stress was found to upregulate one of these, ZmBIPb. Conclusions The splicing of ZmbZIP60 mRNA is an indicator of ER stress in maize seedlings resulting from adverse environmental conditions such as heat stress. ZmbZIP60 mRNA splicing in maize leads predictively to the formation of active bZIP transcription factor targeted to the nucleus to upregulate stress response genes. Among the genes upregulated by ER stress in maize is one of 22 BIP-like genes, ZmBIPb.

  19. HOLLYWOOD: a comparative relational database of alternative splicing.

    Science.gov (United States)

    Holste, Dirk; Huo, George; Tung, Vivian; Burge, Christopher B

    2006-01-01

    RNA splicing is an essential step in gene expression, and is often variable, giving rise to multiple alternatively spliced mRNA and protein isoforms from a single gene locus. The design of effective databases to support experimental and computational investigations of alternative splicing (AS) is a significant challenge. In an effort to integrate accurate exon and splice site annotation with current knowledge about splicing regulatory elements and predicted AS events, and to link information about the splicing of orthologous genes in different species, we have developed the Hollywood system. This database was built upon genomic annotation of splicing patterns of known genes derived from spliced alignment of complementary DNAs (cDNAs) and expressed sequence tags, and links features such as splice site sequence and strength, exonic splicing enhancers and silencers, conserved and non-conserved patterns of splicing, and cDNA library information for inferred alternative exons. Hollywood was implemented as a relational database and currently contains comprehensive information for human and mouse. It is accompanied by a web query tool that allows searches for sets of exons with specific splicing characteristics or splicing regulatory element composition, or gives a graphical or sequence-level summary of splicing patterns for a specific gene. A streamlined graphical representation of gene splicing patterns is provided, and these patterns can alternatively be layered onto existing information in the UCSC Genome Browser. The database is accessible at http://hollywood.mit.edu.

  20. Protein splicing and its evolution in eukaryotes

    Directory of Open Access Journals (Sweden)

    Starokadomskyy P. L.

    2010-02-01

    Full Text Available Inteins, or protein introns, are parts of protein sequences that are post-translationally excised, their flanking regions (exteins being spliced together. This process was called protein splicing. Originally inteins were found in prokaryotic or unicellular eukaryotic organisms. But the general principles of post-translation protein rearrangement are evolving yielding different post-translation modification of proteins in multicellular organisms. For clarity, these non-intein mediated events call either protein rearrangements or protein editing. The most intriguing example of protein editing is proteasome-mediated splicing of antigens in vertebrates that may play important role in antigen presentation. Other examples of protein rearrangements are maturation of Hg-proteins (critical receptors in embryogenesis as well as maturation of several metabolic enzymes. Despite a lack of experimental data we try to analyze some intriguing examples of protein splicing evolution.

  1. Fat phenotype, associated factors and rs9939609 polymorphism of the FTO gene DOI:10.5007/1980-0037.2010v12n2p164

    Directory of Open Access Journals (Sweden)

    William Alves Lima

    2010-07-01

    Full Text Available The purpose of this work was to review the main results of studies that have analysed the relationship between the rs9939609 single nucleotide polymorphism (SNP of the FTO gene and the manifestation of overweight/obesity with its associated co-morbidity, and to discuss the interaction of this polymorphism with the other factors which cause obesity. The search was performed using the MEDLINE, Highwire, Science Direct and SciELO databases, applying the following key words: FTO rs9939609, obesity genetic, gene associated obesity, FTO contributes obesity. Inclusion criteria were: original articles where the search was performed in humans and including the rs9939609. Articles that analysed the FTO gene associated with preinstalled hormonal diseases were excluded. Of the several SNP associated with the FTO gene, rs9939609 has been the most researched (studied. This SNP comprises the A and T alleles, with the A homozygote being most susceptible to the development of overweight/obesity in all age ranges, especially in the caucasian population. In this situation, the control of environmental factors (alimentation and physical activity can prevent the excessive build up of fats. Obesity is related to the development of non-transmissible chronic illnesses. Association of rs9939609 polymorphism with the lipidic profile and glycemia were observed. The practicing of physical exercise and feeding habits seem to be the main contributors in the development of overweight/obesity and its resulting co-morbidity.

  2. Variation in alternative splicing across human tissues

    OpenAIRE

    Yeo, Gene; Holste, Dirk; Kreiman, Gabriel; Burge, Christopher B

    2004-01-01

    Background: Alternative pre-mRNA splicing (AS) is widely used by higher eukaryotes to generate different protein isoforms in specific cell or tissue types. To compare AS events across human tissues, we analyzed the splicing patterns of genomically aligned expressed sequence tags (ESTs) derived from libraries of cDNAs from different tissues. Results: Controlling for differences in EST coverage among tissues, we found that the brain and testis had the highest levels of exon skipping. The most p...

  3. Role of cytokine gene (interferon-γ, transforming growth factor-β1, tumor necrosis factor-α, interleukin-6, and interleukin-10 polymorphisms in the risk of oral precancerous lesions in Taiwanese

    Directory of Open Access Journals (Sweden)

    Han-Jen Hsu

    2014-11-01

    Full Text Available Oral squamous cell carcinoma can be preceded by some benign oral lesions with malignant potential, including leukoplakia, erythroplakia, oral lichen planus, and oral submucous fibrosis. There are different degrees of inflammatory cells infiltration in histopathology. Inflammatory cytokines may play a pathogenic role in the development of oral precancerous lesions (OPCLs. Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. We hypothesized that the risk of OPCLs might be associated with cytokine gene polymorphisms of interferon (IFN-γ, transforming growth factor (TGF-β1, tumor necrosis factor (TNF-α, interleukin (IL-6, and IL-10. In the present study, 42 OPCL patients and 128 controls were analyzed for eight polymorphisms in five different cytokine genes [IFN-γ (+874 T/A, TGF-β1 (codons 10 T/C and 25 G/C, TNF-α (−308 G/A, IL-6 (−174 G/C, and IL-10 (−1082 A/G, –819 T/C, and −592 A/C]. Cytokine genotyping was determined by the polymerase chain reaction sequence-specific primer technique using commercial primers. Allele and genotype data were analyzed for significance of differences between cases and controls using the Chi-square (χ2 test. Two-sided p < 0.05 were considered to be statistically significant. A series of multivariate logistic regression models, adjusted for age, sex, betel quid chewing, alcohol consumption, and smoking, was constructed in order to access the contribution of homozygous or heterozygous variant genotypes of polymorphisms. The TNF-α (−308 polymorphism was significantly associated with OPCLs. There were significant differences in the distribution of AA, GA, and GG genotypes between OPCL patients and controls (p = 0.0004. Patients with the AA or GA genotype had a 3.63-fold increased risk of OPCLs. The TGF-β1 (codon 10 and 25 polymorphism was also significantly associated with OPCLs (p < 0.001. The IL-6 polymorphism was significantly associated with OPCLs

  4. [A protective effect of GLY272SER polymorphism of GNB3 gene in development of essential hypertension and its relations with environmental hypertension risk factors].

    Science.gov (United States)

    Polonikov, A V; Solodilova, M A; Ivanov, V P; Shestakov, A M; Ushachev, D V; Vialykh, E K; Vasil'eva, O V; Poliakova, N V; Antsupov, V V; Kabanina, V A; Kupriianova, Ia S; Bulgakova, I V; Kozhukhov, M A; Tevs, D S

    2011-01-01

    To study associations of C825T (rs5443) and G272S (rs16932941) polymorphisms of GNB3 gene in Russian population of the Central Chernozem region with essential hypertension (EH) risk; to elicit the role of environmental risk factors in realization of EH predisposition in this gene genotypes carriers. We studied DNA samples obtained from 205 EH patients and 207 healthy individuals. EH patients were treated in Kursk hospitals. Genotyping of GNB3 gene polymorphisms was conducted by polymerase chain reaction and restriction analysis. Prevalence of 82ST allele of GNB3 gene in EH patients and healthy individual was 0.334 and 0.295, respectively, of 272S allele--0.037 and 0.058, respectively. We found no significant differences by prevalence of genotypes of gene GNB3 polymorphisms C825T and G272S in EH patients and healthy individuals. Non-smoking carriers of 272GS genotype had a low risk of EH (OR 0.42 in 95% CI from 0.18 to 0.97; p = 0.04). Smokers had no protective effect of this genotype. The protective effect of 272GS genotype was also found in individuals with low or moderate alcohol drinking habits (OR 0.29 in 95% CI from 0.11 to 0.77, p = 0.02) and in individuals without chronic exposure to stress (OR 0.29 in 95% CI from 0.09 to 0.91, p = 0.04). In contrast, hard drinkers and patients exposed to chronic stress had no protective effect of heterozygous genotype 272GS of gene GNB3. G272S polymorphism of GNB3 gene can be considered as a new genetic marker of predisposition to EH. The protective effect depends of environmental factors associated with high risk to develop EH.

  5. Effect of interactions of polymorphisms in the Melanocortin-4 receptor gene with dietary factors on the risk of obesity and Type 2 diabetes: a systematic review.

    Science.gov (United States)

    Koochakpoor, G; Hosseini-Esfahani, F; Daneshpour, M S; Hosseini, S A; Mirmiran, P

    2016-08-01

    To perform a systematic review of the effect of interaction between Melanocortin-4 receptor (MC4R) single nucleotide polymorphisms and diet on the development of obesity and Type 2 diabetes. Environmental factors, such as nutrient intakes or feeding behaviours, can modulate the association of polymorphism in the MC4R gene with obesity and Type 2 diabetes mellitus. A systematic literature search was conducted in the PubMed, Scopus and Google Scholar databases, with a combination of the following keywords: Diet*, nutr*, melanocortin receptor, melanocortin 4 receptor and MC4R. To assess the quality of observational studies, we used a 12-item quality checklist, derived from the STREGA statement. A total of 14 articles were selected based on the inclusion and exclusion criteria. Consumption of highly salty foods and adherence to a Mediterranean dietary pattern can modulate the association between MC4R polymorphisms and the risk of obesity or Type 2 diabetes. Despite the highly contradictory results of intervention studies, after short-term lifestyle interventions, children with variant alleles of MC4R single nucleotide polymorphisms can lose more body weight, compared with non-carriers, although they may have difficulty in maintaining this weight loss in the long-term. To interpret the results of studies on adults, we need further studies. The interaction between MC4R genes with dietary factors plays a significant role in the development of obesity or Type 2 diabetes phenotypes. Early detection of MC4R risk alleles in individuals and modification of their diet based on these results could be an efficient strategy to prevent obesity or diabetes in these subgroups. © 2015 Diabetes UK.

  6. Review Paper: Association of Transforming Growth Factor Beta-1 -509C/T Gene Polymorphism with Ischemic Stroke: A Meta Analysis

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    Pradeep Kumar

    2016-05-01

    Full Text Available Introduction: Transforming Growth Factor-Beta 1 (TGF-β1 is a pleiotropic cytokine with potent anti-inflammatory property, which has been considered as an essential risk factor in the inflammatory process of Ischemic Stroke (IS, by involving in the pathophysiological progression of hypertension, atherosclerosis, and lipid metabolisms. -509C/T TGF-β1 gene polymorphism has been found to be associated with the risk of IS. The aim of this meta-analysis was to provide a relatively comprehensive account of the relation between -509C/T gene polymorphisms of TGF-β1 and susceptibility to IS. Methods: A review of literature for eligible genetic association Studies published before October 20, 2014 was conducted in the PubMed, EMBASE, Google Scholar and Trip database. The strength of association was calculated by pooled odds ratios (ORs with 95% confidence intervals using RevMan 5.3 software. Heterogeneity was examined using Higgins I-squared, Tau-squared, and Chi-squared tests. Results: A total of 2 studies involving 614 cases and 617 controls were found. The overall estimates did not show any significant relation between TGF-β1-509C/T polymorphism and risk of IS under dominant (CC+CT vs. TT: OR=1.01, 95%CI=0.31 to 3.26; P=0.99, recessive (CC vs. CT+TT: OR=0.94, 95%CI=0.47 to 1.90; P=0.87, and allelic models (T vs. C: OR=1.06, 95%CI=0.55 to 2.04; P=0.86. Conclusion: This meta-analysis showed that TGF-β1-509C/T gene polymorphism has no significant association with the susceptibility of IS. Further well-designed prospective studies with larger sample size are needed to confirm these findings.

  7. Polymorphisms in TAS2R38 and the taste bud trophic factor, gustin gene co-operate in modulating PROP taste phenotype.

    Science.gov (United States)

    Calò, Carla; Padiglia, Alessandra; Zonza, Andrea; Corrias, Laura; Contu, Paolo; Tepper, Beverly J; Barbarossa, Iole Tomassini

    2011-10-24

    The PROP taste phenotype varies greatly among individuals, influencing eating behavior and therefore may play a role in body composition. This variation is associated with polymorphisms in the bitter receptor gene TAS2R38 and the taste-bud trophic factor gustin gene. The aim of this study was to examine the relationship between TAS2R38 haplotypes and the gustin gene polymorphism rs2274333 in modulating PROP taste phenotype. PROP phenotype was determined in seventy-six volunteers (29 males, 47 females, age 25±3 y) by scaling methods and threshold measurements. TAS2R38 and gustin gene genotyping was performed using PCR techniques. The lowest responsiveness in PROP nontasters is strongly associated with the AVI nontasting TAS2R38 variant and the highest responsiveness in supertasters is strongly associated to allele A and genotype AA of the gustin gene. These data support the hypothesis that the greater sensitivity of supertasters could be mediated by a greater taste-bud density. Polymorphisms in TAS2R38 and gustin gene, together, accounted for up to 60% of the phenotypic variance in PROP bitterness and to 40% in threshold values. These data, suggest that other unidentified factors may be more relevant for detecting low concentrations of PROP. Moreover, the presence of the PAV variant receptor may be important for detecting high concentrations of PROP, whereas the presence of allele A in gustin polymorphism may be relevant for perceiving low concentrations. These data show how the combination of the TAS2R38 and gustin gene genotypes modulate PROP phenotype, providing an additional tool for the evaluation of human eating behavior and nutritional status. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Serum Anti-TPO and TPO Gene Polymorphism as a Predictive Factor for Hidden Autoimmune Thyroiditis in Patient with Bronchial Asthma and Allergic Rhinitis.

    Science.gov (United States)

    El Shabrawy, Reham M; Atta, Amal H; Rashad, Nearmeen M

    2016-01-01

    Thyroid peroxidase (TPO) is the key enzyme in the biosynthesis of thyroid hormones T3 and T4. Autoimmune thyroiditis is a common disorder affecting 10% of population worldwide. A key feature of autoimmune thyroiditis is the presence of anti TPO antibodies, and some mutation of the TPO gene. Association between autoimmune thyroiditis and other autoimmune disorders has been reported but little is known about association with allergic diseases. In this study, we aimed to evaluate frequency of hidden autoimmune thyroiditis among allergic patient and examine possible relationship between anti-TPO levels and polymorphism at the TPO gene A2173/C exon 12 and different types of allergens. The study included 50 adult Egyptian patients with allergic rhinitis and /or bronchial asthma and 50 controls. For each subject, thyroid stimulating hormone (TSH), thyroxin 4 (T4) and Triiodothyronine (T3) hormones were measured. Anti-thyroid peroxidase (anti-TPO) level was detected by ELISA; and TPO gene polymorphism 2173A>C exon 12 was analyzed using restriction fragment length polymorphism (RFLP). Skin prick test was done to assess allergic response in patients. Serum levels of T3, T4 and TSH did not show any statistical significant difference between patients and groups. However, mean serum anti-TPO level was statistically higher in patients than controls, and correlated positively with body mass index, age, diastolic blood pressure, suggesting higher prevalence of hidden autoimmune thyroiditis in allergic patients than in control group. 2173A>C Genotyping revealed that the frequency of C allele is increased in the patient group. C allele represents a risk factor with odds ratio of 2.37 (1.035-5.44) and a significant P value C polymorphism may be considered as a risk factor for developing autoimmune thyroiditis in patients with allergic rhinitis and asthma and that these patients should regularly be checked for hidden thyroiditis. Copyright© by the Egyptian Association of

  9. Thermopriming Triggers Splicing Memory in Arabidopsis

    KAUST Repository

    Ling, Yu

    2018-02-20

    Abiotic and biotic stresses limit crop productivity. Exposure to a non-lethal stress, referred to as priming, can allow plants to survive subsequent and otherwise lethal conditions; the priming effect persists even after a prolonged stress-free period. However, the molecular mechanisms underlying priming are not fully understood. Here, we investigated the molecular basis of heat shock memory and the role of priming in Arabidopsisthaliana. Comprehensive analysis of transcriptome-wide changes in gene expression and alternative splicing in primed and non-primed plants revealed that alternative splicing functions as a novel component of heat shock memory. We show that priming of plants with a non-lethal heat stress results in de-repression of splicing after a second exposure to heat stress. By contrast, non-primed plants showed significant repression of splicing. These observations link ‘splicing memory’ to the ability of plants to survive subsequent and otherwise lethal heat stress. This newly discovered priming-induced splicing memory may represent a general feature of heat stress responses in plants and other organisms as many of the key components of heat shock responses are conserved among eukaryotes. Furthermore, this finding could facilitate the development of novel approaches to improve plant survival under extreme heat stress.

  10. XRCC1 and XPD DNA repair gene polymorphisms: a potential risk factor for glaucoma in the Pakistani population

    NARCIS (Netherlands)

    Yousaf, S.; Khan, M.I.; Micheal, S.; Akhtar, F.; Ali, S.H.; Riaz, M.; Ali, M.; Lall, P.; Waheed, N.K.; Hollander, A.I. den; Ahmed, A.; Qamar, R.

    2011-01-01

    PURPOSE: The present study was designed to determine the association of polymorphisms of the DNA repair genes X-ray cross-complementing group 1 (XRCC1) (c.1316G>A [rs25487]) and xeroderma pigmentosum complementation group D (XPD) (c.2298A>C [rs13181]) with primary open-angle glaucoma (POAG) and

  11. Vascular endothelial growth factor (VEGF) gene polymorphisms and breast cancer risk in Punjabi population from North West India.

    Science.gov (United States)

    Kapahi, Ruhi; Guleria, Kamlesh; Sambyal, Vasudha; Manjari, Mridu; Sudan, Meena; Uppal, Manjit Singh; Singh, Neeti Rajan

    2014-11-01

    The purpose of this study was to evaluate the association of seven VEGF promoter polymorphisms with breast cancer risk in Punjabi population from North West India. We screened DNA samples of 102 sporadic breast cancer patients and 102 unrelated healthy, gender, and age-matched individuals for seven VEGF promoter polymorphisms [-417 C/T (rs833062), -172 C/A (rs59260042), -165 C/T (rs79469752), -160 C/T, -152 G/A (rs13207351), -141 A/C (rs28357093) and -116 G/A (rs1570360)] by direct sequencing. The frequency of GG, GA, and AA genotype of -152 G/A polymorphism was 26.47 vs 38.34%, 46.08 vs 51.96%, and 27.45 vs 9.80%, in patients and controls, respectively. VEGF -152 AA genotype was significantly associated with increased risk for breast cancer (OR = 4.04, 95%CI, 1.69-9.68, p = 0.001; recessive model OR = 3.48, 95%CI, 1.59-7.63, p = 0.001). For VEGF -116 G/A polymorphism, G and A allele frequencies were 65.2 vs 76.47% and 34.8 vs 23.53% in patients and controls, respectively. Individuals having -116 AA genotype (OR = 3.40; 95%CI, 1.24-9.37; p = 0.014) and A allele (OR = 1.73; 95%CI, 1.12-2.67; p = 0.012) were associated with increased risk for breast cancer. VEGF -165 C/T and -141 A/C polymorphisms were associated with reduced risk for breast cancer. There was significantly decreased frequency of CT genotype (4.90 vs 18.63%; p = 0.002) and T allele (2.45 vs 9.31%; p = 0.003) of -165 C/T polymorphism among breast cancer patients as compared to controls. VEGF -141 A and C allele frequency were 96.57 vs 91.18% and 3.43 vs 8.82% in patients and controls, respectively. Significant reduced risk for breast cancer was observed with AC genotype (OR = 0.34, 95%CI, 0.14-0.86; p = 0.019) and C allele (OR = 0.37; 95%CI, 0.15-0.89; p = 0.023) of -141 A/C polymorphism. We did not observe association of VEGF -417 T/C, -172 C/A, -160 C/T polymorphisms with breast cancer risk in the studied subjects (p > 0.05). The VEGF -152 G/A and -116 G/A polymorphisms were found to be significantly

  12. The impact of Folate Pathway Polymorphisms Combined to Nutritional Deficiency As a Maternal Predisposition Factor for Down Syndrome

    Directory of Open Access Journals (Sweden)

    C. B. Santos-Rebouças

    2008-01-01

    Full Text Available Polymorphisms in genes encoding folate metabolizing enzymes have been linked to an increased risk of maternal chromosomal nondisjunction in several populations. With the purpose of evaluating this relationship, we compared the frequencies of 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR and 66A>G in the methionine synthase reductase gene (MTRR between 103 young mothers of Down syndrome (DS individuals and 108 control mothers, whose offspring was karyotypically normal, correlating it with an estimative of folate and – related micronutrients levels intake. Maternal and paternal transmission frequencies of MTHFR 677T allele were also examined to access potential parent-of-origin effects. PCR-RFLP for genomic DNA was accomplished and allele/genotype frequencies differences were determined using the x2 test, whereas pattern of transmission of the MTHFR 677 allele was analyzed by transmission disequilibrium test. None of the polymorphisms seemed to be more frequent in case mothers than in controls, either individually or combined. The estimative of nutritional intake revealed that folate consumption median was inadequate in both groups, whereas methionine and zinc consumption medians were significantly greater in control mothers. It suggests that such interaction between genetic profile and environment could predispose this sub group of women to have a DS child. Additional studies focusing the interaction between nutritional intakes, biochemical data and folate pathway polymorphisms are needed to confirm the present results. The possibility of neutralize the biochemical negative effects of folate-related polymorphisms through oral supplementation could provide new targets for DS prevention.

  13. Genetics of alternative splicing evolution during sunflower domestication.

    Science.gov (United States)

    Smith, Chris C R; Tittes, Silas; Mendieta, J Paul; Collier-Zans, Erin; Rowe, Heather C; Rieseberg, Loren H; Kane, Nolan C

    2018-06-11

    Alternative splicing enables organisms to produce the diversity of proteins necessary for multicellular life by using relatively few protein-coding genes. Although differences in splicing have been identified among divergent taxa, the shorter-term evolution of splicing is understudied. The origins of novel splice forms, and the contributions of alternative splicing to major evolutionary transitions, are largely unknown. This study used transcriptomes of wild and domesticated sunflowers to examine splice differentiation and regulation during domestication. We identified substantial splicing divergence between wild and domesticated sunflowers, mainly in the form of intron retention. Transcripts with divergent splicing were enriched for seed-development functions, suggesting that artificial selection impacted splicing patterns. Mapping of quantitative trait loci (QTLs) associated with 144 differential splicing cases revealed primarily trans -acting variation affecting splicing patterns. A large proportion of identified QTLs contain known spliceosome proteins and are associated with splicing variation in multiple genes. Examining a broader set of wild and domesticated sunflower genotypes revealed that most differential splicing patterns in domesticated sunflowers likely arose from standing variation in wild Helianthus annuus and gained frequency during the domestication process. However, several domesticate-associated splicing patterns appear to be introgressed from other Helianthus species. These results suggest that sunflower domestication involved selection on pleiotropic regulatory alleles. More generally, our findings indicate that substantial differences in isoform abundances arose rapidly during a recent evolutionary transition and appear to contribute to adaptation and population divergence.

  14. HIV-1 splicing is controlled by local RNA structure and binding of splicing regulatory proteins at the major 5' splice site

    NARCIS (Netherlands)

    Mueller, Nancy; Berkhout, Ben; Das, Atze T.

    2015-01-01

    The 5' leader region of the human immunodeficiency virus 1 (HIV-1) RNA genome contains the major 5' splice site (ss) that is used in the production of the many spliced viral RNAs. This splice-donor (SD) region can fold into a stable stem-loop structure and the thermodynamic stability of this RNA

  15. Alternative splicing at the intersection of biological timing, development, and stress responses.

    Science.gov (United States)

    Staiger, Dorothee; Brown, John W S

    2013-10-01

    High-throughput sequencing for transcript profiling in plants has revealed that alternative splicing (AS) affects a much higher proportion of the transcriptome than was previously assumed. AS is involved in most plant processes and is particularly prevalent in plants exposed to environmental stress. The identification of mutations in predicted splicing factors and spliceosomal proteins that affect cell fate, the circadian clock, plant defense, and tolerance/sensitivity to abiotic stress all point to a fundamental role of splicing/AS in plant growth, development, and responses to external cues. Splicing factors affect the AS of multiple downstream target genes, thereby transferring signals to alter gene expression via splicing factor/AS networks. The last two to three years have seen an ever-increasing number of examples of functional AS. At a time when the identification of AS in individual genes and at a global level is exploding, this review aims to bring together such examples to illustrate the extent and importance of AS, which are not always obvious from individual publications. It also aims to ensure that plant scientists are aware that AS is likely to occur in the genes that they study and that dynamic changes in AS and its consequences need to be considered routinely.

  16. Tumor necrosis factor −308 polymorphism (rs1800629) is associated with mortality and ventilator duration in 1057 Caucasian patients

    Science.gov (United States)

    Watanabe, Eizo; Zehnbauer, Barbara A.; Oda, Shigeto; Sato, Yasunori; Hirasawa, Hiroyuki; Buchman, Timothy G.

    2012-01-01

    Purpose Management of sepsis in critically ill patients remains difficult and requires prolonged intensive care. Genetic testing has been proposed as a strategy to identify patients at risk for adverse outcome of critical illnesses. Therefore, we wished to determine the influence of heredity on predisposition to poor outcome and on duration of ventilator support of intensive care unit (ICU) patients. Methods A study was conducted from July 2001 to December 2005 in heterogeneous population of patients from 12 US ICUs represented by the Genetic Predisposition to Severe Sepsis (GenPSS) archive. In 1057 Caucasian critically ill patients with SAPS II probability of survival of >0.2 in the US, six functional single nucleotide polymorphisms in relation to inflammatory cytokines and innate immunity (rs1800629, rs16944, rs1800795, rs1800871, rs2569190, and rs909253) were evaluated in terms of mortality and ventilator free days. Results The AA homozygote of TNF(−308) (rs1800629) was most over-represented in the deceased patient group (P = 0.015 with recessive model). The carriage of the TNF(−308)* AA genotype showed significantly higher odds ratio of 2.67(1.29–5.55) (P = 0.008) after adjustment with the covariates. However, the presence of 1, 2, or 3 acute organ dysfunctions was larger prognostic factors for the adverse outcome (OR(95%CI) = 2.98(2.00–4.45), 4.01(2.07–7.77), or 19.95(4.99–79.72), P < 0.001 for all). Kaplan–Mayer plot on ventilator duration of TNF(−308)* AA patient significantly diverged from that of TNF(−308)* (GG + GA) ((AA v GG + GA), Adjusted HR(95%CI) = 2.53(1.11–5.79) with Cox regression, P = 0.028). Conclusions TNF(−308)* AA is significantly associated with susceptibility to adverse outcome and to longer ventilator duration. Therefore, heredity likely affects both predisposition to ICU prognosis as well as the resource utilization. PMID:22749237

  17. Controlled chaos of polymorphic mucins in a metazoan parasite (Schistosoma mansoni interacting with its invertebrate host (Biomphalaria glabrata.

    Directory of Open Access Journals (Sweden)

    Emmanuel Roger

    Full Text Available Invertebrates were long thought to possess only a simple, effective and hence non-adaptive defence system against microbial and parasitic attacks. However, recent studies have shown that invertebrate immunity also relies on immune receptors that diversify (e.g. in echinoderms, insects and mollusks (Biomphalaria glabrata. Apparently, individual or population-based polymorphism-generating mechanisms exists that permit the survival of invertebrate species exposed to parasites. Consequently, the generally accepted arms race hypothesis predicts that molecular diversity and polymorphism also exist in parasites of invertebrates. We investigated the diversity and polymorphism of parasite molecules (Schistosoma mansoni Polymorphic Mucins, SmPoMucs that are key factors for the compatibility of schistosomes interacting with their host, the mollusc Biomphalaria glabrata. We have elucidated the complex cascade of mechanisms acting both at the genomic level and during expression that confer polymorphism to SmPoMuc. We show that SmPoMuc is coded by a multi-gene family whose members frequently recombine. We show that these genes are transcribed in an individual-specific manner, and that for each gene, multiple splice variants exist. Finally, we reveal the impact of this polymorphism on the SmPoMuc glycosylation status. Our data support the view that S. mansoni has evolved a complex hierarchical system that efficiently generates a high degree of polymorphism-a "controlled chaos"-based on a relatively low number of genes. This contrasts with protozoan parasites that generate antigenic variation from large sets of genes such as Trypanosoma cruzi, Trypanosoma brucei and Plasmodium falciparum. Our data support the view that the interaction between parasites and their invertebrate hosts are far more complex than previously thought. While most studies in this matter have focused on invertebrate host diversification, we clearly show that diversifying mechanisms also

  18. Genetic polymorphism in matrix metalloproteinase-9 and transforming growth factor-β1 and susceptibility to combined pulmonary fibrosis and emphysema in a Chinese population.

    Science.gov (United States)

    Xu, Ling; Bian, Wei; Gu, Xiao-Hua; Shen, Ce

    2017-03-01

    In this study, we aimed to explore the association of genetic polymorphism in matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β1 (TGF-β1) and the susceptibility to combined pulmonary fibrosis and emphysema (CPFE). We examined the polymorphisms of the MMP-9 C-1562T and TGF-β1 T869C in 38 CPFE patients, 50 pulmonary emphysema patients, and 34 idiopathic pulmonary fibrosis (IPF) patients. The frequencies of polymorphic genotypes in MMP-9 were 78.95% CC and 21.05% CT in CPFE group, 76.0% CC and 24.0% CT in emphysema group, and 100.0% CC in IPF group. There were highly statistically significant increased frequencies of the CT genotype and T allele in CPFE and emphysema groups compared with IPF group (p emphysema group, and 5.88% CC, 41.18% CT, 52.94% TT in IPF group. Significant increases in the TT genotype and T allele frequencies were observed in emphysema group compared with IPF group (p pulmonary emphysema. The T allele in MMP-9 (C-1562T) possibly predisposes patients with pulmonary fibrosis to develop emphysema. Copyright © 2017. Published by Elsevier Taiwan.

  19. Human leukocyte antigen class I, class II, and tumor necrosis factor-alpha polymorphisms in a healthy elder Mexican Mestizo population

    Directory of Open Access Journals (Sweden)

    Llorente Luis

    2005-11-01

    Full Text Available Abstract Background There is strong evidence that an individual's genetic background is an important predisposing factor to longevity. In the present study we analysed the frequency of HLA class I, class II, as well as the TNF-α -308 polymorphism that may be related to an increased life span in Mexican Mestizo healthy elders. Results HLA typing was performed by polymerase chain reaction sequence specific oligonucleotide (PCR SSO reverse dot blot. The TNF-α -308 polymorphism was assessed by PCR restriction fragment length polymorphism. A significant increased frequency of HLA-DRB1*11 was found in elderly women whereas this allele was not present in elderly males. The TNF2 allele was also increased in the elder group when compared to young controls. The frequencies of the remaining alleles tested were not statistically different among groups. Conclusion These data suggest an ethnicity independent tendency of HLA-DRB1*11 in elder females to increase life span and a possible role of the TNF2 allele with the successful remodelling of senescent immune system.

  20. Macrophage Migration Inhibitory Factor (MIF) Gene Promotor Polymorphism Is Associated with Increased Fibrosis in Biliary Atresia Patients, but Not with Disease Susceptibility.

    Science.gov (United States)

    Sadek, Khaled H; Ezzat, Sameera; Abdel-Aziz, Samira A; Alaraby, Hanaa; Mosbeh, Asmaa; Abdel-Rahman, Mohamed H

    2017-09-01

    Two polymorphisms, rs755622 and rs5844572, in the promoter region of the macrophage migration inhibitory factor (MIF) gene influence the basal and/or induced transcriptional activity and have been linked to several inflammatory and autoimmune diseases. The aim of this study was to investigate the association between these two polymorphisms and disease susceptibility in patients with biliary atresia (BA). Allele frequencies of rs755622 and rs5844572 were assessed in 60 Egyptian infants with a confirmed diagnosis of BA. DNA was extracted from archival material. For the rs755622, samples were tested using Taqman real-time PCR, and for the rs5844572, samples were tested using fluorescence-based genotyping. The allele frequency in the general population was assessed in 141 healthy adults from the same geographical location. No statistical differences were observed in the allele frequencies of either rs755622 or rs5844572 between BA patients and controls. The homozygous and heterozygous short repeats (5/5, or 5/X) of rs5844572 were observed more frequently (16/28, 57.1%) in BA patients with mild to moderate fibrosis compared with those with marked fibrosis (10/32, 31.3%). The difference was statistically significant (P  =  0.032). In conclusion, we observed no association between MIF rs755622 and rs5844572 polymorphisms and susceptibility to BA; however, the rs5844572 could be linked to the rate of progression of the disease and extent of fibrosis. © 2017 John Wiley & Sons Ltd/University College London.

  1. Polymorphism of Insulin-like growth factor-I (IGF-I gene and their effect on growth traits in Indonesia native chicken

    Directory of Open Access Journals (Sweden)

    M.A Mu'in

    2009-12-01

    Full Text Available The research was aimed is to detect Insulin-like growth factor-I (IGF-I gene polymorphism and their effect on growth traits in Indonesia natives chicken. Seventy two Indonesian native chicken are going to be used in this research. The polymorphism of IGF-I gene was detected by PCR-RFLP/Pst-I. Four growth traits (body weight at 1, 2, 3, and 4 months were recorded for analyzing the association between IGF-I gene polymorphism and growth performance.The results showed that allele A (621 bp and allele B (364 and 257 bp were found in this research. It was found that Indonesian native chicken carried high frequencies of allele A (0.82, and frequencies of IGF-I genotypes (AA, AB, BB were 68.0, 27.8, and 4,2%, respectively. When compared to the IGF-I genotypes, the BB genotype had the highest body weight at 1, 2, 3, and 4 month (P<0.05. The results showed that the B allele was positive of associated to a higher growth rate. Therefore, these results suggest that there is a possibility of IGF-I genotypes acting as a molecular marker for growth rate of Indonesia native.

  2. Warfarin dose requirement in Turkish patients: the influences of patient characteristics and polymorphisms in CYP2C9, VKORC1 and factor VII.

    Science.gov (United States)

    Yildirim, E; Erol, K; Birdane, A

    2014-01-01

    To determine the contribution of cytochrome P4502C9 (CYP2C9), vitamin K epoxide reductase (VKORC1) and factor VII genotypes, age, body mass index (BMI), international normalized ratio (INR) and other individual patient characteristics on warfarin dose requirements in an adult Turkish population. Blood samples were collected from 101 Turkish patients. Genetic analyses for CYP2C9*2 and *3, VKORC1 -1639 G>A and factor VII -401 G>T polymorphisms were performed. Age, INR, BMI values and other individual patient characteristics were also recorded. The mean daily warfarin dosage was significantly higher in patients with the CYP2C9*1/*1 genotype than in the CYP2C9*2/*2 and CYP2C9*1/*3 groups (p ≤ 0.05). With respect to the VKORC1 -1639 G>A polymorphism, the mean warfarin daily dose requirement was higher in the wild type group compared to the heterozygous group (p≤0.001). The mean daily dose requirement for patients with the GG form of factor VII was significantly higher than that of patients with the TT genotype (p ≤ 0.05). Age, gender, BMI, INR had no statistically significant correlation with warfarin dose (p ≥ 0.05). Polymorphisms in CYP2C9, VKORC1 and factor VII did partially affect daily warfarin dose requirements, while age, gender, BMI and INR do not. However, further case-control studies with a larger study size and different genetic loci are needed to confirm our study.

  3. Structural Insight Into the Role of Mutual Polymorphism and Conservatism in the Contact Zone of the NFR5-K1 Heterodimer With the Nod Factor.

    Science.gov (United States)

    Igolkina, A A; Porozov, Yu B; Chizhevskaya, E P; Andronov, E E

    2018-01-01

    Sandwich-like docking configurations of the heterodimeric complex of NFR5 and K1 Vicia sativa receptor-like kinases together with the putative ligand, Nod factor (NF) of Rhizobium leguminosarum bv. viciae , were modeled and two of the most probable configurations were assessed through the analysis of the mutual polymorphisms and conservatism. We carried out this analysis based on the hypothesis that in a contact zone of two docked components (proteins or ligands) the population polymorphism or conservatism is mutual, i.e., the variation in one component has a reflected variation in the other component. The population material of 30 wild-growing V. sativa (leaf pieces) was collected from a large field (uncultivated for the past 25-years) and pooled; form this pool, 100 randomly selected cloned fragments of NFR5 gene and 100 of K1 gene were sequenced by the Sanger method. Congruence between population trees of NFR5 and K1 haplotypes allowed us to select two respective haplotypes, build their 3D structures, and perform protein-protein docking. In a separate simulation, the protein-ligand docking between NFR5 and NF was carried out. We merged the results of the two docking experiments and extracted NFR5-NF-K1 complexes, in which NF was located within the cavity between two receptors. Molecular dynamics simulations indicated two out of six complexes as stable. Regions of mutual polymorphism in the contact zone of one complex overlapped with known NF structural variations produced by R. leguminosarum bv. viciae . A total of 74% of the contact zone of another complex contained mutually polymorphic and conservative areas. Common traits of the obtained two stable structures allowed us to hypothesize the functional role of three-domain structure of plant LysM-RLKs in their heteromers.

  4. The protein tyrosine phosphatase, nonreceptor type 22-1858C->T (rs2476601 polymorphism is not a genetic risk factor for systemic lupus erythematosus in Indian Tamils

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    Panneer Devaraju

    2017-01-01

    Full Text Available Background: Systemic lupus erythematosus (SLE, a systemic autoimmune disease, occurs due to disruption of immune homeostasis against self-antigens. The etiology of SLE is complex and multiple genetic factors contribute to disease susceptibility and clinical phenotypes. Protein tyrosine phosphatase, nonreceptor type 22 (PTPN22 is a lymphoid-specific phosphatase that negatively regulates T-cell receptor signaling and is responsible for the maintenance of T-cell homeostasis. Genetic aberrations affecting the function of PTPN22 result in the proliferation of autoreactive T-cells and development of autoimmune diseases. Methods: We carried out a case–control genetic study to analyze the association of PTPN22 R620W polymorphism (rs2476601 with disease susceptibility and clinical and autoantibody profile in Indian Tamils with SLE. Three hundred SLE patients satisfying the 1997 revised American College of Rheumatology classification criteria for SLE were enrolled in the study. Disease activity was measured using the SLE Disease Activity Index. We recruited 460 age-, sex-, and ethnicity-matched individuals without a family history of autoimmune diseases as control population. Genomic DNA was extracted from the blood sample by salting-out method. The PTPN22-1858C->T (rs2476601 polymorphism was screened by polymerase chain reaction-restriction fragment length polymorphism. Results: The frequency of the ancestral allele “C” was similar in both cases and controls (99.3% and 99.8%, respectively and the mutant allele “T” was less frequent in South Indian Tamil population; it did not influence clinical or serological phenotypes. Conclusion: Our findings suggest that the PTPN22 (rs2476601 polymorphism is less frequent and did not confer a risk for lupus or its associated clinical or serological phenotypes in South Indian Tamils.

  5. Structural Insight Into the Role of Mutual Polymorphism and Conservatism in the Contact Zone of the NFR5–K1 Heterodimer With the Nod Factor

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    A. A. Igolkina

    2018-04-01

    Full Text Available Sandwich-like docking configurations of the heterodimeric complex of NFR5 and K1 Vicia sativa receptor-like kinases together with the putative ligand, Nod factor (NF of Rhizobium leguminosarum bv. viciae, were modeled and two of the most probable configurations were assessed through the analysis of the mutual polymorphisms and conservatism. We carried out this analysis based on the hypothesis that in a contact zone of two docked components (proteins or ligands the population polymorphism or conservatism is mutual, i.e., the variation in one component has a reflected variation in the other component. The population material of 30 wild-growing V. sativa (leaf pieces was collected from a large field (uncultivated for the past 25-years and pooled; form this pool, 100 randomly selected cloned fragments of NFR5 gene and 100 of K1 gene were sequenced by the Sanger method. Congruence between population trees of NFR5 and K1 haplotypes allowed us to select two respective haplotypes, build their 3D structures, and perform protein–protein docking. In a separate simulation, the protein-ligand docking between NFR5 and NF was carried out. We merged the results of the two docking experiments and extracted NFR5–NF–K1 complexes, in which NF was located within the cavity between two receptors. Molecular dynamics simulations indicated two out of six complexes as stable. Regions of mutual polymorphism in the contact zone of one complex overlapped with known NF structural variations produced by R. leguminosarum bv. viciae. A total of 74% of the contact zone of another complex contained mutually polymorphic and conservative areas. Common traits of the obtained two stable structures allowed us to hypothesize the functional role of three-domain structure of plant LysM-RLKs in their heteromers.

  6. A brain-derived neurotrophic factor polymorphism Val66Met identifies fibromyalgia syndrome subgroup with higher body mass index and C-reactive protein.

    Science.gov (United States)

    Xiao, Yangming; Russell, I Jon; Liu, Ya-Guang

    2012-08-01

    A common single nucleotide polymorphism (SNP) in the gene of brain-derived neurotrophic factor (BDNF) results from a substitution at position 66 from valine (Val) to methionine (Met) and may predispose to human neuropsychiatric disorders. We proposed to determine whether these BDNF gene SNPs were associated with fibromyalgia syndrome (FMS) and/or any of its typical phenotypes. Patients with FMS (N = 95) and healthy normal controls (HNC, N = 58) were studied. Serum high-sensitivity C-reactive protein (hsCRP) levels were measured using an enzyme-linked immunosorbent assay (ELISA). The BDNF SNPs were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The BDNF SNP distribution was 65 (68%) Val/Val, 28 (30%) Val/Met, and 2 (2%) Met/Met for FMS and 40 (69%), 17(29%), and 1 (2%) for HNC, respectively. The serum high-sensitivity C-reactive protein (hsCRP)and body mass index (BMI) in FMS were higher than in HNC. The FMS with BDNF Val66Val had significantly higher mean BMI (P = 0.0001) and hsCRP (P = 0.02) than did FMS carrying the Val66Met genotype. This pattern was not found in HNC. Phenotypic measures of subjective pain, pain threshold, depression, or insomnia did not relate to either of the BDNF SNPs in FMS. The relative distribution BDNF SNPs did not differ between FMS and HNC. The BDNF Val66Met polymorphism is not selective for FMS. The BDNF Val66Val SNP identifies a subgroup of FMS with elevated hsCRP and higher BMI. This is the first study to associate a BDNF polymorphism with a FMS subgroup phenotype.

  7. Serotonin Transporter Gene 5-HTTLPR Polymorphism as a Protective Factor Against the Progression of Post-Stroke Depression.

    Science.gov (United States)

    Zhao, Qiang; Guo, Yi; Yang, Dong; Yang, Tiansong; Meng, Xianghui

    2016-04-01

    Polymorphisms in the 5-HTT and BDNF genes are shown to affect their function at the molecular and serum level. Prior work has tried to correlate the polymorphisms with post-stroke depression (PSD), the results nevertheless remain indefinitive. A plausible reason accounting for the uncertainty relates to the small sample of each published trial. In this study, we have performed a comprehensive meta-analysis in order to evaluate the effects of 5-HTT and BDNF polymorphisms (5-HTTLPR, STin2 VNTR, 5-HTR2a 102 T/C, Val66Met) on genetic risk of PSD. Human case-control trials were identified by computer-assisted and manual searches. The article search was performed until October 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed effects meta-analysis to measure the effects 5-HTT and BDNF polymorphisms exerted on PSD. We also performed test of heterogeneity, test of publication bias, and sensitivity analysis to examine the reliability and stability of combined effects. 5-HTTLPR was clearly associated with genetic risk of PSD. The association seemed to be more pronounced in the homozygous model (OR = 0.34, 95% CI = 0.23-0.51, P(Q-test) = 0.63). Both the heterozygous model and the recessive model showed 50% decreased risk of PSD (OR = 0.50, 95% CI = 0.37-0.67, P(Q-test) = 0.91; OR = 0.50, 95% CI = 0.36-0.70, P(Q-test) = 0.43, respectively). Such significant association was also detected for Caucasian and Asian. These results were reliable and stable based on related analyses. Taken together, 5-HTTLPR polymorphism of the 5-HTT gene seems to protect against the occurrence of PSD. Small sample size for the polymorphisms within 5-HTT and BDNF genes may have caused underestimated associations, and a larger study is required to further assess the relations.

  8. Modulation of 5' splice site selection using tailed oligonucleotides carrying splicing signals

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    Elela Sherif

    2006-01-01

    Full Text Available Abstract Background We previously described the use of tailed oligonucleotides as a means of reprogramming alternative pre-mRNA splicing in vitro and in vivo. The tailed oligonucleotides that were used interfere with splicing because they contain a portion complementary to sequences immediately upstream of the target 5' splice site combined with a non-hybridizing 5' tail carrying binding sites for the hnRNP A1/A2 proteins. In the present study, we have tested the inhibitory activity of RNA oligonucleotides carrying different tail structures. Results We show that an oligonucleotide with a 5' tail containing the human β-globin branch site sequence inhibits the use of the 5' splice site of Bcl-xL, albeit less efficiently than a tail containing binding sites for the hnRNP A1/A2 proteins. A branch site-containing tail positioned at the 3' end of the oligonucleotide also elicited splicing inhibition but not as efficiently as a 5' tail. The interfering activity of a 3' tail was improved by adding a 5' splice site sequence next to the branch site sequence. A 3' tail carrying a Y-shaped branch structure promoted similar splicing interference. The inclusion of branch site or 5' splice site sequences in the Y-shaped 3' tail further improved splicing inhibition. Conclusion Our in vitro results indicate that a variety of tail architectures can be used to elicit splicing interference at low nanomolar concentrations, thereby broadening the scope and the potential impact of this antisense technology.

  9. Tumor Necrosis Factor (TNF) –308G>A, Nitric Oxide Synthase 3 (NOS3) +894G>T Polymorphisms and Migraine Risk: A Meta-Analysis

    Science.gov (United States)

    Chen, Min; Tang, Wenjing; Hou, Lei; Liu, Ruozhuo; Dong, Zhao; Han, Xun; Zhang, Xiaofei; Wan, Dongjun; Yu, Shengyuan

    2015-01-01

    Background and Objective Conflicting data have been reported on the association between tumor necrosis factor (TNF) –308G>A and nitric oxide synthase 3 (NOS3) +894G>T polymorphisms and migraine. We performed a meta-analysis of case-control studies to evaluate whether the TNF –308G>A and NOS3 +894G>T polymorphisms confer genetic susceptibility to migraine. Method We performed an updated meta-analysis for TNF –308G>A and a meta-analysis for NOS3 +894G>T based on studies published up to July 2014. We calculated study specific odds ratios (OR) and 95% confidence intervals (95% CI) assuming allele contrast, dominant model, recessive model, and co-dominant model as pooled effect estimates. Results Eleven studies in 6682 migraineurs and 22591 controls for TNF –308G>A and six studies in 1055 migraineurs and 877 controls for NOS3 +894G>T were included in the analysis. Neither indicated overall associations between gene polymorphisms and migraine risk. Subgroup analyses suggested that the “A” allele of the TNF –308G>A variant increases the risk of migraine among non-Caucasians (dominant model: pooled OR = 1.82; 95% CI 1.15 – 2.87). The risk of migraine with aura (MA) was increased among both Caucasians and non-Caucasians. Subgroup analyses suggested that the “T” allele of the NOS3 +894G>T variant increases the risk of migraine among non-Caucasians (co-dominant model: pooled OR = 2.10; 95% CI 1.14 – 3.88). Conclusions Our findings appear to support the hypothesis that the TNF –308G>A polymorphism may act as a genetic susceptibility factor for migraine among non-Caucasians and that the NOS3 +894G>T polymorphism may modulate the risk of migraine among non-Caucasians. PMID:26098763

  10. Homologous SV40 RNA trans-splicing: Special case or prime example of viral RNA trans-splicing?

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    Sushmita Poddar

    2014-06-01

    Full Text Available To date the Simian Virus 40 (SV40 is the only proven example of a virus that recruits the mechanism of RNA trans-splicing to diversify its sequences and gene products. Thereby, two identical viral transcripts are efficiently joined by homologous trans-splicing triggering the formation of a highly transforming 100 kDa super T antigen. Sequences of other viruses including HIV-1 and the human adenovirus type 5 were reported to be involved in heterologous trans-splicing towards cellular or viral sequences but the meaning of these events remains unclear. We computationally and experimentally investigated molecular features associated with viral RNA trans-splicing and identified a common pattern: Viral RNA trans-splicing occurs between strong cryptic or regular viral splice sites and strong regular or cryptic splice sites of the trans-splice partner sequences. The majority of these splice sites are supported by exonic splice enhancers. Splice sites that could compete with the trans-splicing sites for cis-splice reactions are weaker or inexistent. Finally, all but one of the trans-splice reactions seem to be facilitated by one or more complementary binding domains of 11 to 16 nucleotides in length which, however occur with a statistical probability close to one for the given length of the involved sequences. The chimeric RNAs generated via heterologous viral RNA trans-splicing either did not lead to fusion proteins or led to proteins of unknown function. Our data suggest that distinct viral RNAs are highly susceptible to trans-splicing and that heterologous viral trans-splicing, unlike homologous SV40 trans-splicing, represents a chance event.

  11. Identification of a chemical inhibitor for nuclear speckle formation: Implications for the function of nuclear speckles in regulation of alternative pre-mRNA splicing

    Energy Technology Data Exchange (ETDEWEB)

    Kurogi, Yutaro; Matsuo, Yota; Mihara, Yuki; Yagi, Hiroaki; Shigaki-Miyamoto, Kaya; Toyota, Syukichi; Azuma, Yuko [Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, Chuo-ku, Kumamoto 860-8555 (Japan); Igarashi, Masayuki [Laboratory of Disease Biology, Institute of Microbial Chemistry, Shinagawa-ku, Tokyo 141-0021 (Japan); Tani, Tokio, E-mail: ttani@sci.kumamoto-u.ac.jp [Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, Chuo-ku, Kumamoto 860-8555 (Japan)

    2014-03-28

    Highlights: • We identified tubercidin as a compound inducing aberrant formation of the speckles. • Tubercidin causes delocalization of poly (A){sup +}RNAs from nuclear speckles. • Tubercidin induces dispersion of splicing factors from nuclear speckles. • Tubercidin affects alternative pre-mRNA splicing. • Nuclear speckles play a role in regulation of alternative pre-mRNA splicing. - Abstract: Nuclear speckles are subnuclear structures enriched with RNA processing factors and poly (A){sup +} RNAs comprising mRNAs and poly (A){sup +} non-coding RNAs (ncRNAs). Nuclear speckles are thought to be involved in post-transcriptional regulation of gene expression, such as pre-mRNA splicing. By screening 3585 culture extracts of actinomycetes with in situ hybridization using an oligo dT probe, we identified tubercidin, an analogue of adenosine, as an inhibitor of speckle formation, which induces the delocalization of poly (A){sup +} RNA and dispersion of splicing factor SRSF1/SF2 from nuclear speckles in HeLa cells. Treatment with tubercidin also decreased steady-state MALAT1 long ncRNA, thought to be involved in the retention of SRSF1/SF2 in nuclear speckles. In addition, we found that tubercidin treatment promoted exon skipping in the alternative splicing of Clk1 pre-mRNA. These results suggest that nuclear speckles play a role in modulating the concentration of splicing factors in the nucleoplasm to regulate alternative pre-mRNA splicing.

  12. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and post-stroke dementia: a hospital-based study from northern Iran.

    Science.gov (United States)

    Rezaei, Sajjad; Asgari Mobarake, Karim; Saberi, Alia; Keshavarz, Parvaneh; Leili, Ehsan Kazemnejad

    2016-06-01

    Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with functional and cognitive outcomes of stroke and plays a key role in preventing neuronal death. This study aimed to answer the following question: does BDNF Val66Met polymorphism prognosticate survival status and risk of post-stroke dementia (PSD)? In a retrospective cohort study, 206 patients with ischemic stroke (IS) entered the study. They were consecutively being admitted to the neurology clinic in Poursina Hospital (northern Iran) from 2012 to 2014. The diagnosis of PSD was based on DSM-5 criteria. The current and the premorbid cognitive statuses of the patients were respectively assessed through the third edition of Addenbrooke's Cognitive Examination and the Informant Questionnaire on Cognitive Decline in the Elderly. BDNF Val66Met gene polymorphism was determined by PCR-RFLP. On average, 48 patients (23.3 %) developed PSD 6 months after IS. Log-rank test showed that the survival rate of at least one Val-allele carriers was significantly lower than that of Met/Met homozygotes (P = 0.0005), and the former developed PSD sooner than the latter (375, 492 days, respectively). Cox model showed that heterozygous carriers of Val/Met were at greater risk of PSD over time (HR 2.280, 95 % CI 1.566-4.106, P = 0.006). However, the risk ratio of patients with PSD among different BDNF genotypes decreased after adjusting demographic, clinical, and vascular risk factors, and was no longer statistically significant (AHR 2.434, 95 % CI 0.597-9.926, P = 0.215). Val-allele carriers or Val/Met genotypes were more quickly diagnosed as having dementia after IS. However, this genetic vulnerability became more destructive when it was added to demographic, clinical, and vascular risk factors.

  13. The relationship of the factor V Leiden mutation or the deletion-deletion polymorphism of the angiotensin converting enzyme to postoperative thromboembolic events following total joint arthroplasty

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    Fang Carrie

    2001-04-01

    Full Text Available Abstract Background Although all patients undergoing total joint arthroplasty are subjected to similar risk factors that predispose to thromboembolism, only a subset of patients develop this complication. The objective of this study was to determine whether a specific genetic profile is associated with a higher risk of developing a postoperative thromboembolic complication. Specifically, we examined if the Factor V Leiden (FVL mutation or the deletion polymorphism of the angiotensin-converting enzyme (ACE gene increased a patient's risk for postoperative thromboembolic events. The FVL mutation has been associated with an increased risk of idiopathic thromboembolism and the deletion polymorphism of the ACE gene has been associated with increased vascular tone, attenuated fibrinolysis and increased platelet aggregation. Methods The presence of these genetic profiles was determined for 38 patients who had a postoperative symptomatic pulmonary embolus or proximal deep venous thrombosis and 241 control patients without thrombosis using molecular biological techniques. Results The Factor V Leiden mutation was present in none of the 38 experimental patients and in 3% or 8 of the 241 controls (p = 0.26. Similarly there was no difference detected in the distribution of polymorphisms for the ACE gene with the deletion-deletion genotype present in 36% or 13 of the 38 experimental patients and in 31% or 74 of the 241 controls (p = 0.32. Conclusions Our results suggest that neither of these potentially hypercoaguable states are associated with an increased risk of symptomatic thromboembolic events following total hip or knee arthroplasty in patients receiving pharmacological thromboprophylaxis.

  14. The COMT Val158 Met polymorphism as an associated risk factor for Alzheimer disease and mild cognitive impairment in APOE 4 carriers

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    Borda Sandra

    2009-09-01

    Full Text Available Abstract Background The aim of this study is to examine the influence of the catechol-O-methyltranferase (COMT gene (polymorphism Val158 Met as a risk factor for Alzheimer's disease (AD and mild cognitive impairment of amnesic type (MCI, and its synergistic effect with the apolipoprotein E gene (APOE. A total of 223 MCI patients, 345 AD and 253 healthy controls were analyzed. Clinical criteria and neuropsychological tests were used to establish diagnostic groups. The DNA Bank of the University of the Basque Country (UPV-EHU (Spain determined COMT Val158 Met and APOE genotypes using real time polymerase chain reaction (rtPCR and polymerase chain reaction (PCR, and restriction fragment length polymorphism (RFLPs, respectively. Multinomial logistic regression models were used to determine the risk of AD and MCI. Results Neither COMT alleles nor genotypes were independent risk factors for AD or MCI. The high activity genotypes (GG and AG showed a synergistic effect with APOE ε4 allele, increasing the risk of AD (OR = 5.96, 95%CI 2.74-12.94, p In MCI patients such as synergistic effect was only found between AG and APOE ε4 allele (OR = 3.21 95%CI 1.56-6.63, p = 0.02 and was greater in men (OR = 5.88 95%CI 1.69-20.42, p Conclusion COMT (Val158 Met polymorphism is not an independent risk factor for AD or MCI, but shows a synergistic effect with APOE ε4 allele that proves greater in women with AD.

  15. Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors.

    Science.gov (United States)

    Skrobik, Yoanna; Leger, Caroline; Cossette, Mariève; Michaud, Veronique; Turgeon, Jacques

    2013-04-01

    Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier. To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU. In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1β, and monocyte chemotactic protein-1. Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05). Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status

  16. The Survivin −31 Snp in Human Colorectal Cancer Correlates with Survivin Splice Variant Expression and Improved Overall Survival

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    Anna G. Antonacopoulou

    2010-01-01

    Full Text Available Background: Survivin is involved in the regulation of cell division and survival, two key processes in cancer. The majority of studies on survivin in colorectal cancer (CRC have focused on protein expression and less is known about the expression of survivin splicing variants or survivin gene polymorphisms in CRC. In the present study, the mRNA levels of the five known isoforms of survivin as well as survivin protein were assessed in matched normal and neoplastic colorectal tissue. Moreover, the 9386C/T and −31G/C polymorphisms were investigated.

  17. ECOGENETICS AND PHARMACOGENETICS: THE IMPORTANCE OF GENETIC POLYMORPHISMS IN THE VARIABILITY OF ORGANISMS RESPONSE TO ENVIRONMENTAL FACTORS

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    Cristian Tudose

    2005-08-01

    protect confidentiality and privacy of individual genetic information may make such research infeasible. In the present paper we expose some general considerations about the importance of the borderline disciplines which are studying the cited aspects (ecogenetics, pharmacogenetics and pharmacogenomics, emphasising the importance of human populations genome polymorphisms affecting drug efficiency and producing adverse reactions; eventually we expose the most recent trends in pharmacogenomics related to the subject

  18. Vascular endothelial growth factor polymorphisms and a synchronized examination of plasma and tissue expression in epithelial ovarian cancers.

    Science.gov (United States)

    Bhaskari, J; Premalata, C S; Shilpa, V; Rahul, B; Pallavi, V R; Ramesh, G; Krishnamoorthy, Lakshmi

    2016-01-01

    In this study, we have analyzed six genetic polymorphisms of the VEGF-A gene and correlated the genetic data with plasma and tissue expression of VEGF-A in epithelial ovarian carcinomas. A total of 130 cases including 95 malignant carcinomas, 17 low malignant potential and 18 benign tumours were studied. rs699947, rs833061, rs1570360, rs2010963, rs1413711 and rs3025039 were studied by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma levels of VEGF-A were estimated by enzyme-linked immunosorbent assay (ELISA) and tissue expression of VEGF-A by immunohistochemistry (IHC). Four polymorphisms of the above excluding rs699947 and rs3025039 showed significant association with malignancy, and we observed the presence of positive correlation between haplotype CCGGCC and increased expression of VEGF-A in both plasma and tissues which also correlated with poor prognosis and recurrence suggesting a probable increase in resistance to treatment in such carriers. Highly upregulated tissue expression of VEGF-A was seen in all epithelial ovarian carcinomas with intensity of expression increasing from benign to malignant cases. ELISA data from our study showed an increase in circulating levels of VEGF-A in malignancies. VEGF-A plasma levels can be employed as a biomarker for high-grade malignancy in epithelial ovarian cancers alongside tissue expression and CA-125 levels. This study is unique due to the fact that a simultaneous analysis of plasma and tissue expression has been demonstrated and is a first such study in epithelial ovarian cancers and representing the Indian population (South-east Asian) synchronized with genetic polymorphism data as well.

  19. Vascular Endothelial Growth Factor Receptor-2 Polymorphisms Have Protective Effect against the Development of Tendinopathy in Volleyball Athletes.

    Science.gov (United States)

    Salles, José Inácio; Duarte, Maria Eugenia Leite; Guimarães, João Matheus; Lopes, Lucas Rafael; Vilarinho Cardoso, Jessica; Aguiar, Diego Pinheiro; Machado Neto, João Olyntho; Machado, Daniel Escorsim; Perini, Jamila Alessandra

    2016-01-01

    The aim of the study was to investigate whether genetic variants in VEGF and KDR genes can be correlated with susceptibility of tendinopathy in volleyball athletes. This study was conducted at the Brazilian Volleyball Federation, and comprised 179 volleyball athletes: 88 had a confirmed diagnosis of tendinopathy (cases), whereas 91 had no evidence of the disease (controls). The VEGF (-2578C>A, -460T>C and +936C>T) and KDR (-604C>T, 1192G>A and 1719T>A) polymorphisms were determined by TaqMan real-time polymerase chain reaction. The odds ratio (OR) with their 95% confidence intervals (CI) were calculated using an unconditional logistic regression model. The evaluation of demographic and clinical characteristics revealed the athlete age (P volleyball (P T, 1192G>A and 1719T>A) haplotypes CGA and CAT were associated with decreased tendinopathy risk (OR: 0.46, 95% CI: 0.21-0.99 and OR: 0.23, 95% CI: 0.07-0.76, respectively). With regards to pain, traumatic lesion and away from training due to injury, VEGF and KDR polymorphisms were not associated with clinical symptoms complaints. The present results provide evidence that the KDR polymorphisms were associated with development of tendinopathy, and can contribute to identify new therapeutic targets or personalized training programs to avoid tendinopathy development in athletes.

  20. Low-loss, robust fusion splicing of silica to chalcogenide fiber for integrated mid-infrared laser technology development.

    Science.gov (United States)

    Thapa, Rajesh; Gattass, Rafael R; Nguyen, Vinh; Chin, Geoff; Gibson, Dan; Kim, Woohong; Shaw, L Brandon; Sanghera, Jasbinder S

    2015-11-01

    We demonstrate a low-loss, repeatable, and robust splice between single-mode silica fiber and single-mode chalcogenide (CHG) fiber. These splices are particularly difficult to create because of the significant difference in the two fibers' glass transition temperatures (∼1000°C) as well as the large difference in the coefficients of thermal expansion between the fibers (∼20×10(-6)/°C). With 90% light coupled through the silica-CHG fiber splice, predominantly in the fundamental circular-symmetric mode, into the core of the CHG fiber and with 0.5 dB of splice loss measured around the wavelength of 2.5 μm, after correcting only for the Fresnel loss, the silica-CHG splice offers excellent beam quality and coupling efficiency. The tensile strength of the splice is greater than 12 kpsi, and the laser damage threshold is greater than 2 W (CW) and was limited by the available laser pump power. We also utilized this splicing technique to demonstrate 2 to 4.5 μm ultrabroadband supercontinuum generation in a monolithic all-fiber system comprising a CHG fiber and a high peak power 2 μm pulsed Raman-shifted thulium fiber laser. This is a major development toward compact form factor commercial applications of soft-glass mid-IR fibers.

  1. Analysis of the intronic single nucleotide polymorphism rs#466452 of the nephrin gene in patients with diabetic nephropathy

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    RODRIGO GONZÁLEZ

    2009-01-01

    Full Text Available We present the analysis of an intronic polymorphism of the nephrin gene and its relationship to the development of diabetic nephropathy in a study of diabetes type 1 and type 2 patients. The frequency of the single nucleotide polymorphism rs#466452 in the nephrin gene was determined in 231 patients and control subjects. The C/T status of the polymorphism was assessed using restriction enzyme digestions and the nephrin transcript from a kidney biopsy was examined. Association between the polymorphism and clinical parameters was evaluated using multivaríate correspondence analysis. A bioinformatics analysis of the single nucleotide polymorphism rs#466452 suggested the appearance of a splicing enhancer sequence in intron 24 of the nephrin gene and a modification of proteins that bind to this sequence. However, no change in the splicing of a nephrin transcript from a renal biopsy was found. No association was found between the polymorphism and diabetes or degree of renal damage in diabetes type 1 or 2 patients. The single nucleotide polymorphism rs#466452 of the nephrin gene seems to be neutral in relation to diabetes and the development of diabetic nephropathy, and does not affect the splicing of a nephrin transcript, in spite of a splicing enhancer site.

  2. CIR, a corepressor of CBF1, binds to PAP-1 and effects alternative splicing

    International Nuclear Information System (INIS)

    Maita, Hiroshi; Kitaura, Hirotake; Ariga, Hiroyoshi; Iguchi-Ariga, Sanae M.M.

    2005-01-01

    We have reported that PAP-1, a product of a causative gene for autosomal retinitis pigmentosa, plays a role in splicing. In this study, CIR, a protein originally identified as a CBF1-interacting protein and reported to act as a transcriptional corepressor, was identified as a PAP-1 binding protein and its function as a splicing factor was investigated. In addition to a basic lysine and acidic serine-rich (BA) domain and a zinc knuckle-like motif, CIR has an arginine/serine dipeptide repeat (RS) domain in its C terminal region. The RS domain has been reported to be present in the superfamily of SR proteins, which are involved in splicing reactions. We generated CIR mutants with deletions of each BA and RS domain and studied their subcellular localizations and interactions with PAP-1 and other SR proteins, including SC35, SF2/ASF, and U2AF 35 . CIR was found to interact with U2AF 35 through the BA domain, with SC35 and SF2/ASF through the RS domain, and with PAP-1 outside the BA domain in vivo and in vitro. CIR was found to be colocalized with SC35 and PAP-1 in nuclear speckles. Then the effect of CIR on splicing was investigated using the E1a minigene as a reporter in HeLa cells. Ectopic expression of CIR with the E1a minigene changed the ratio of spliced isoforms of E1a that were produced by alternative selection of 5'-splice sites. These results indicate that CIR is a member of the family of SR-related proteins and that CIR plays a role in splicing regulation

  3. Spliced XBP1 promotes macrophage survival and autophagy by interacting with Beclin-1

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    Tian, Ping-Ge [Southern Medical University, Guangzhou, Guangdong 510515 (China); Jiang, Zhi-Xin [Centre Laboratory, The 305th Hospital of the People' s Liberation Army, Beijing 100017 (China); Li, Jian-Hua [Department of Geriatric Cardiology, Chinese PLA General Hosptial, Beijing 100853 (China); Zhou, Zhe, E-mail: zhouzhe76@126.com [Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Zhang, Qing-Hua, E-mail: 1056055170@qq.com [Department of Cardiology, The 305th Hospital of the People' s Liberation Army, Beijing 100017 (China)

    2015-08-07

    Macrophage autophagy plays an important role in the development of atherosclerosis, but the precise mechanism mediating this process is unclear. The potential role of the X-box binding protein 1 (XBP1), a crucial transduction factor that is involved in endoplasmic reticulum stress and the unfolded protein response, in bone marrow-derived macrophage autophagy is unknown. This study mainly explores the roles of XBP1 mRNA splicing in bone marrow-derived macrophage autophagy. The present study shows that the transient overexpression of spliced XBP1 via adenovirus-mediated gene transfer induces autophagy and promotes proliferation in bone marrow-derived macrophages via the down-regulation of Beclin-1, but that the sustained overexpression of spliced XBP1 leads to apoptosis. When XBP1 is down-regulated in bone marrow-derived macrophages using siRNA, rapamycin-induced autophagosome formation is ablated. Furthermore, we have detected the overexpression of XBP1 in areas of atherosclerotic plaques in the arteries of ApoE−/− mice. These results demonstrate that XBP1 mRNA splicing plays an important role in maintaining the function of bone marrow-derived macrophages and provide new insight into the study and treatment of atherosclerosis. - Highlights: • XBP1 was up-regulated in atherosclerotic plaques of ApoE−/− mice. • Transient spliced XBP1 overexpression induced macrophages autophagy via Beclin-1. • Sustained spliced XBP1 overexpression triggered macrophages apoptosis. • Spliced XBP1 plays a key role in maintaining the macrophages survival.

  4. Carriage of a Tumor Necrosis Factor Polymorphism Amplifies the Cytotoxic T-Lymphocyte Antigen 4 Attributed Risk of Primary Biliary Cirrhosis: Evidence for a Gene–Gene Interaction

    Science.gov (United States)

    Juran, Brian D.; Atkinson, Elizabeth J.; Larson, Joseph J.; Schlicht, Erik M.; Liu, Xiangdong; Heathcote, E. Jenny; Hirschfield, Gideon M.; Siminovitch, Katherine A.; Lazaridis, Konstantinos N.

    2010-01-01

    Common genetic variants significantly influence complex diseases such as primary biliary cirrhosis (PBC). We recently reported an association between PBC and a single nucleotide polymorphism (rs231725) of the immunoreceptor gene cytotoxic T-lymphocyte antigen 4 (CTLA4). We hypothesized that PBC risk attributed to this polymorphism might be increased by propensity to an overly robust inflammatory response. Thus, we examined its potential interaction with the commonly studied −308AG promoter polymorphism (rs1800629) of the tumor necrosis factor (TNF) gene for which the variant TNF2A allele causes increased TNF production. The polymorphisms were genotyped in 866 PBC patients and 761 controls from independent US and Canadian registries; the effects of individual single nucleotide polymorphisms (SNPs) and their interaction on PBC risk was assessed by logistic regression. The reported association of PBC with the CTLA4 “A/A” genotype was replicated in the Canadian cohort and significant for PBC risk in the combined data (odds ratio [OR], 1.68; P = 0.0005). TNF2A allele frequency was elevated in PBC patients, but only reached borderline significance using the combined data (OR, 1.21; P = 0.042). Analysis showed that TNF2A carriage was significantly increased in CTLA4 “A/A” PBC patients compared with CTLA4 “A/A” controls (39.7% versus 16.5%, P = 0.0004); no apparent increase of TNF2A carriage was noted in CTLA4 “A/G” or “G/G” individuals. Finally, interaction under a logistic model was highly significant, as TNF2A carriage in combination with the CTLA4 “A/A” genotype was present in 6.5% of PBC patients, compared with 1.7% of controls (OR, 3.98; P < 0.0001). Conclusion TNF2A amplifies the CTLA4 rs231725 “A/A” genotype risk for PBC. Although the mechanisms remain unclear, the premise that deficiency in T-cell regulation resulting in an increased risk of PBC is amplified by overexpression of an important proinflammatory cytokine provides a basis

  5. The 20S proteasome splicing activity discovered by SpliceMet.

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    Juliane Liepe

    2010-06-01

    Full Text Available The identification of proteasome-generated spliced peptides (PSP revealed a new unpredicted activity of the major cellular protease. However, so far characterization of PSP was entirely dependent on the availability of patient-derived cytotoxic CD8+ T lymphocytes (CTL thus preventing a systematic investigation of proteasome-catalyzed peptide splicing (PCPS. For an unrestricted PSP identification we here developed SpliceMet, combining the computer-based algorithm ProteaJ with in vitro proteasomal degradation assays and mass spectrometry. By applying SpliceMet for the analysis of proteasomal processing products of four different substrate polypeptides, derived from human tumor as well as viral antigens, we identified fifteen new spliced peptides generated by PCPS either by cis or from two separate substrate molecules, i.e., by trans splicing. Our data suggest that 20S proteasomes represent a molecular machine that, due to its catalytic and structural properties, facilitates the generation of spliced peptides, thereby providing a pool of qualitatively new peptides from which functionally relevant products may be selected.

  6. Landscape of the spliced leader trans-splicing mechanism in Schistosoma mansoni.

    Science.gov (United States)

    Boroni, Mariana; Sammeth, Michael; Gava, Sandra Grossi; Jorge, Natasha Andressa Nogueira; Macedo, Andréa Mara; Machado, Carlos Renato; Mourão, Marina Moraes; Franco, Glória Regina

    2018-03-01

    Spliced leader dependent trans-splicing (SLTS) has been described as an important RNA regulatory process that occurs in different organisms, including the trematode Schistosoma mansoni. We identified more than seven thousand putative SLTS sites in the parasite, comprising genes with a wide spectrum of functional classes, which underlines the SLTS as a ubiquitous mechanism in the parasite. Also, SLTS gene expression levels span several orders of magnitude, showing that SLTS frequency is not determined by the expression level of the target gene, but by the presence of particular gene features facilitating or hindering the trans-splicing mechanism. Our in-depth investigation of SLTS events demonstrates widespread alternative trans-splicing (ATS) acceptor sites occurring in different regions along the entire gene body, highlighting another important role of SLTS generating alternative RNA isoforms in the parasite, besides the polycistron resolution. Particularly for introns where SLTS directly competes for the same acceptor substrate with cis-splicing, we identified for the first time additional and important features that might determine the type of splicing. Our study substantially extends the current knowledge of RNA processing by SLTS in S. mansoni, and provide basis for future studies on the trans-splicing mechanism in other eukaryotes.

  7. Functional and evolutionary analysis of alternatively spliced genes is consistent with an early eukaryotic origin of alternative splicing

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    Penny David

    2007-10-01

    Full Text Available Abstract Background Alternative splicing has been reported in various eukaryotic groups including plants, apicomplexans, diatoms, amoebae, animals and fungi. However, whether widespread alternative splicing has evolved independently in the different eukaryotic groups or was inherited from their last common ancestor, and may therefore predate multicellularity, is still unknown. To better understand the origin and evolution of alternative splicing and its usage in diverse organisms, we studied alternative splicing in 12 eukaryotic species, comparing rates of alternative splicing across genes of different functional classes, cellular locations, intron/exon structures and evolutionary origins. Results For each species, we find that genes from most functional categories are alternatively spliced. Ancient genes (shared between animals, fungi and plants show high levels of alternative splicing. Genes with products expressed in the nucleus or plasma membrane are generally more alternatively spliced while those expressed in extracellular location show less alternative splicing. We find a clear correspondence between incidence of alternative splicing and intron number per gene both within and between genomes. In general, we find several similarities in patterns of alternative splicing across these diverse eukaryotes. Conclusion Along with previous studies indicating intron-rich genes with weak intron boundary consensus and complex spliceosomes in ancestral organisms, our results suggest that at least a simple form of alternative splicing may already have been present in the unicellular ancestor of plants, fungi and animals. A role for alternative splicing in the evolution of multicellularity then would largely have arisen by co-opting the preexisting process.

  8. The allelic distribution of -308 Tumor Necrosis Factor-alpha gene polymorphism in South African women with cervical cancer and control women

    International Nuclear Information System (INIS)

    Govan, Vandana A; Constant, Debbie; Hoffman, Margaret; Williamson, Anna-Lise

    2006-01-01

    Cervical cancer is due to infection with specific high-risk types of human papillomavirus (HPV). Although the incidence of genital HPV infection in various population groups is high, most of these regress without intervention. Investigating genetic host factors and cellular immune responses, particularly cytokines, could help to understand the association between genital HPV infection and carcinogenesis. The tumor necrosis factor alpha (TNF-α) cytokine plays an important role in all stages of cervical cancer and has the ability to induce the regression of human tumors. Therefore the aim of the study was to investigate the allelic distribution of -308 TNF-α gene polymorphism in South African women with cervical cancer compared to control women. Included in our study were women with histologically proven cancer of the cervix (n = 244) and hospital-based controls (n = 228). All patients and controls were from mixed race and black population groups in South Africa. The detection of a bi-allelic -308 (A/G) polymorphism in the promoter region of TNF-α was investigated using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups. In this study we observed no association between the distribution of -308 TNF-α polymorphism and the risk of developing cervical cancer even after combining the data from the two ethnic populations (X 2 = 2.26). In addition, using the chi-squared test we found no significant association between the known risk factors for cervical cancer and the allele distribution of -308 TNF-α. However, the frequency of the rare high-producing allele -308A of TNF-α was significantly lower in the South African population when compared to Caucasians and Chinese population groups. We demonstrated no association between -308 TNF-α polymorphism and the risk of cervical cancer among two

  9. Identification of haplotype tag single nucleotide polymorphisms within the nuclear factor-κB family genes and their clinical relevance in patients with major trauma.

    Science.gov (United States)

    Pan, Wei; Zhang, An Qiang; Gu, Wei; Gao, Jun Wei; Du, Ding Yuan; Zhang, Lian Yang; Zeng, Ling; Du, Juan; Wang, Hai Yan; Jiang, Jian Xin

    2015-03-20

    Nuclear factor-κB (NF-κB) family plays an important role in the development of sepsis in critically ill patients. Although several single nucleotide polymorphisms (SNPs) have been identified in the NF-κB family genes, only a few SNPs have been studied. A total of 753 patients with major blunt trauma were included in this study. Tag SNPs (tSNPs) were selected from the NF-κB family genes (NFKB1, NFKB2, RELA, RELB and REL) through construction of haplotype blocks. The SNPs selected from genes within the canonical NF-κB pathway (including NFKB1, RELA and REL), which played a critical role in innate immune responses were genotyped using pyrosequencing method and analyzed in relation to the risk of development of sepsis and multiple organ dysfunction (MOD) syndrome. Moreover, the rs842647 polymorphism was analyzed in relation to tumor necrosis factor α (TNF-α) production by peripheral blood leukocytes in response to bacterial lipoprotein stimulation. Eight SNPs (rs28362491, rs3774932, rs4648068, rs7119750, rs4803789, rs12609547, rs1560725 and rs842647) were selected from the NF-κB family genes. All of them were shown to be high-frequency SNPs in this study cohort. Four SNPs (rs28362491, rs4648068, rs7119750 and rs842647) within the canonical NF-κB pathway were genotyped, and rs842647 was associated with sepsis morbidity rate and MOD scores. An association was also observed between the rs842647 A allele and lower TNF-α production. rs842647 polymorphism might be used as relevant risk estimate for the development of sepsis and MOD syndrome in patients with major trauma.

  10. SPA: a probabilistic algorithm for spliced alignment.

    Directory of Open Access Journals (Sweden)

    2006-04-01

    Full Text Available Recent large-scale cDNA sequencing efforts show that elaborate patterns of splice variation are responsible for much of the proteome diversity in higher eukaryotes. To obtain an accurate account of the repertoire of splice variants, and to gain insight into the mechanisms of alternative splicing, it is essential that cDNAs are very accurately mapped to their respective genomes. Currently available algorithms for cDNA-to-genome alignment do not reach the necessary level of accuracy because they use ad hoc scoring models that cannot correctly trade off the likelihoods of various sequencing errors against the probabilities of different gene structures. Here we develop a Bayesian probabilistic approach to cDNA-to-genome alignment. Gene structures are assigned prior probabilities based on the lengths of their introns and exons, and based on the sequences at their splice boundaries. A likelihood model for sequencing errors takes into account the rates at which misincorporation, as well as insertions and deletions of different lengths, occurs during sequencing. The parameters of both the prior and likelihood model can be automatically estimated from a set of cDNAs, thus enabling our method to adapt itself to different organisms and experimental procedures. We implemented our method in a fast cDNA-to-genome alignment program, SPA, and applied it to the FANTOM3 dataset of over 100,000 full-length mouse cDNAs and a dataset of over 20,000 full-length human cDNAs. Comparison with the results of four other mapping programs shows that SPA produces alignments of significantly higher quality. In particular, the quality of the SPA alignments near splice boundaries and SPA's mapping of the 5' and 3' ends of the cDNAs are highly improved, allowing for more accurate identification of transcript starts and ends, and accurate identification of subtle splice variations. Finally, our splice boundary analysis on the human dataset suggests the existence of a novel non

  11. Hereditary cancer genes are highly susceptible to splicing mutations

    Science.gov (United States)

    Soemedi, Rachel; Maguire, Samantha; Murray, Michael F.; Monaghan, Sean F.

    2018-01-01

    Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5′ and 3′ splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing. PMID:29505604

  12. Hereditary cancer genes are highly susceptible to splicing mutations.

    Directory of Open Access Journals (Sweden)

    Christy L Rhine

    2018-03-01

    Full Text Available Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77% of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36% of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing.

  13. Effects of airborne particulate matter on alternative pre-mRNA splicing in colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Buggiano, Valeria; Petrillo, Ezequiel; Alló, Mariano; Lafaille, Celina [Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EHA Buenos Aires (Argentina); Redal, María Ana [Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires (Argentina); Alghamdi, Mansour A. [Department of Environmental Sciences, Faculty of Meteorology, Environment and Arid Land Agriculture, King Abdulaziz University, Jeddah (Saudi Arabia); Khoder, Mamdouh I. [Department of Environmental Sciences, Faculty of Meteorology, Environment and Arid Land Agriculture, King Abdulaziz University, Jeddah (Saudi Arabia); Center of Excellence in Environmental Studies, King Abdulaziz University, Jeddah (Saudi Arabia); Shamy, Magdy [Department of Environmental Sciences, Faculty of Meteorology, Environment and Arid Land Agriculture, King Abdulaziz University, Jeddah (Saudi Arabia); Muñoz, Manuel J., E-mail: mmunoz@fbmc.fcen.uba.ar [Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EHA Buenos Aires (Argentina); and others

    2015-07-15

    Alternative pre-mRNA splicing plays key roles in determining tissue- and species-specific cell differentiation as well as in the onset of hereditary disease and cancer, being controlled by multiple post- and co-transcriptional regulatory mechanisms. We report here that airborne particulate matter, resulting from industrial pollution, inhibits expression and specifically affects alternative splicing at the 5′ untranslated region of the mRNA encoding the bone morphogenetic protein BMP4 in human colon cells in culture. These effects are consistent with a previously reported role for BMP4 in preventing colon cancer development, suggesting that ingestion of particulate matter could contribute to the onset of colon cell proliferation. We also show that the underlying mechanism might involve changes in transcriptional elongation. This is the first study to demonstrate that particulate matter causes non-pleiotropic changes in alternative splicing. - Highlights: • Airborne particulate matter (PM10) affects alternative splicing in colon cells. • PM10 upregulates one of the two mRNA variants of the growth factor BMP-4. • This variant has a longer 5′ unstranslated region and introduces an upstream AUG. • By regulating BMP-4 mRNA splicing PM10 inhibits total expression of BMP-4 protein. • BMP-4 downregulation was previously reported to be associated to colon cancer.

  14. CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery.

    Science.gov (United States)

    Ricciardi, Sara; Kilstrup-Nielsen, Charlotte; Bienvenu, Thierry; Jacquette, Aurélia; Landsberger, Nicoletta; Broccoli, Vania

    2009-12-01

    Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause severe neurodevelopmental disorders including infantile spasms, encephalopathy, West-syndrome and an early-onset variant of Rett syndrome. CDKL5 is a serine/threonine kinase whose involvement in Rett syndrome can be inferred by its ability to directly bind and mediate phosphorylation of MeCP2. However, it remains to be elucidated how CDKL5 exerts its function. Here, we report that CDKL5 localizes to specific nuclear foci referred to as nuclear speckles in both cell lines and tissues. These sub-nuclear structures are traditionally considered as storage/modification sites of pre-mRNA splicing factors. Interestingly, we provide evidence that CDKL5 regulates the dynamic behaviour of nuclear speckles. Indeed, CDKL5 overexpression leads to nuclear speckle disassembly, and this event is strictly dependent on its kinase activity. Conversely, its down-regulation affects nuclear speckle morphology leading to abnormally large and uneven speckles. Similar results were obtained for primary adult fibroblasts isolated from CDKL5-mutated patients. Altogether, these findings indicate that CDKL5 controls nuclear speckle morphology probably by regulating the phosphorylation state of splicing regulatory proteins. Nuclear speckles are dynamic sites that can continuously supply splicing factors to active transcription sites, where splicing occurs. Notably, we proved that CDKL5 influences alternative splicing, at least as proved in heterologous minigene assays. In conclusion, we provide evidence that CDKL5 is involved indirectly in pre-mRNA processing, by controlling splicing factor dynamics. These findings identify a biological process whose disregulation might affect neuronal maturation and activity in CDKL5-related disorders.

  15. Interactions between the vascular endothelial growth factor gene polymorphism and life events in susceptibility to major depressive disorder in a Chinese population.

    Science.gov (United States)

    Han, Dong; Qiao, Zhengxue; Chen, Lu; Qiu, Xiaohui; Fang, Deyu; Yang, Xiuxian; Ma, Jingsong; Chen, Mingqi; Yang, Jiarun; Wang, Lin; Zhu, Xiongzhao; Zhang, Congpei; Yang, Yanjie; Pan, Hui

    2017-08-01

    Recent studies suggest that vascular endothelial growth factor (VEGF) is involved in the development of major depressive disorder. The aim of this study is to investigate the interaction between vascular endothelial growth factor (VEGF) polymorphism (+405G/C, rs2010963) and negative life events in the pathogenesis of major depressive disorder (MDD). DNA genotyping was performed on peripheral blood leukocytes in 274 patients with MDD and 273 age-and sex-matched controls. The frequency and severity of negative life events were assessed by the Life Events Scale (LES). A logistics method was employed to assess the gene-environment interaction (G×E). Differences in rs2010963 genotype distributions were observed between MDD patients and controls. Significant G×E interactions between allelic variation of rs2010963 and negative life events were observed. Individuals carrying the C alleles were susceptible to MDD only when exposed to high-negative life events. These results indicate that interactions between the VEGF rs2010963 polymorphism and environment increases the risk of developing MDD. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. The transcription factor 7-like 2 (TCF7L2 polymorphism may be associated with focal arteriolar narrowing in Caucasians with hypertension or without diabetes: the ARIC Study

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    Boerwinkle Eric

    2010-05-01

    Full Text Available Abstract Background Transcription factor 7-like 2 (TCF7L2 has emerged as a consistently replicated susceptibility gene for type 2 diabetes, however, whether the TCF7L2 gene also has similar effects on the retinal microvasculature is less clear. We therefore aimed to investigate the association between the transcription factor 7-like 2 (TCF7L2 rs7903146 polymorphism and retinal microvascular phenotypes in the Atherosclerosis Risk in Communities (ARIC Study (1993-1995. Methods This was a population-based, cross-sectional study of 10,320 middle-aged African American (n = 2,199 and Caucasian (n = 8,121 men and women selected from four United States communities to examine the association between TCF7L2 rs7903146 polymorphism and retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking, arteriolar and venular calibers. Photographs on one randomly selected eye were graded for presence of retinal microvascular signs and used to measure retinal vessel calibres. Results After adjusting for age, sex, study center, mean arterial blood pressure, total serum cholesterol, triglycerides, and other covariates, few associations of TCF7L2 rs7903146 and retinal microvascular signs were noted. TCF7L2 rs7903146 T risk allele was significantly associated with focal arteriolar narrowing in Caucasians with hypertension [odds ratio (ORCT vs. CC (95% CI = 1.25 (1.09-1.44; ORTT vs. CC = 1.56 (1.18-2.06; P = 0.002] and in Caucasians without diabetes [OR CT vs. CC = 1.18 (1.06-1.32; OR TT vs. CC = 1.40 (1.12, 1.75; P = 0.003]. No significant association of the TCF7L2 rs7903146 polymorphism and retinal vascular signs was noted among African American individuals. Conclusions TCF7L2 rs7903146 is not consistently associated with retinal microvascular signs. However, we report an association between the TCF7L2 rs7903146 polymorphism and focal arteriolar narrowing in Caucasians with hypertension or without diabetes. Further research in other

  17. Catechol-O-Methyltransferase (COMT) Gene (Val158Met) and Brain-Derived Neurotropic Factor (BDNF) (Val66Met) Genes Polymorphism in Schizophrenia: A Case-Control Study.

    Science.gov (United States)

    Saravani, Ramin; Galavi, Hamid Reza; Lotfian Sargazi, Marzieh

    2017-10-01

    Objective: Several studies have shown that some polymorphisms of genes encoding catechol-O-methyltransferase (COMT), the key enzyme in degrading dopamine, and norepinephrine and the human brain-derived neurotropic factor (BDNF), a nerve growth factor, are strong candidates for risk of schizophrenia (SCZ). In the present study, we aimed at examining the effects of COMT Val158Met (G>A) and BDNF Val66Met (G>A) polymorphisms on SCZ risk in a sample of Iranian population. Method: This case- control study included 92 SCZ patients and 92 healthy controls (HCs). Genotyping of both variants (COMT Val158Met (G>A) and BDNF Val66Met (G>A)) were conducted using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Results: The findings revealed that the COMT Val158Met (G>A) polymorphism was not associated with the risk/protective of SCZ in all models (OR=0.630, 95%CI=0.299-1.326, P=0.224, GA vs. GG, OR=1.416, 95%CI=0.719-2.793, P=0.314, AA vs. GG, OR=1.00, 95%CI=0.56-1.79, P=1.00 GA+AA vs. GG, OR=1.667, 95%CI=0.885-3.125, P=0.11, AA vs. GG+GA, OR=1.247, 95%CI=0.825-1.885, P=0.343, A vs. G,). However, BDNF Val66Met (G>A) variant increased the risk of SCZ (OR = 2.008 95%CI = 1.008-4.00, P = 0.047, GA vs. GG, OR = 3.876 95%CI = 1.001-14.925, P = 0.049. AA vs. GG, OR = 2.272. 95%CI = 1.204-4.347, P = 0.011, GA+AA vs. GG, OR = 2.22 95%CI = 1.29-3.82. P = 0.005, A vs. G). Conclusion: The results did not support an association between COMT Val158Met (G>A) variant and risk/protective of SCZ. Moreover, it was found that BDNF Val66Met (G>A) polymorphism may increase the risk of SCZ development. Further studies and different ethnicities are recommended to confirm the findings.

  18. Pharmacogenetic Study in Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy: Polymorphisms in Thymidylate Synthase, Epidermal Growth Factor Receptor, GSTP1, and DNA Repair Genes

    International Nuclear Information System (INIS)

    Páez, David; Salazar, Juliana; Paré, Laia; Pertriz, Lourdes; Targarona, Eduardo; Rio, Elisabeth del; Barnadas, Agusti; Marcuello, Eugenio; Baiget, Montserrat

    2011-01-01

    Purpose: Several studies have been performed to evaluate the usefulness of neoadjuvant treatment using oxaliplatin and fluoropyrimidines for locally advanced rectal cancer. However, preoperative biomarkers of outcome are lacking. We studied the polymorphisms in thymidylate synthase, epidermal growth factor receptor, glutathione S-transferase pi 1 (GSTP1), and several DNA repair genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 128 rectal cancer patients treated with preoperative chemoradiotherapy. Methods and Materials: Blood samples were obtained from 128 patients with Stage II-III rectal cancer. DNA was extracted from the peripheral blood nucleated cells, and the genotypes were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were thymidylate synthase, (VNTR/5′UTR, 2R G>C single nucleotide polymorphism [SNP], 3R G>C SNP), epidermal growth factor receptor (Arg497Lys), GSTP1 (Ile105val), excision repair cross-complementing 1 (Asn118Asn, 8092C>A, 19716G>C), X-ray repair cross-complementing group 1 (XRCC1) (Arg194Trp, Arg280His, Arg399Gln), and xeroderma pigmentosum group D (Lys751Gln). The pathologic response, pathologic regression, progression-free survival, and overall survival were evaluated according to each genotype. Results: The ∗3/∗3 thymidylate synthase genotype was associated with a greater response rate (pathologic complete remission and microfoci residual tumor, 59% in ∗3/∗3 vs. 35% in ∗2/∗2 and ∗2/∗3; p = .013). For the thymidylate synthase genotype, the median progression-free survival was 103 months for the ∗3/∗3 patients and 84 months for the ∗2/∗2 and ∗2/∗3 patients (p = .039). For XRCC1 Arg399Gln SNP, the median progression-free survival was 101 months for the G/G, 78 months for the G/A, and 31 months for the A/A patients (p = .048). Conclusions: The thymidylate

  19. Tumor necrosis factor-alpha G-238A polymorphism and coronary artery disease risk: a meta-analysis of 4,222 patients and 4,832 controls

    Directory of Open Access Journals (Sweden)

    Hua XP

    2015-09-01

    Full Text Available Xian-Ping Hua,1,* Xiao-Dong Zhang,2,* Joey SW Kwong,3,* Xian-Tao Zeng,4 Zhen-Jian Zhang,1 Wan-Lin Wei21Department of Cardiology, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei Province, 2Department of Cardiology and 4th Cadres Ward, General Hospital of Beijing Military Command, Beijing, 3Chinese Evidence-Based Medicine Center and Chinese Cochrane Center, West China Hospital, Sichuan University, Chengdu, 4Center for Evidence-Based and Translational Medicine, Zhongnan Hospital, Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workBackground: The aim of the present study was to investigate the association between tumor necrosis factor-alpha (TNF-α gene G-238A polymorphism and risk of coronary artery disease (CAD using a meta-analytical approach.Methods: The PubMed and Embase databases were searched for relevant publications up to January 13, 2015. Four authors (XPH, XDZ, XTZ, and ZJZ independently selected the studies, extracted, and analyzed the data using the Comprehensive Meta-Analysis software. The sensitivity and subgroups analyses were also performed. Either a fixed effects or a random effects model was used to estimate pooled odds ratios (ORs and their 95% confidence intervals (CIs.Results: Finally, ten articles including eleven case-control studies involving 4,222 patients and 4,832 controls were yielded. The results indicated no significant association between G-238A polymorphism and CAD risk (A vs G: OR =1.08, 95% CI =0.89–1.30; AA vs GG: OR =1.15, 95% CI =0.59–2.25; GA vs GG: OR =1.14, 95% CI =0.88–1.48; AA vs [GG + GA]: OR =1.09, 95% CI =0.56–2.14; (GA + AA vs GG: OR =1.11, 95% CI =0.90–1.38. In the subgroup analyses, similar results were obtained with overall populations. The sensitivity analyses showed that the overall results were robust. No publication bias was detected.Conclusion: Based on current evidence, we can conclude that TNF-α G-238A polymorphism

  20. Pharmacogenetic Study in Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy: Polymorphisms in Thymidylate Synthase, Epidermal Growth Factor Receptor, GSTP1, and DNA Repair Genes

    Energy Technology Data Exchange (ETDEWEB)

    Paez, David, E-mail: dpaez@santpau.cat [Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Salazar, Juliana; Pare, Laia [Centre for Biomedical Network Research on Rare Diseases, Barcelona (Spain); Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Pertriz, Lourdes [Department of Radiotherapy, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Targarona, Eduardo [Department of Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Rio, Elisabeth del [Centre for Biomedical Network Research on Rare Diseases, Barcelona (Spain); Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Barnadas, Agusti; Marcuello, Eugenio [Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain); Baiget, Montserrat [Centre for Biomedical Network Research on Rare Diseases, Barcelona (Spain); Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona (Spain)

    2011-12-01

    Purpose: Several studies have been performed to evaluate the usefulness of neoadjuvant treatment using oxaliplatin and fluoropyrimidines for locally advanced rectal cancer. However, preoperative biomarkers of outcome are lacking. We studied the polymorphisms in thymidylate synthase, epidermal growth factor receptor, glutathione S-transferase pi 1 (GSTP1), and several DNA repair genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 128 rectal cancer patients treated with preoperative chemoradiotherapy. Methods and Materials: Blood samples were obtained from 128 patients with Stage II-III rectal cancer. DNA was extracted from the peripheral blood nucleated cells, and the genotypes were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were thymidylate synthase, (VNTR/5 Prime UTR, 2R G>C single nucleotide polymorphism [SNP], 3R G>C SNP), epidermal growth factor receptor (Arg497Lys), GSTP1 (Ile105val), excision repair cross-complementing 1 (Asn118Asn, 8092C>A, 19716G>C), X-ray repair cross-complementing group 1 (XRCC1) (Arg194Trp, Arg280His, Arg399Gln), and xeroderma pigmentosum group D (Lys751Gln). The pathologic response, pathologic regression, progression-free survival, and overall survival were evaluated according to each genotype. Results: The Asterisk-Operator 3/ Asterisk-Operator 3 thymidylate synthase genotype was associated with a greater response rate (pathologic complete remission and microfoci residual tumor, 59% in Asterisk-Operator 3/ Asterisk-Operator 3 vs. 35% in Asterisk-Operator 2/ Asterisk-Operator 2 and Asterisk-Operator 2/ Asterisk-Operator 3; p = .013). For the thymidylate synthase genotype, the median progression-free survival was 103 months for the Asterisk-Operator 3/ Asterisk-Operator 3 patients and 84 months for the Asterisk-Operator 2/ Asterisk-Operator 2 and Asterisk-Operator 2/ Asterisk

  1. Sexy splicing: regulatory interplays governing sex determination from Drosophila to mammals.

    Science.gov (United States)

    Lalli, Enzo; Ohe, Kenji; Latorre, Elisa; Bianchi, Marco E; Sassone-Corsi, Paolo

    2003-02-01

    A remarkable array of strategies is used to produce sexual differentiation in different species. Complex gene hierarchies govern sex determination pathways, as exemplified by the classic D. melanogaster paradigm, where an interplay of transcriptional, splicing and translational mechanisms operate. Molecular studies support the hypothesis that genetic sex determination pathways evolved in reverse order, from downstream to upstream genes, in the cascade. The recent identification of a role for the key regulatory factors SRY and WT1(+KTS) in pre-mRNA splicing indicates that important steps in the mammalian sex determination process are likely to operate at the post-transcriptional level.

  2. Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

    DEFF Research Database (Denmark)

    Krejsgaard, T; Gjerdrum, L M; Ralfkiaer, E

    2008-01-01

    Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3...... in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress...... the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF...

  3. Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing

    DEFF Research Database (Denmark)

    Fedorov, Oleg; Huber, Kilian; Eisenreich, Andreas

    2011-01-01

    There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19......, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix aC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19...... effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue...

  4. High qualitative and quantitative conservation of alternative splicing in Caenorhabditis elegans and Caenorhabditis briggsae

    DEFF Research Database (Denmark)

    Rukov, Jakob Lewin; Irimia, Manuel; Mørk, Søren

    2007-01-01

    Alternative splicing (AS) is an important contributor to proteome diversity and is regarded as an explanatory factor for the relatively low number of human genes compared with less complex animals. To assess the evolutionary conservation of AS and its developmental regulation, we have investigated...... the qualitative and quantitative expression of 21 orthologous alternative splice events through the development of 2 nematode species separated by 85-110 Myr of evolutionary time. We demonstrate that most of these alternative splice events present in Caenorhabditis elegans are conserved in Caenorhabditis briggsae....... Moreover, we find that relative isoform expression levels vary significantly during development for 78% of the AS events and that this quantitative variation is highly conserved between the 2 species. Our results suggest that AS is generally tightly regulated through development and that the regulatory...

  5. Antithetical effect of tumor necrosis factor-alpha gene polymorphism on coal workers' pneumoconiosis (CWP)

    Energy Technology Data Exchange (ETDEWEB)

    Wang, X.T.; Ohtsuka, Y.; Kimura, K.; Muroi, M.; Ishida, T.; Saito, J.; Munakata, M. [Fukushima Medical University, Fukushima (Japan). School of Medicine

    2005-07-01

    Inter-individual variation in the severity of pneumoconiosis has been described, even with the same environmental exposure. We hypothesized that TNF-alpha promoter polymorphisms associate with lung responses to environmental exposure in coal worker's pneumoconiosis (CWP) patients. We examined polymorphisms at -238, -308, and -376 in 124 patients with CWP who had similar dust exposure history and in 122 non-exposed controls. CWP patients were divided into two groups: (1) nodular CWP (n = 84): (2) progressive massive fibrosis (PMF) (n = 44). The -308 A allele frequency was higher in patients with CWP compared to controls (6.35% and 2.05%, P {lt} 0.01). It was also higher in patients with nodular CWP compared to PMF (P {lt} 0.05). Logistic regression analysis revealed that patients with the -308 A allele were 3.8 times (P = 0.036) and those with smoking habit were 2.3 times (P {lt} 0.002) more likely to have nodular CWP than PMF. Thus TNF-alpha-308 A allele might interact with smoking to enhance susceptibility to nodular CWP.

  6. The hnRNP 2H9 gene, which is involved in the splicing reaction, is a multiply spliced gene

    DEFF Research Database (Denmark)

    Honoré, B

    2000-01-01

    The hnRNP 2H9 gene products are involved in the splicing process and participate in early heat shock-induced splicing arrest. By combining low/high stringency hybridisation, database search, Northern and Western blotting it is shown that the gene is alternatively spliced into at least six...

  7. No Effect of the Transforming Growth Factor {beta}1 Promoter Polymorphism C-509T on TGFB1 Gene Expression, Protein Secretion, or Cellular Radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Reuther, Sebastian; Metzke, Elisabeth [Laboratory of Radiobiology and Experimental Radiooncology, University Hospital Hamburg-Eppendorf, Hamburg (Germany); Bonin, Michael [Department of Medical Genetics, University of Tuebingen (Germany); Petersen, Cordula [Clinic of Radiotherapy and Radiooncology, University Hospital Hamburg-Eppendorf, Hamburg (Germany); Dikomey, Ekkehard, E-mail: dikomey@uke.de [Laboratory of Radiobiology and Experimental Radiooncology, University Hospital Hamburg-Eppendorf, Hamburg (Germany); Raabe, Annette [Laboratory of Radiobiology and Experimental Radiooncology, University Hospital Hamburg-Eppendorf, Hamburg (Germany)

    2013-02-01

    Purpose: To study whether the promoter polymorphism (C-509T) affects transforming growth factor {beta}1 gene (TGFB1) expression, protein secretion, and/or cellular radiosensitivity for both human lymphocytes and fibroblasts. Methods and Materials: Experiments were performed with lymphocytes taken either from 124 breast cancer patients or 59 pairs of normal monozygotic twins. We used 15 normal human primary fibroblast strains as controls. The C-509T genotype was determined by polymerase chain reaction-restriction fragment length polymorphism or TaqMan single nucleotide polymorphism (SNP) genotyping assay. The cellular radiosensitivity of lymphocytes was measured by G0/1 assay and that of fibroblasts by colony assay. The amount of extracellular TGFB1 protein was determined by enzyme-linked immunosorbent assay, and TGFB1 expression was assessed via microarray analysis or reverse transcription-polymerase chain reaction. Results: The C-509T genotype was found not to be associated with cellular radiosensitivity, neither for lymphocytes (breast cancer patients, P=.811; healthy donors, P=.181) nor for fibroblasts (P=.589). Both TGFB1 expression and TGFB1 protein secretion showed considerable variation, which, however, did not depend on the C-509T genotype (protein secretion: P=.879; gene expression: lymphocytes, P=.134, fibroblasts, P=.605). There was also no general correlation between TGFB1 expression and cellular radiosensitivity (lymphocytes, P=.632; fibroblasts, P=.573). Conclusion: Our data indicate that any association between the SNP C-509T of TGFB1 and risk of normal tissue toxicity cannot be ascribed to a functional consequence of this SNP, either on the level of gene expression, protein secretion, or cellular radiosensitivity.

  8. Elevated Serum Brain-Derived Neurotrophic Factor (BDNF) but not BDNF Gene Val66Met Polymorphism Is Associated with Autism Spectrum Disorders.

    Science.gov (United States)

    Meng, Wei-Dong; Sun, Shao-Jun; Yang, Jie; Chu, Rui-Xue; Tu, Wenjun; Liu, Qiang

    2017-03-01

    The aim of our study was to illuminate the potential role of brain-derived neurotrophic factor (BDNF) in autism spectrum disorder (ASD). We measured the circulating levels of BDNF in serum and BDNF gene (Val66Met) polymorphisms, in which two indicators were then compared between ASD and normal controls. A total of 82 drug-naïve ASD children and 82 age- and gender-matched normal controls were enrolled in the study. Their serum BDNF levels were detected by the ELISA. BDNF Val66Met polymorphism genotyping was conducted as according to the laboratory's standard protocol in laboratory. The ASD severity assessment was mainly determined by the score of the Childhood Autism Rating Scale (CARS). ELISA assay showed that the mean serum BDNF level of children with ASD was significantly (P BDNF levels and CARS scores (P BDNF genotyping results showed that there was no difference between the ASD cases and the control. Among the children with ASD, the mean serum BDNF level of Met/Met group was lower than other groups. According to the ROC curve generated from our clinical data, the optimal cutoff value of serum BDNF levels, an indicator for diagnosis of ASD, was projected to be 12.50 ng/ml. Thus, it yielded a corresponding sensitivity of 81.7 % and the specificity of 66.9 %. Accordingly, area value under the curve was 0.836 (95 % CI, 0.774-0.897); the positive predictive value (PPV) and the negative predictive value (NPV) were 70.1 and 79.1 %, respectively. These results suggested that rather than Val66Met polymorphism, BDNF was more possible to impact the pathogenesis of ASD.

  9. Associations of Cigarette Smoking and Polymorphisms in Brain-Derived Neurotrophic Factor and Catechol-O-Methyltransferase with Neurocognition in Alcohol Dependent Individuals during Early Abstinence

    Directory of Open Access Journals (Sweden)

    Timothy eDurazzo

    2012-10-01

    Full Text Available Chronic cigarette smoking and polymorphisms in brain-derived neurotrophic factor (BDNF and catechol-o-methyltransferase (COMT are associated with neurocognition in normal controls and those with various neuropsychiatric conditions. The influence of these polymorphisms on neurocognition in alcohol dependence is unclear. The goal of this report was to investigate the associations of single nucleotide polymorphisms (SNP in BDNF Val66Met and COMT Val158Met with neurocognition in a treatment-seeking alcohol dependent cohort and determine if neurocognitive differences between non-smokers and smokers previously observed in this cohort persist when controlled for these functional SNPs. Genotyping was conducted on 70 primarily male treatment-seeking alcohol dependent participants (ALC who completed a comprehensive neuropsychological battery after 33 ± 9 days of monitored abstinence. Smoking ALC performed significantly worse than non-smoking ALC on the domains of auditory-verbal and visuospatial learning and memory, cognitive efficiency, general intelligence, processing speed and global neurocognition. In smoking ALC, greater number of years of smoking over lifetime was related to poorer performance on multiple domains. COMT Met homozygotes were superior to Val homozygotes on measures of executive skills and showed trends for higher general intelligence and visuospatial skills, while COMT Val/Met heterozygotes showed significantly better general intelligence than Val homozygotes. COMT Val homozygotes performed better than heterozygotes on auditory-verbal memory. BDNF genotype was not related to any neurocognitive domain. The findings are consistent with studies in normal controls and neuropsychiatric cohorts that observed COMT Met carriers showed better performance on measures of executive skills and general intelligence. Overall, the findings support to the expanding clinical movement to make smoking cessation programs available at the inception of

  10. Controlled Chaos of Polymorphic Mucins in a Metazoan Parasite (Schistosoma mansoni) Interacting with Its Invertebrate Host (Biomphalaria glabrata)

    Science.gov (United States)

    Roger, Emmanuel; Grunau, Christoph; Pierce, Raymond J.; Hirai, Hirohisa; Gourbal, Benjamin; Galinier, Richard; Emans, Rémi; Cesari, Italo M.; Cosseau, Céline; Mitta, Guillaume

    2008-01-01

    Invertebrates were long thought to possess only a simple, effective and hence non-adaptive defence system against microbial and parasitic attacks. However, recent studies have shown that invertebrate immunity also relies on immune receptors that diversify (e.g. in echinoderms, insects and mollusks (Biomphalaria glabrata)). Apparently, individual or population-based polymorphism-generating mechanisms exists that permit the survival of invertebrate species exposed to parasites. Consequently, the generally accepted arms race hypothesis predicts that molecular diversity and polymorphism also exist in parasites of invertebrates. We investigated the diversity and polymorphism of parasite molecules (Schistosoma mansoni Polymorphic Mucins, SmPoMucs) that are key factors for the compatibility of schistosomes interacting with their host, the mollusc Biomphalaria glabrata. We have elucidated the complex cascade of mechanisms acting both at the genomic level and during expression that confer polymorphism to SmPoMuc. We show that SmPoMuc is coded by a multi-gene family whose members frequently recombine. We show that these genes are transcribed in an individual-specific manner, and that for each gene, multiple splice varia