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Sample records for exon skipping activity

  1. SR proteins induce alternative exon skipping through their activities on the flanking constitutive exons.

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    Han, Joonhee; Ding, Jian-Hua; Byeon, Cheol W; Kim, Jee H; Hertel, Klemens J; Jeong, Sunjoo; Fu, Xiang-Dong

    2011-02-01

    SR proteins are well known to promote exon inclusion in regulated splicing through exonic splicing enhancers. SR proteins have also been reported to cause exon skipping, but little is known about the mechanism. We previously characterized SRSF1 (SF2/ASF)-dependent exon skipping of the CaMKIIδ gene during heart remodeling. By using mouse embryo fibroblasts derived from conditional SR protein knockout mice, we now show that SR protein-induced exon skipping depends on their prevalent actions on a flanking constitutive exon and requires collaboration of more than one SR protein. These findings, coupled with other established rules for SR proteins, provide a theoretical framework to understand the complex effect of SR protein-regulated splicing in mammalian cells. We further demonstrate that heart-specific CaMKIIδ splicing can be reconstituted in fibroblasts by downregulating SR proteins and upregulating a RBFOX protein and that SR protein overexpression impairs regulated CaMKIIδ splicing and neuronal differentiation in P19 cells, illustrating that SR protein-dependent exon skipping may constitute a key strategy for synergism with other splicing regulators in establishing tissue-specific alternative splicing critical for cell differentiation programs.

  2. SR Proteins Induce Alternative Exon Skipping through Their Activities on the Flanking Constitutive Exons▿

    Science.gov (United States)

    Han, Joonhee; Ding, Jian-Hua; Byeon, Cheol W.; Kim, Jee H.; Hertel, Klemens J.; Jeong, Sunjoo; Fu, Xiang-Dong

    2011-01-01

    SR proteins are well known to promote exon inclusion in regulated splicing through exonic splicing enhancers. SR proteins have also been reported to cause exon skipping, but little is known about the mechanism. We previously characterized SRSF1 (SF2/ASF)-dependent exon skipping of the CaMKIIδ gene during heart remodeling. By using mouse embryo fibroblasts derived from conditional SR protein knockout mice, we now show that SR protein-induced exon skipping depends on their prevalent actions on a flanking constitutive exon and requires collaboration of more than one SR protein. These findings, coupled with other established rules for SR proteins, provide a theoretical framework to understand the complex effect of SR protein-regulated splicing in mammalian cells. We further demonstrate that heart-specific CaMKIIδ splicing can be reconstituted in fibroblasts by downregulating SR proteins and upregulating a RBFOX protein and that SR protein overexpression impairs regulated CaMKIIδ splicing and neuronal differentiation in P19 cells, illustrating that SR protein-dependent exon skipping may constitute a key strategy for synergism with other splicing regulators in establishing tissue-specific alternative splicing critical for cell differentiation programs. PMID:21135118

  3. Splice donor site mutation in the lysosomal neuraminidase gene causing exon skipping and complete loss of enzyme activity in a sialidosis patient.

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    Penzel, R; Uhl, J; Kopitz, J; Beck, M; Otto, H F; Cantz, M

    2001-07-20

    Sialidosis is a lysosomal storage disease caused by the deficiency of alpha-N-acetylneuraminidase (NEU1; sialidase), the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates. We have identified a homozygous transversion in the last intron (IVSE +1 G>C) in neu1 of a sialidosis patient. Sequencing of the truncated cDNA revealed an alternatively spliced neu1 transcript which lacks the complete sequence of exon 5. Skipping of exon 5 leads to a frameshift and results in a premature termination codon. This is the first description of an intronic point mutation causing a complete deficiency of the lysosomal neuraminidase activity.

  4. Skipping Multiple Exons to Treat DMD-Promises and Challenges.

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    Aslesh, Tejal; Maruyama, Rika; Yokota, Toshifumi

    2018-01-02

    Duchenne muscular dystrophy (DMD) is a lethal disorder caused by mutations in the DMD gene. Antisense-mediated exon-skipping is a promising therapeutic strategy that makes use of synthetic nucleic acids to skip frame-disrupting exon(s) and allows for short but functional protein expression by restoring the reading frame. In 2016, the U.S. Food and Drug Administration (FDA) approved eteplirsen, which skips DMD exon 51 and is applicable to approximately 13% of DMD patients. Multiple exon skipping, which is theoretically applicable to 80-90% of DMD patients in total, have been demonstrated in animal models, including dystrophic mice and dogs, using cocktail antisense oligonucleotides (AOs). Although promising, current drug approval systems pose challenges for the use of a cocktail AO. For example, both exons 6 and 8 need to be skipped to restore the reading frame in dystrophic dogs. Therefore, the cocktail of AOs targeting these exons has a combined therapeutic effect and each AO does not have a therapeutic effect by itself. The current drug approval system is not designed to evaluate such circumstances, which are completely different from cocktail drug approaches in other fields. Significant changes are needed in the drug approval process to promote the cocktail AO approach.

  5. Antisense mediated exon skipping therapy for duchenne muscular dystrophy (DMD)

    DEFF Research Database (Denmark)

    Brolin, Camilla; Shiraishi, Takehiko

    2011-01-01

    Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in the dystrophin gene (DMD) that result in the absence of essential muscle protein dystrophin. Among many different approaches for DMD treatment, exon skipping, mediated by antisense oligonucleotides, is one of the most...

  6. Translational and Regulatory Challenges for Exon Skipping Therapies

    NARCIS (Netherlands)

    Aartsma-Rus, Annemieke; Ferlini, Alessandra; Goemans, Nathalie; Pasmooij, Anna M. G.; Wells, Dominic J.; Bushby, Katerine; Vroom, Elizabeth; Balabanov, Pavel

    2014-01-01

    Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and

  7. Histone hyperacetylation and exon skipping: a calcium-mediated dynamic regulation in cardiomyocytes

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    Sharma, Alok; Nguyen, Hieu; Cai, Lu; Lou, Hua

    2015-01-01

    In contrast to cell type-specific pre-mRNA alternative splicing, mechanisms controlling activity-dependent alternative splicing is under-studied and not well understood. In a recent study, we conducted a comprehensive analysis of calcium-mediated mechanism that regulates alternative exon skipping in mouse cardiomyocytes. Our results reveal a strong link between histone hyperacetylation and skipping of cassette exons, and provide support to the kinetic coupling model of the epigenetic regulation of alternative splicing at the chromatin level. PMID:26325491

  8. A novel splicing silencer generated by DMD exon 45 deletion junction could explain upstream exon 44 skipping that modifies dystrophinopathy.

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    Dwianingsih, Ery Kus; Malueka, Rusdy Ghazali; Nishida, Atsushi; Itoh, Kyoko; Lee, Tomoko; Yagi, Mariko; Iijima, Kazumoto; Takeshima, Yasuhiro; Matsuo, Masafumi

    2014-08-01

    Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disease, is mostly caused by exon deletion mutations in the DMD gene. The reading frame rule explains that out-of-frame deletions lead to muscle dystrophin deficiency in DMD. In outliers to this rule, deletion junction sequences have never previously been explored as splicing modulators. In a Japanese case, we identified a single exon 45 deletion in the patient's DMD gene, indicating out-of-frame mutation. However, immunohistochemical examination disclosed weak dystrophin signals in his muscle. Reverse transcription-PCR amplification of DMD exons 42 to 47 revealed a major normally spliced product with exon 45 deletion and an additional in-frame product with deletion of both exons 44 and 45, indicating upstream exon 44 skipping. We considered the latter to underlie the observed dystrophin expression. Remarkably, the junction sequence cloned by PCR walking abolished the splicing enhancer activity of the upstream intron in a chimeric doublesex gene pre-mRNA in vitro splicing. Furthermore, antisense oligonucleotides directed against the junction site counteracted this effect. These indicated that the junction sequence was a splicing silencer that induced upstream exon 44 skipping. It was strongly suggested that creation of splicing regulator is a modifier of dystrophinopathy.

  9. Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy

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    van Ommen Gert-Jan B

    2007-07-01

    Full Text Available Abstract Background Antisense-mediated exon skipping is currently one of the most promising therapeutic approaches for Duchenne muscular dystrophy (DMD. Using antisense oligonucleotides (AONs targeting specific exons the DMD reading frame is restored and partially functional dystrophins are produced. Following proof of concept in cultured muscle cells from patients with various deletions and point mutations, we now focus on single and multiple exon duplications. These mutations are in principle ideal targets for this approach since the specific skipping of duplicated exons would generate original, full-length transcripts. Methods Cultured muscle cells from DMD patients carrying duplications were transfected with AONs targeting the duplicated exons, and the dystrophin RNA and protein were analyzed. Results For two brothers with an exon 44 duplication, skipping was, even at suboptimal transfection conditions, so efficient that both exons 44 were skipped, thus generating, once more, an out-of-frame transcript. In such cases, one may resort to multi-exon skipping to restore the reading frame, as is shown here by inducing skipping of exon 43 and both exons 44. By contrast, in cells from a patient with an exon 45 duplication we were able to induce single exon 45 skipping, which allowed restoration of wild type dystrophin. The correction of a larger duplication (involving exons 52 to 62, by combinations of AONs targeting the outer exons, appeared problematic due to inefficient skipping and mistargeting of original instead of duplicated exons. Conclusion The correction of DMD duplications by exon skipping depends on the specific exons targeted. Its options vary from the ideal one, restoring for the first time the true, wild type dystrophin, to requiring more 'classical' skipping strategies, while the correction of multi-exon deletions may need the design of tailored approaches.

  10. Variants affecting exon skipping contribute to complex traits.

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    Younghee Lee

    Full Text Available DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1 experimentally validate our in silico predictions of skipped exons and 2 characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.

  11. Translational and regulatory challenges for exon skipping therapies.

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    Aartsma-Rus, Annemieke; Ferlini, Alessandra; Goemans, Nathalie; Pasmooij, Anna M G; Wells, Dominic J; Bushby, Katerine; Vroom, Elizabeth; Balabanov, Pavel

    2014-10-01

    Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.

  12. Pip6-PMO, A New Generation of Peptide-oligonucleotide Conjugates With Improved Cardiac Exon Skipping Activity for DMD Treatment

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    Corinne Betts

    2012-01-01

    Full Text Available Antisense oligonucleotides (AOs are currently the most promising therapeutic intervention for Duchenne muscular dystrophy (DMD. AOs modulate dystrophin pre-mRNA splicing, thereby specifically restoring the dystrophin reading frame and generating a truncated but semifunctional dystrophin protein. Challenges in the development of this approach are the relatively poor systemic AO delivery and inefficient dystrophin correction in affected non-skeletal muscle tissues, including the heart. We have previously reported impressive heart activity including high-splicing efficiency and dystrophin restoration following a single administration of an arginine-rich cell-penetrating peptide (CPPs conjugated to a phosphorodiamidate morpholino oligonucleotide (PMO: Pip5e-PMO. However, the mechanisms underlying this activity are poorly understood. Here, we report studies involving single dose administration (12.5 mg/kg of derivatives of Pip5e-PMO, consecutively assigned as Pip6-PMOs. These peptide-PMOs comprise alterations to the central hydrophobic core of the Pip5e peptide and illustrate that certain changes to the peptide sequence improves its activity; however, partial deletions within the hydrophobic core abolish its efficiency. Our data indicate that the hydrophobic core of the Pip sequences is critical for PMO delivery to the heart and that specific modifications to this region can enhance activity further. The results have implications for therapeutic PMO development for DMD.

  13. Assessment of the feasibility of exon 45–55 multiexon skipping for duchenne muscular dystrophy

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    van Ommen Gert-Jan B

    2008-12-01

    Full Text Available Abstract Background The specific skipping of an exon, induced by antisense oligonucleotides (AON during splicing, has shown to be a promising therapeutic approach for Duchenne muscular dystrophy (DMD patients. As different mutations require skipping of different exons, this approach is mutation dependent. The skipping of an entire stretch of exons (e.g. exons 45 to 55 has recently been suggested as an approach applicable to larger groups of patients. However, this multiexon skipping approach is technically challenging. The levels of intended multiexon skips are typically low and highly variable, and may be dependent on the order of intron removal. We hypothesized that the splicing order might favor the induction of multiexon 45–55 skipping. Methods We here tested the feasibility of inducing multiexon 45–55 in control and patient muscle cell cultures using various AON cocktails. Results In all experiments, the exon 45–55 skip frequencies were minimal and comparable to those observed in untreated cells. Conclusion We conclude that current state of the art does not sufficiently support clinical development of multiexon skipping for DMD.

  14. Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency

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    HaiFang Yin

    2013-01-01

    Full Text Available We have recently reported that cell-penetrating peptides (CPPs and novel chimeric peptides containing CPP (referred as B peptide and muscle-targeting peptide (referred as MSP motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was investigated. Four additional chimeric peptide-PMO conjugates including newly identified peptide 9 (B-9-PMO and 9-B-PMO and control peptide 3 (B-3-PMO and 3-B-PMO were tested in mdx mice. Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO, further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue-targeting peptide motif within the chimeric peptide with respect to PMOs. Subsequent mechanistic studies showed that enhanced cellular uptake of B-MSP-PMO into muscle cells leads to increased exon-skipping activity in comparison with MSP-B-PMO. Surprisingly, further evidence showed that the uptake of chimeric peptide-PMO conjugates of both orientations (B-MSP-PMO and MSP-B-PMO was ATP- and temperature-dependent and also partially mediated by heparan sulfate proteoglycans (HSPG, indicating that endocytosis is likely the main uptake pathway for both chimeric peptide-PMO conjugates. Collectively, our data demonstrate that peptide orientation in chimeric peptides is an important parameter that determines cellular uptake and activity when conjugated directly to oligonucleotides. These observations provide insight into the design of improved cell targeting compounds for future therapeutics studies.

  15. The silent mutation nucleotide 744 G --> A, Lys172Lys, in exon 6 of BRCA2 results in exon skipping

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Steffensen, Ane Y; Jønson, Lars

    2009-01-01

    and intron variants are of unknown significance. Here, we describe the functional characterization of a silent mutation (nucleotide 744 G --> A/c.516 G --> A, Lys172Lys) in exon 6 of BRCA2 in a Danish family with breast and ovarian cancer. Exon trapping analysis showed that the mutation results in skipping...... of exon 6 and/or both exon 5 and 6, which was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient. We therefore conclude that the BRCA2 silent mutation Lys172Lys is a disease-causing mutation....

  16. Clinical phenotypes as predictors of the outcome of skipping around DMD exon 45.

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    Findlay, Andrew R; Wein, Nicolas; Kaminoh, Yuuki; Taylor, Laura E; Dunn, Diane M; Mendell, Jerry R; King, Wendy M; Pestronk, Alan; Florence, Julaine M; Mathews, Katherine D; Finkel, Richard S; Swoboda, Kathryn J; Howard, Michael T; Day, John W; McDonald, Craig; Nicolas, Aurélie; Le Rumeur, Elisabeth; Weiss, Robert B; Flanigan, Kevin M

    2015-04-01

    Exon-skipping therapies aim to convert Duchenne muscular dystrophy (DMD) into less severe Becker muscular dystrophy (BMD) by altering pre-mRNA splicing to restore an open reading frame, allowing translation of an internally deleted and partially functional dystrophin protein. The most common single exon deletion-exon 45 (Δ45)-may theoretically be treated by skipping of either flanking exon (44 or 46). We sought to predict the impact of these by assessing the clinical severity in dystrophinopathy patients. Phenotypic data including clinical diagnosis, age at wheelchair use, age at loss of ambulation, and presence of cardiomyopathy were analyzed from 41 dystrophinopathy patients containing equivalent in-frame deletions. As expected, deletions of either exons 45 to 47 (Δ45-47) or exons 45 to 48 (Δ45-48) result in BMD in 97% (36 of 37) of subjects. Unexpectedly, deletion of exons 45 to 46 (Δ45-46) is associated with the more severe DMD phenotype in 4 of 4 subjects despite an in-frame transcript. Notably, no patients with a deletion of exons 44 to 45 (Δ44-45) were found within the United Dystrophinopathy Project database, and this mutation has only been reported twice before, which suggests an ascertainment bias attributable to a very mild phenotype. The observation that Δ45-46 patients have typical DMD suggests that the conformation of the resultant protein may result in protein instability or altered binding of critical partners. We conclude that in DMD patients with Δ45, skipping of exon 44 and multiexon skipping of exons 46 and 47 (or exons 46-48) are better potential therapies than skipping of exon 46 alone. © 2015 American Neurological Association.

  17. Antisense Oligonucleotide-mediated Exon Skipping as a Systemic Therapeutic Approach for Recessive Dystrophic Epidermolysis Bullosa

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    Jeroen Bremer

    2016-01-01

    Full Text Available The “generalized severe” form of recessive dystrophic epidermolysis bullosa (RDEB-gen sev is caused by bi-allelic null mutations in COL7A1, encoding type VII collagen. The absence of type VII collagen leads to blistering of the skin and mucous membranes upon the slightest trauma. Because most patients carry exonic point mutations or small insertions/deletions, most exons of COL7A1 are in-frame, and low levels of type VII collagen already drastically improve the disease phenotype, this gene seems a perfect candidate for antisense oligonucleotide (AON-mediated exon skipping. In this study, we examined the feasibility of AON-mediated exon skipping in vitro in primary cultured keratinocytes and fibroblasts, and systemically in vivo using a human skin-graft mouse model. We show that treatment with AONs designed against exon 105 leads to in-frame exon 105 skipping at the RNA level and restores type VII collagen protein production in vitro. Moreover, we demonstrate that systemic delivery in vivo induces de novo expression of type VII collagen in skin grafts generated from patient cells. Our data demonstrate strong proof-of-concept for AON-mediated exon skipping as a systemic therapeutic strategy for RDEB.

  18. Efficient Skipping of Single Exon Duplications in DMD Patient-Derived Cell Lines Using an Antisense Oligonucleotide Approach.

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    Wein, Nicolas; Vulin, Adeline; Findlay, Andrew R; Gumienny, Felecia; Huang, Nianyuan; Wilton, Steve D; Flanigan, Kevin M

    2017-01-01

    Exon skipping strategies in Duchenne muscular dystrophy (DMD) have largely been directed toward altering splicing of exons flanking out-of-frame deletions, with the goal of restoring an open mRNA reading frame that leads to production of an internally deleted but partially functional dystrophin protein. We sought to apply exon skipping to duplication mutations, assuming that the inherently limited efficiency of antisense oligonucleotide-induced exon skipping would more frequently skip a single copy of a duplicated exon, rather than both and result in significant amounts of wild-type DMD mRNA. We tested this hypothesis in fibroblast cell lines derived from patients with a variety of single or multiple exon duplications that have been modified to allow transdifferentiation into a myogenic lineage. Using a variety of 2'O-methyl antisense oligonucleotides, significant skipping was induced for each duplication leading to a wild-type transcript as a major mRNA product. This study provides another proof of concept for the feasibility of therapeutic skipping in patients carrying exon duplications in order to express wild-type, full-length mRNA, although careful evaluation of the skipping efficiency should be performed as some exons are easier to skip than others. Such a personalized strategy is expected to be highly beneficial for this subset of DMD patients, compared to inducing expression of an internally-deleted dystrophin.

  19. FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor

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    Peterlongo, Paolo; Catucci, Irene; Colombo, Mara; Caleca, Laura; Mucaki, Eliseos; Bogliolo, Massimo; Marin, Maria; Damiola, Francesca; Bernard, Loris; Pensotti, Valeria; Volorio, Sara; Dall'Olio, Valentina; Meindl, Alfons; Bartram, Claus; Sutter, Christian; Surowy, Harald; Sornin, Valérie; Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Sinilnikova, Olga M.; Mitchell, Gillian; James, Paul A.; Thompson, Ella; Marchetti, Marina; Verzeroli, Cristina; Tartari, Carmen; Capone, Gabriele Lorenzo; Putignano, Anna Laura; Genuardi, Maurizio; Medici, Veronica; Marchi, Isabella; Federico, Massimo; Tognazzo, Silvia; Matricardi, Laura; Agata, Simona; Dolcetti, Riccardo; Puppa, Lara Della; Cini, Giulia; Gismondi, Viviana; Viassolo, Valeria; Perfumo, Chiara; Mencarelli, Maria Antonietta; Baldassarri, Margherita; Peissel, Bernard; Roversi, Gaia; Silvestri, Valentina; Rizzolo, Piera; Spina, Francesca; Vivanet, Caterina; Tibiletti, Maria Grazia; Caligo, Maria Adelaide; Gambino, Gaetana; Tommasi, Stefania; Pilato, Brunella; Tondini, Carlo; Corna, Chiara; Bonanni, Bernardo; Barile, Monica; Osorio, Ana; Benitez, Javier; Balestrino, Luisa; Ottini, Laura; Manoukian, Siranoush; Pierotti, Marco A.; Renieri, Alessandra; Varesco, Liliana; Couch, Fergus J.; Wang, Xianshu; Devilee, Peter; Hilbers, Florentine S.; van Asperen, Christi J.; Viel, Alessandra; Montagna, Marco; Cortesi, Laura; Diez, Orland; Balmaña, Judith; Hauke, Jan; Schmutzler, Rita K.; Papi, Laura; Pujana, Miguel Angel; Lázaro, Conxi; Falanga, Anna; Offit, Kenneth; Vijai, Joseph; Campbell, Ian; Burwinkel, Barbara; Kvist, Anders; Ehrencrona, Hans; Mazoyer, Sylvie; Pizzamiglio, Sara; Verderio, Paolo; Surralles, Jordi; Rogan, Peter K.; Radice, Paolo

    2015-01-01

    Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28–12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04–12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09–13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer. PMID:26130695

  20. Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients

    NARCIS (Netherlands)

    Aartsma-Rus, Annemieke; Janson, Anneke A. M.; Kaman, Wendy E.; Bremmer-Bout, Mattie; den Dunnen, Johan T.; Baas, Frank; van Ommen, Gert-Jan B.; van Deutekom, Judith C. T.

    2003-01-01

    The dystrophin deficiency leading to the severely progressing muscle degeneration in Duchenne muscular dystrophy (DMD) patients is caused by frame-shifting mutations in the DMD gene. We are developing a reading frame correction therapy aimed at the antisense-induced skipping of targeted exons from

  1. Dual exon skipping in myostatin and dystrophin for Duchenne muscular dystrophy

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    van Ommen Gert Jan B

    2011-04-01

    Full Text Available Abstract Background Myostatin is a potent muscle growth inhibitor that belongs to the Transforming Growth Factor-β (TGF-β family. Mutations leading to non functional myostatin have been associated with hypermuscularity in several organisms. By contrast, Duchenne muscular dystrophy (DMD is characterized by a loss of muscle fibers and impaired regeneration. In this study, we aim to knockdown myostatin by means of exon skipping, a technique which has been successfully applied to reframe the genetic defect of dystrophin gene in DMD patients. Methods We targeted myostatin exon 2 using antisense oligonucleotides (AON in healthy and DMD-derived myotubes cultures. We assessed the exon skipping level, transcriptional expression of myostatin and its target genes, and combined myostatin and several dystrophin AONs. These AONs were also applied in the mdx mice models via intramuscular injections. Results Myostatin AON induced exon 2 skipping in cell cultures and to a lower extent in the mdx mice. It was accompanied by decrease in myostatin mRNA and enhanced MYOG and MYF5 expression. Furthermore, combination of myostatin and dystrophin AONs induced simultaneous skipping of both genes. Conclusions We conclude that two AONs can be used to target two different genes, MSTN and DMD, in a straightforward manner. Targeting multiple ligands of TGF-beta family will be more promising as adjuvant therapies for DMD.

  2. Exon skipping: a first in class strategy for Duchenne muscular dystrophy.

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    Niks, Erik H; Aartsma-Rus, Annemieke

    2017-02-01

    Exon skipping is a therapeutic approach for Duchenne muscular dystrophy (DMD) that has been in development for close to two decades. This approach uses antisense oligonucleotides (AONs) to modulate pre-mRNA splicing of dystrophin transcripts to restore the disrupted DMD reading frame. The approach has moved from in vitro proof of concept studies to the clinical trial phase and marketing authorization applications with regulators. The first AON (eteplirsen) has recently received accelerated approval by the Food and Drug Administration in the US. Areas covered: In this review the authors explain the antisense-mediated exon skipping approach, outline how it needs be tailored for different DMD mutation types and describe the challenges and opportunities for each mutation type. The authors summarize the clinical development of antisense-mediated exon 51 skipping, and discuss methods to improve efficiency. Finally, the authors provide their opinion on current developments and identify topics for future prioritization. Expert opinion: Exon skipping development has been a learning experience for all those involved. Aside from an approved therapy, its development has yielded side benefits including the development of tools for clinical trials and has increased collaboration between academics, patients, industry and regulators.

  3. Endogenous Multiple Exon Skipping and Back-Splicing at the DMD Mutation Hotspot.

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    Suzuki, Hitoshi; Aoki, Yoshitsugu; Kameyama, Toshiki; Saito, Takashi; Masuda, Satoru; Tanihata, Jun; Nagata, Tetsuya; Mayeda, Akila; Takeda, Shin'ichi; Tsukahara, Toshifumi

    2016-10-13

    Duchenne muscular dystrophy (DMD) is a severe muscular disorder. It was reported that multiple exon skipping (MES), targeting exon 45-55 of the DMD gene, might improve patients' symptoms because patients who have a genomic deletion of all these exons showed very mild symptoms. Thus, exon 45-55 skipping treatments for DMD have been proposed as a potential clinical cure. Herein, we detected the expression of endogenous exons 44-56 connected mRNA transcript of the DMD using total RNAs derived from human normal skeletal muscle by reverse transcription polymerase chain reaction (RT-PCR), and identified a total of eight types of MES products around the hotspot. Surprisingly, the 5' splice sites of recently reported post-transcriptional introns (remaining introns after co-transcriptional splicing) act as splicing donor sites for MESs. We also tested exon combinations to generate DMD circular RNAs (circRNAs) and determined the preferential splice sites of back-splicing, which are involved not only in circRNA generation, but also in MESs. Our results fit the current circRNA-generation model, suggesting that upstream post-transcriptional introns trigger MES and generate circRNA because its existence is critical for the intra-intronic interaction or for extremely distal splicing.

  4. Nucleobase-modified antisense oligonucleotides containing 5-(phenyltriazol)-2′-deoxyuridine nucleotides induce exon-skipping

    DEFF Research Database (Denmark)

    Le, Bao T.; Hornum, Mick; Sharma, Pawan K.

    2017-01-01

    Chemically-modified antisense oligonucleotide-mediated exon-skipping has been validated as a therapeutic strategy for tackling several disease pathologies, particularly duchenne muscular dystrophy. To date, only sugar-modified and internucleotide linkage-modified oligonucleotide chemistries have...

  5. The effect of 6-thioguanine on alternative splicing and antisense-mediated exon skipping treatment for duchenne muscular dystrophy.

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    Verhaart, Ingrid E C; Aartsma-Rus, Annemieke

    2012-12-12

    The severe muscle wasting disorder Duchenne muscular dystrophy (DMD) is caused by genetic defects in the DMD gene, leading to a complete absence of dystrophin protein. Of the therapeutic approaches addressing the underlying genetic defect, exon skipping through antisense oligonucleotides (AONs) is the closest to clinical application. Several strategies to improve the efficiency of this approach are currently being investigated, such as the use of small chemical compounds that improve AONmediated exon skipping levels. Recently, enhanced exon skipping in combination with a guanine analogue, 6-thioguanine (6TG) was reported for phosphorodiamidate morpholino oligomers (PMO). Here the effect of 6TG on the exon skipping efficacy of 2'-O-methyl phosphorothioate RNA (2OMePS) and PMO AONs in vitro and in vivo was further evaluated, as well as the effect of 6TG by itself. Results confirm an increase of exon skipping levels in vitro, however, in contrast to the previous report, no effect was observed in vivo. Importantly, 6TG treatment in vitro resulted in numerous additional DMD exon skipping events. This, in combination with the known cytotoxic effects of 6TG after incorporation in DNA, warrants reconsidering of the use of 6TG as enhancer of AON efficiency in DMD, were chronic treatment will be required.

  6. Clinical characterisation of Becker muscular dystrophy patients predicts favourable outcome in exon-skipping therapy.

    Science.gov (United States)

    van den Bergen, J C; Schade van Westrum, S M; Dekker, L; van der Kooi, A J; de Visser, M; Wokke, B H A; Straathof, C S; Hulsker, M A; Aartsma-Rus, A; Verschuuren, J J; Ginjaar, H B

    2014-01-01

    Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD. Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD. Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6-67). Nine patients were wheelchair users (26-56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively. This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a 'skipped' DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD.

  7. Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Straub, Volker; Hemmings, Robert; Haas, Manuel; Schlosser-Weber, Gabriele; Stoyanova-Beninska, Violeta; Mercuri, Eugenio; Muntoni, Francesco; Sepodes, Bruno; Vroom, Elizabeth

    2017-01-01

    Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience. PMID:28796573

  8. In silico screening based on predictive algorithms as a design tool for exon skipping oligonucleotides in Duchenne muscular dystrophy.

    Science.gov (United States)

    Echigoya, Yusuke; Mouly, Vincent; Garcia, Luis; Yokota, Toshifumi; Duddy, William

    2015-01-01

    The use of antisense 'splice-switching' oligonucleotides to induce exon skipping represents a potential therapeutic approach to various human genetic diseases. It has achieved greatest maturity in exon skipping of the dystrophin transcript in Duchenne muscular dystrophy (DMD), for which several clinical trials are completed or ongoing, and a large body of data exists describing tested oligonucleotides and their efficacy. The rational design of an exon skipping oligonucleotide involves the choice of an antisense sequence, usually between 15 and 32 nucleotides, targeting the exon that is to be skipped. Although parameters describing the target site can be computationally estimated and several have been identified to correlate with efficacy, methods to predict efficacy are limited. Here, an in silico pre-screening approach is proposed, based on predictive statistical modelling. Previous DMD data were compiled together and, for each oligonucleotide, some 60 descriptors were considered. Statistical modelling approaches were applied to derive algorithms that predict exon skipping for a given target site. We confirmed (1) the binding energetics of the oligonucleotide to the RNA, and (2) the distance in bases of the target site from the splice acceptor site, as the two most predictive parameters, and we included these and several other parameters (while discounting many) into an in silico screening process, based on their capacity to predict high or low efficacy in either phosphorodiamidate morpholino oligomers (89% correctly predicted) and/or 2'O Methyl RNA oligonucleotides (76% correctly predicted). Predictions correlated strongly with in vitro testing for sixteen de novo PMO sequences targeting various positions on DMD exons 44 (R² 0.89) and 53 (R² 0.89), one of which represents a potential novel candidate for clinical trials. We provide these algorithms together with a computational tool that facilitates screening to predict exon skipping efficacy at each position of

  9. Dynamic ASXL1 Exon Skipping and Alternative Circular Splicing in Single Human Cells.

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    Winston Koh

    Full Text Available Circular RNAs comprise a poorly understood new class of noncoding RNA. In this study, we used a combination of targeted deletion, high-resolution splicing detection, and single-cell sequencing to deeply probe ASXL1 circular splicing. We found that efficient circular splicing required the canonical transcriptional start site and inverted AluSx elements. Sequencing-based interrogation of isoforms after ASXL1 overexpression identified promiscuous linear splicing between all exons, with the two most abundant non-canonical linear products skipping the exons that produced the circular isoforms. Single-cell sequencing revealed a strong preference for either the linear or circular ASXL1 isoforms in each cell, and found the predominant exon skipping product is frequently co-expressed with its reciprocal circular isoform. Finally, absolute quantification of ASXL1 isoforms confirmed our findings and suggests that standard methods overestimate circRNA abundance. Taken together, these data reveal a dynamic new view of circRNA genesis, providing additional framework for studying their roles in cellular biology.

  10. Two-exon skipping within MLPH is associated with coat color dilution in rabbits.

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    Stefanie Lehner

    Full Text Available Coat color dilution turns black coat color to blue and red color to cream and is a characteristic in many mammalian species. Matings among Netherland Dwarf, Loh, and Lionhead Dwarf rabbits over two generations gave evidence for a monogenic autosomal recessive inheritance of coat colour dilution. Histological analyses showed non-uniformly distributed, large, agglomerating melanin granules in the hair bulbs of coat color diluted rabbits. We sequenced the cDNA of MLPH in two dilute and one black rabbit for polymorphism detection. In both color diluted rabbits, skipping of exons 3 and 4 was present resulting in altered amino acids at p.QGL[37-39]QWA and a premature stop codon at p.K40*. Sequencing of genomic DNA revealed a c.111-5C>A splice acceptor mutation within the polypyrimidine tract of intron 2 within MLPH. This mutation presumably causes skipping of exons 3 and 4. In 14/15 dilute rabbits, the c.111-5C>A mutation was homozygous and in a further dilute rabbit, heterozygous and in combination with a homozygous frame shift mutation within exon 6 (c.585delG. In conclusion, our results demonstrated a colour dilution associated MLPH splice variant causing a strongly truncated protein (p.Q37QfsX4. An involvement of further MLPH-associated mutations needs further investigations.

  11. Novel Cationic Carotenoid Lipids as Delivery Vectors of Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Vassilia Partali

    2012-01-01

    Full Text Available Duchenne Muscular Dystrophy (DMD is a common, inherited, incurable, fatal muscle wasting disease caused by deletions that disrupt the reading frame of the DMD gene such that no functional dystrophin protein is produced. Antisense oligonucleotide (AO-directed exon skipping restores the reading frame of the DMD gene, and truncated, yet functional dystrophin protein is expressed. The aim of this study was to assess the efficiency of two novel rigid, cationic carotenoid lipids, C30-20 and C20-20, in the delivery of a phosphorodiamidate morpholino (PMO AO, specifically designed for the targeted skipping of exon 45 of DMD mRNA in normal human skeletal muscle primary cells (hSkMCs. The cationic carotenoid lipid/PMO-AO lipoplexes yielded significant exon 45 skipping relative to a known commercial lipid, 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC.

  12. Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation.

    Science.gov (United States)

    Jorge, Susan E; Schulman, Sol; Freed, Jason A; VanderLaan, Paul A; Rangachari, Deepa; Kobayashi, Susumu S; Huberman, Mark S; Costa, Daniel B

    2015-12-01

    Genomic aberrations involving ALK, ROS1 and MET can be driver oncogenes in lung adenocarcinomas. Identification of tyrosine kinase inhibitors (TKIs) with activity against these tumors and of preclinical systems to model response are warranted. We analyzed cases with lung adenocarcinomas for representative genomic aberrations, evaluated the response to the multitargeted MET/ALK/ROS1 crizotinib TKI in cases with MET aberrations and profiled lung cancer cell lines with the aforementioned genomic changes. Lung cancer cell lines with ALK rearrangement, ROS1 rearrangement or MET amplification had expected in vitro responses to crizotinib and the ALK/ROS1 TKI ceritinib. However, a commercially-available cell line with MET exon 14 skipping mutation and co-occurring PIK3CA-p.Glu545Lys mutation did not respond to crizotinib; suggesting the latter abrogated response. 10% of MET exon 14 skipping mutation co-occurred with PIK3CA mutation in the TCGA cohort. Putative crizotinib-responsive somatic mutations (ALK rearrangements, ROS1 rearrangements, high level MET amplification or MET exon 14 skipping mutations) were present in 10% of lung adenocarcinomas analyzed at our service and in 9.5% of the TCGA lung adenocarcinoma database. One patient each whose advanced tumors harbored high level MET amplification with wild-type PIK3CA or MET exon 14 skipping mutation with PIK3CA-p.Glu542Lys had significant responses to crizotinib; suggesting that PIK3CA co-mutation did not affect clinical response. Approximately 10% of lung adenocarcinomas harbor aberrations that are targetable using the approved multitargeted TKI crizotinib. MET exon 14 skipping mutation predicts for response to MET TKIs in human lung adenocarcinomas but co-occurrence of PIK3CA mutation needs to be better evaluated as a modifier of response to TKI therapy. MET TKIs should not be omitted from MET exon 14 skipping mutated tumors until further preclinical and clinical data can confirm or refute mechanisms of primary or

  13. Exon skipping and translation in patients with frameshift deletions in the dystrophin gene

    Energy Technology Data Exchange (ETDEWEB)

    Sherratt, T.G.; Dubowitz, V.; Sewry, C.A.; Strong, P.N. (Royal Postgraduate Medical School, London (United Kingdom)); Vulliamy, T. (Hammersmith Hospital, London (United Kingdom))

    1993-11-01

    Although many Duchenne muscular dystrophy patients have a deletion in the dystrophin gene which disrupts the translational reading frame, they express dystrophin in a small proportion of skeletal muscle fibers ([open quotes]revertant fibers[close quotes]). Antibody studies have shown, indirectly, that dystrophin synthesis in revertant fibers is facilitated by a frame-restoring mechanism; in the present study, the feasibility of mRNA splicing was investigated. Dystrophin transcripts were analyzed in skeletal muscle from individuals possessing revertant fibers and a frameshift deletion in the dystrophin gene. In each case a minor in-frame transcript was detected, in which exons adjacent to those deleted from the genome had been skipped. There appeared to be some correlation between the levels of in-frame transcripts and the predicted translation products. Low levels of alternatively spliced transcripts were also present in normal muscle. The results provide further evidence of exon skipping in the dystrophin gene and indicate that this may be involved in the synthesis of dystrophin by revertant fibers. 44 refs., 12 figs.

  14. AON-mediated Exon Skipping Restores Ciliation in Fibroblasts Harboring the Common Leber Congenital Amaurosis CEP290 Mutation

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    Xavier Gerard

    2012-01-01

    Full Text Available Leber congenital amaurosis (LCA is a severe hereditary retinal dystrophy responsible for congenital or early-onset blindness. The most common disease-causing mutation (>10% is located deep in intron 26 of the CEP290 gene (c.2991+1655A>G. It creates a strong splice donor site that leads to insertion of a cryptic exon encoding a premature stop codon. In the present study, we show that the use of antisense oligonucleotides (AONs allow an efficient skipping of the mutant cryptic exon and the restoration of ciliation in fibroblasts of affected patients. These data support the feasibility of an AON-mediated exon skipping strategy to correct the aberrant splicing.

  15. Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping.

    Science.gov (United States)

    Vulin, Adeline; Barthélémy, Inès; Goyenvalle, Aurélie; Thibaud, Jean-Laurent; Beley, Cyriaque; Griffith, Graziella; Benchaouir, Rachid; le Hir, Maëva; Unterfinger, Yves; Lorain, Stéphanie; Dreyfus, Patrick; Voit, Thomas; Carlier, Pierre; Blot, Stéphane; Garcia, Luis

    2012-11-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease.

  16. Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Δ48-50 DMD cells

    Science.gov (United States)

    De Angelis, Fernanda Gabriella; Sthandier, Olga; Berarducci, Barbara; Toso, Silvia; Galluzzi, Giuliana; Ricci, Enzo; Cossu, Giulio; Bozzoni, Irene

    2002-01-01

    Deletions and point mutations in the dystrophin gene cause either the severe progressive myopathy Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. Because internal in-frame deletions in the protein produce only mild myopathic symptoms, it should be possible, by preventing the inclusion of specific mutated exon(s) in the mature dystrophin mRNA, to restore a partially corrected phenotype. Such control has been previously accomplished by the use of synthetic oligonucleotides; nevertheless, a significant drawback to this approach is caused by the fact that oligonucleotides would require periodic administrations. To circumvent this problem, we have produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. In this paper we show that antisense molecules against exon 51 splice junctions are able to direct skipping of this exon in the human DMD deletion 48–50 and to rescue dystrophin synthesis. We also show that the highest skipping activity was found when antisense constructs against the 5′ and 3′ splice sites are coexpressed in the same cell. PMID:12077324

  17. Exon Skipping and Gene Transfer Restore Dystrophin Expression in Human Induced Pluripotent Stem Cells-Cardiomyocytes Harboring DMD Mutations

    Science.gov (United States)

    Dick, Emily; Kalra, Spandan; Anderson, David; George, Vinoj; Ritso, Morten; Laval, Steven H.; Barresi, Rita; Aartsma-Rus, Annemieke; Lochmüller, Hanns

    2013-01-01

    With an incidence of ∼1:3,500 to 5,000 in male children, Duchenne muscular dystrophy (DMD) is an X-linked disorder in which progressive muscle degeneration occurs and affected boys usually die in their twenties or thirties. Cardiac involvement occurs in 90% of patients and heart failure accounts for up to 40% of deaths. To enable new therapeutics such as gene therapy and exon skipping to be tested in human cardiomyocytes, we produced human induced pluripotent stem cells (hiPSC) from seven patients harboring mutations across the DMD gene. Mutations were retained during differentiation and analysis indicated the cardiomyocytes showed a dystrophic gene expression profile. Antisense oligonucleotide-mediated skipping of exon 51 restored dystrophin expression to ∼30% of normal levels in hiPSC-cardiomyocytes carrying exon 47–50 or 48–50 deletions. Alternatively, delivery of a dystrophin minigene to cardiomyocytes with a deletion in exon 35 or a point mutation in exon 70 allowed expression levels similar to those seen in healthy cells. This demonstrates that DMD hiPSC-cardiomyocytes provide a novel tool to evaluate whether new therapeutics can restore dystrophin expression in the heart. PMID:23829870

  18. The Effect of 6-Thioguanine on Alternative Splicing and Antisense-Mediated Exon Skipping Treatment for Duchenne Muscular Dystrophy

    OpenAIRE

    Verhaart, Ingrid E. C.; Aartsma-Rus, Annemieke

    2012-01-01

    The severe muscle wasting disorder Duchenne muscular dystrophy (DMD) is caused by genetic defects in the DMD gene, leading to a complete absence of dystrophin protein. Of the therapeutic approaches addressing the underlying genetic defect, exon skipping through antisense oligonucleotides (AONs) is the closest to clinical application. Several strategies to improve the efficiency of this approach are currently being investigated, such as the use of small chemical compounds that improve AONmedia...

  19. Long-term Exon Skipping Studies With 2′-O-Methyl Phosphorothioate Antisense Oligonucleotides in Dystrophic Mouse Models

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    Christa L Tanganyika-de Winter

    2012-01-01

    Full Text Available Antisense-mediated exon skipping for Duchenne muscular dystrophy (DMD is currently tested in phase 3 clinical trials. The aim of this approach is to modulate splicing by skipping a specific exon to reframe disrupted dystrophin transcripts, allowing the synthesis of a partly functional dystrophin protein. Studies in animal models allow detailed analysis of the pharmacokinetic and pharmacodynamic profile of antisense oligonucleotides (AONs. Here, we tested the safety and efficacy of subcutaneously administered 2′-O-methyl phosphorothioate AON at 200 mg/kg/week for up to 6 months in mouse models with varying levels of disease severity: mdx mice (mild phenotype and mdx mice with one utrophin allele (mdx/utrn+/−; more severe phenotype. Long-term treatment was well tolerated and exon skipping and dystrophin restoration confirmed for all animals. Notably, in the more severely affected mdx/utrn+/− mice the therapeutic effect was larger: creatine kinase (CK levels were more decreased and rotarod running time was more increased. This suggests that the mdx/utrn+/− model may be a more suitable model to test potential therapies than the regular mdx mouse. Our results also indicate that long-term subcutaneous treatment in dystrophic mouse models with these AONs is safe and beneficial.

  20. Antisense oligonucleotide-mediated exon skipping of CHRNA1 pre-mRNA as potential therapy for Congenital Myasthenic Syndromes.

    Science.gov (United States)

    Tei, Shoin; Ishii, Hiroshige T; Mitsuhashi, Hiroaki; Ishiura, Shoichi

    2015-06-05

    CHRNA1 encodes the α subunit of nicotinic acetylcholine receptors (nAChRs) and is expressed at the neuromuscular junction. Moreover, it is one of the causative genes of Congenital Myasthenic Syndromes (CMS). CHRNA1 undergoes alternative splicing to produce two splice variants: P3A(-), without exon P3A, and P3A(+), with the exon P3A. Only P3A(-) forms functional nAChR. Aberrant alternative splicing caused by intronic or exonic point mutations in patients leads to an extraordinary increase in P3A(+) and a concomitant decrease in P3A(-). Consequently this resulted in a shortage of functional receptors. Aiming to restore the imbalance between the two splice products, antisense oligonucleotides (AONs) were employed to induce exon P3A skipping. Three AON sequences were designed to sterically block the putative binding sequences for splicing factors necessary for exon recognition. Herein, we show that AON complementary to the 5' splice site of the exon was the most effective at exon skipping of the minigene with causative mutations, as well as endogenous wild-type CHRNA1. We conclude that single administration of the AON against the 5' splice site is a promising therapeutic approach for patients based on the dose-dependent effect of the AON and the additive effect of combined AONs. This conclusion is favorable to patients with inherited diseases of uncertain etiology that arise from aberrant splicing leading to a subsequent loss of functional translation products because our findings encourage the option of AON treatment as a therapeutic for these prospectively identified diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. De novo exonic mutation in MYH7 gene leading to exon skipping in a patient with early onset muscular weakness and fiber-type disproportion.

    Science.gov (United States)

    Pajusalu, Sander; Talvik, Inga; Noormets, Klari; Talvik, Tiina; Põder, Haide; Joost, Kairit; Puusepp, Sanna; Piirsoo, Andres; Stenzel, Werner; Goebel, Hans H; Nikopensius, Tiit; Annilo, Tarmo; Nõukas, Margit; Metspalu, Andres; Õunap, Katrin; Reimand, Tiia

    2016-03-01

    Here we report on a case of MYH7-related myopathy in a boy with early onset of muscular weakness and delayed motor development in infancy. His most affected muscles were neck extensors showing a dropped head sign, proximal muscles of lower limbs with positive Gower's sign, and trunk muscles. Brain and spinal cord MRI scans, echocardiography, and laboratory analyses including creatine kinase and lactate did not reveal any abnormalities. Muscle histopathology showed fiber-type disproportion. Whole exome sequencing of the parents-offspring trio revealed a novel de novo c.5655G>A p.(Ala1885=) synonymous substitution of the last nucleotide in exon 38 of the MYH7 gene. Further RNA investigations proved the skipping of exon 38 (p.1854_1885del). This is a first report of an exon-skipping mutation in the MYH7 gene causing myopathy. This report broadens both the phenotypic and genotypic spectra of MYH7-related myopathies. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Parallel synthesis of cell-penetrating peptide conjugates of PMO toward exon skipping enhancement in Duchenne muscular dystrophy.

    Science.gov (United States)

    O'Donovan, Liz; Okamoto, Itaru; Arzumanov, Andrey A; Williams, Donna L; Deuss, Peter; Gait, Michael J

    2015-02-01

    We describe two new methods of parallel chemical synthesis of libraries of peptide conjugates of phosphorodiamidate morpholino oligonucleotide (PMO) cargoes on a scale suitable for cell screening prior to in vivo analysis for therapeutic development. The methods represent an extension of the SELection of PEPtide CONjugates (SELPEPCON) approach previously developed for parallel peptide-peptide nucleic acid (PNA) synthesis. However, these new methods allow for the utilization of commercial PMO as cargo with both C- and N-termini unfunctionalized. The synthetic methods involve conjugation in solution phase, followed by rapid purification via biotin-streptavidin immobilization and subsequent reductive release into solution, avoiding the need for painstaking high-performance liquid chromatography purifications. The synthesis methods were applied for screening of PMO conjugates of a 16-member library of variants of a 10-residue ApoE peptide, which was suggested for blood-brain barrier crossing. In this work the conjugate library was tested in an exon skipping assay using skeletal mouse mdx cells, a model of Duchene's muscular dystrophy where higher activity peptide-PMO conjugates were identified compared with the starting peptide-PMO. The results demonstrate the power of the parallel synthesis methods for increasing the speed of optimization of peptide sequences in conjugates of PMO for therapeutic screening.

  3. Biochemical characterization of patients with in-frame or out-of-frame DMD deletions pertinent to exon 44 or 45 skipping.

    Science.gov (United States)

    Anthony, Karen; Arechavala-Gomeza, Virginia; Ricotti, Valeria; Torelli, Silvia; Feng, Lucy; Janghra, Narinder; Tasca, Giorgio; Guglieri, Michela; Barresi, Rita; Armaroli, Annarita; Ferlini, Alessandra; Bushby, Katherine; Straub, Volker; Ricci, Enzo; Sewry, Caroline; Morgan, Jennifer; Muntoni, Francesco

    2014-01-01

    In Duchenne muscular dystrophy (DMD), the reading frame of an out-of-frame DMD deletion can be repaired by antisense oligonucleotide (AO)-mediated exon skipping. This creates a shorter dystrophin protein, similar to those expressed in the milder Becker muscular dystrophy (BMD). The skipping of some exons may be more efficacious than others. Patients with exon 44 or 45 skippable deletions (AOs in clinical development) have a less predictable phenotype than those skippable for exon 51, a group in advanced clinical trials. A way to predict the potential of AOs is the study of patients with BMD who have deletions that naturally mimic those that would be achieved by exon skipping. To quantify dystrophin messenger RNA (mRNA) and protein expression in patients with DMD deletions treatable by, or mimicking, exon 44 or 45 skipping. Retrospective study of nondystrophic controls (n = 2), patients with DMD (n = 5), patients with intermediate muscular dystrophy (n = 3), and patients with BMD (n = 13) at 4 university-based academic centers and pediatric hospitals. Biochemical analysis of existing muscle biopsies was correlated with the severity of the skeletal muscle phenotype. Dystrophin mRNA and protein expression. Patients with DMD who have out-of-frame deletions skippable for exon 44 or 45 had an elevated number of revertant and trace dystrophin expression (approximately 19% of control, using quantitative immunohistochemistry) with 4 of 9 patients presenting with an intermediate muscular dystrophy phenotype (3 patients) or a BMD-like phenotype (1 patient). Corresponding in-frame deletions presented with predominantly mild BMD phenotypes and lower dystrophin levels (approximately 42% of control) than patients with BMD modeling exon 51 skipping (approximately 80% of control). All 12 patients with in-frame deletions had a stable transcript compared with 2 of 9 patients with out-of-frame deletions (who had intermediate muscular dystrophy and BMD phenotypes). Exon

  4. Restoring dystrophin expression in duchenne muscular dystrophy muscle progress in exon skipping and stop codon read through.

    Science.gov (United States)

    Hoffman, Eric P; Bronson, Abby; Levin, Arthur A; Takeda, Shin'ichi; Yokota, Toshifumi; Baudy, Andreas R; Connor, Edward M

    2011-07-01

    The identification of the Duchenne muscular dystrophy gene and protein in the late 1980s led to high hopes of rapid translation to molecular therapeutics. These hopes were fueled by early reports of delivering new functional genes to dystrophic muscle in mouse models using gene therapy and stem cell transplantation. However, significant barriers have thwarted translation of these approaches to true therapies, including insufficient therapeutic material (eg, cells and viral vectors), challenges in systemic delivery, and immunological hurdles. An alternative approach is to repair the patient's own gene. Two innovative small-molecule approaches have emerged as front-line molecular therapeutics: exon skipping and stop codon read through. Both approaches are in human clinical trials and aim to coax dystrophin protein production from otherwise inactive mutant genes. In the clinically severe dog model of Duchenne muscular dystrophy, the exon-skipping approach recently improved multiple functional outcomes. We discuss the status of these two methods aimed at inducing de novo dystrophin production from mutant genes and review implications for other disorders. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. A splice site mutation in the PAX6 gene which induces exon skipping causes autosomal dominant inherited aniridia

    Science.gov (United States)

    Wissinger, Bernd; Gramer, Eugen

    2012-01-01

    Purpose To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia. Methods All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX6 variants in HEK293 cells. Results We identified a PAX6 sequence variant at the splice donor site (+5) of intron 12. This variant has been described before in another family with aniridia but has not been characterized at the transcript level. We could demonstrate that the mutant allele causes the skipping of exon 12 during transcript processing. The mutation is predicted to result in a ‘run on’ translation past the normal translational stop codon. Conclusions A splice site mutation resulting in exon skipping was found in a family with autosomal dominant aniridia. The mutation is predicted to result in an enlarged protein with an extra COOH-terminal domain. This very likely affects the transactivation properties of the PAX6 protein. PMID:22509105

  6. Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy.

    Science.gov (United States)

    Falzarano, Maria Sofia; Passarelli, Chiara; Ferlini, Alessandra

    2014-02-01

    Antisense therapy is a powerful tool for inducing post-transcriptional modifications and thereby regulating target genes associated with disease. There are several classes of antisense oligonucleotides (AONs) with therapeutic use, such as double-stranded RNAs (interfering RNAs, utilized for gene silencing, and single-stranded AONs with various chemistries, which are useful for antisense targeting of micro-RNAs and mRNAs. In particular, the use of AONs for exon skipping, by targeting pre-mRNA, is proving to be a highly promising therapy for some genetic disorders like Duchenne muscular dystrophy and spinal muscular atrophy. However, AONs are unable to cross the plasma membrane unaided, and several other obstacles still remain to be overcome, in particular their instability due to their nuclease sensitivity and their lack of tissue specificity. Various drug delivery systems have been explored to improve the bioavailability of nucleic acids, and nanoparticles (NPs) have been suggested as potential vectors for DNA/RNA. This review describes the recent progress in AON conjugation with natural and synthetic delivery systems, and provides an overview of the efficacy of NP-AON complexes as an exon-skipping treatment for Duchenne muscular dystrophy.

  7. Dynamics of co-transcriptional pre-mRNA folding influences the induction of dystrophin exon skipping by antisense oligonucleotides.

    Directory of Open Access Journals (Sweden)

    Keng Boon Wee

    Full Text Available Antisense oligonucleotides (AONs mediated exon skipping offers potential therapy for Duchenne muscular dystrophy. However, the identification of effective AON target sites remains unsatisfactory for lack of a precise method to predict their binding accessibility. This study demonstrates the importance of co-transcriptional pre-mRNA folding in determining the accessibility of AON target sites for AON induction of selective exon skipping in DMD. Because transcription and splicing occur in tandem, AONs must bind to their target sites before splicing factors. Furthermore, co-transcriptional pre-mRNA folding forms transient secondary structures, which redistributes accessible binding sites. In our analysis, to approximate transcription elongation, a "window of analysis" that included the entire targeted exon was shifted one nucleotide at a time along the pre-mRNA. Possible co-transcriptional secondary structures were predicted using the sequence in each step of transcriptional analysis. A nucleotide was considered "engaged" if it formed a complementary base pairing in all predicted secondary structures of a particular step. Correlation of frequency and localisation of engaged nucleotides in AON target sites accounted for the performance (efficacy and efficiency of 94% of 176 previously reported AONs. Four novel insights are inferred: (1 the lowest frequencies of engaged nucleotides are associated with the most efficient AONs; (2 engaged nucleotides at 3' or 5' ends of the target site attenuate AON performance more than at other sites; (3 the performance of longer AONs is less attenuated by engaged nucleotides at 3' or 5' ends of the target site compared to shorter AONs; (4 engaged nucleotides at 3' end of a short target site attenuates AON efficiency more than at 5' end.

  8. Adeno-Associated Virus (AAV) Mediated Dystrophin Gene Transfer Studies and Exon Skipping Strategies for Duchenne Muscular Dystrophy (DMD).

    Science.gov (United States)

    Kawecka, Klaudia; Theodoulides, Michael; Hasoglu, Yalin; Jarmin, Susan; Kymalainen, Hanna; Le-Heron, Anita; Popplewell, Linda; Malerba, Alberto; Dickson, George; Athanasopoulos, Takis

    2015-01-01

    Duchenne muscular dystrophy (DMD), an X-linked inherited musclewasting disease primarily affecting young boys with prevalence of between1:3,500- 1:5,000, is a rare genetic disease caused by defects in the gene for dystrophin. Dystrophin protein is critical to the stability of myofibers in skeletal and cardiac muscle. There is currently no cure available to ameliorate DMD and/or its patho-physiology. A number of therapeutic strategies including molecular-based therapeutics that replace or correct the missing or nonfunctional dystrophin protein have been devised to correct the patho-physiological consequences induced by dystrophin absence. We will review the current in vivo experimentation status (including preclinical models and clinical trials) for two of these approaches, namely: 1) Adeno-associated virus (AAV) mediated (micro) dystrophin gene augmentation/ supplementation and 2) Antisense oligonucleotide (AON)-mediated exon skipping strategies.

  9. A missense mutation in the APC tumor suppressor gene disrupts an ASF/SF2 splicing enhancer motif and causes pathogenic skipping of exon 14.

    Science.gov (United States)

    Gonçalves, Vânia; Theisen, Patrícia; Antunes, Ofélia; Medeira, Ana; Ramos, José Silva; Jordan, Peter; Isidro, Glória

    2009-03-09

    A missense mutation at codon 640 in the APC gene was identified in a familial adenomatous polyposis (FAP) patient, however, its pathological consequence remained unclear. Here we found that this missense mutation interferes at the nucleotide level with an exonic splicing regulatory element and leads to aberrant splicing of the mutant APC transcript rather than exerting its effect through the observed amino acid change. Analysis of the patient RNA revealed complete skipping of exon 14 in transcripts from the mutant APC allele, leading to a frameshift and a premature stop codon. When cloned into a splicing reporter minigene and transfected into colorectal cell lines, the exon 14 point mutation c.1918C>G (pR640G) was found sufficient to cause the observed exon skipping. Bioinformatic analysis predicted the mutation to change SRp55, hnRNP A1 or ASF/SF2 splicing factor binding sites. Using RNA interference methodology these predictions were experimentally validated and revealed that only ASF/SF2 was required for exon 14 inclusion. These research data identify APC mutation c.1918C>G (pR640G) as pathogenic and indicate a mechanism involving disruption of an ASF/SF2 exonic splicing enhancer element. The results allow genetic diagnosis of a hereditary tumour predisposition but also illustrate the need to complement in silico prediction by splicing reporter assays.

  10. Skipping of exon 30 in C5 gene results in complete human C5 deficiency and demonstrates the importance of C5d and CUB domains for stability.

    Science.gov (United States)

    Aguilar-Ramirez, P; Reis, E S; Florido, M P C; Barbosa, A S; Farah, C S; Costa-Carvalho, B T; Isaac, L

    2009-06-01

    The deficiency of complement C5 is rare and frequently associated with severe and recurrent infections, especially caused by Neisseria spp. We observed the absence of component C5 in the serum of 3 siblings from a Brazilian family with history of consanguinity. The patients had suffered from recurrent episodes of meningitis and other less severe infections. Sera from these patients were unable to mediate hemolytic activity either by the classical or alternative pathways and presented extremely low levels of C5 protein (1.3, 0.9 and 1.0 microg/ml-normal range: 45-190 microg/ml). Hemolytic activity could be restored by the addition of purified C5 to deficient serum. Sequencing of sibling C5 cDNA revealed a homozygous 153 bp deletion that corresponds precisely to exon 30. The parents carried the same deletion but only in one allele. Sequencing of the corresponding region in the genomic DNA revealed a C to G substitution within intron 30 and, most significantly, the substitution of GAG(4028) for GAA(4028) at the 3' end of exon 30 which is most likely responsible for skipping of exon 30. The resulting in-frame deletion in the C5 mRNA codes for a mutant C5 protein lacking residues 1289-1339. These residues map to the CUB and C5d domains of the C5 alpha chain. This deletion is expected to produce a non-functional and unstable C5 protein which is more susceptible to degradation.

  11. Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy.

    Science.gov (United States)

    Nakamura, Akinori; Fueki, Noboru; Shiba, Naoko; Motoki, Hirohiko; Miyazaki, Daigo; Nishizawa, Hitomi; Echigoya, Yusuke; Yokota, Toshifumi; Aoki, Yoshitsugu; Takeda, Shin'ichi

    2016-07-01

    Few cases of dystrophinopathy show an asymptomatic phenotype with mutations in the 5' (exons 3-7) hot spot in the Duchenne muscular dystrophy (DMD) gene. Our patient showed increased serum creatine kinase levels at 12 years of age. A muscle biopsy at 15 years of age led to a diagnosis of Becker muscular dystrophy. The patient showed a slight decrease in cardiac function at the age of 21 years and was administered a β-blocker, but there was no muscle involvement even at the age of 27 years. A deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene was detected, and dystrophin protein expression was ∼15% that of control level. We propose that in-frame deletion of exons 3-9 may produce a functional protein, and that multiexon skipping therapy targeting these exons may be feasible for severe dystrophic patients with a mutation in the 5' hot spot of the DMD gene.

  12. Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice

    OpenAIRE

    Sirsi Shashank R; Schray Rebecca C; Williams Jason H; Lutz Gordon J

    2008-01-01

    Abstract Background Exon skipping oligonucleotides (ESOs) of 2'O-Methyl (2'OMe) and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD). However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine) (PEI) and poly(ethylene glycol) (PEG) are regarded as effect...

  13. AAV genome loss from dystrophic mouse muscles during AAV-U7 snRNA-mediated exon-skipping therapy.

    Science.gov (United States)

    Le Hir, Maëva; Goyenvalle, Aurélie; Peccate, Cécile; Précigout, Guillaume; Davies, Kay E; Voit, Thomas; Garcia, Luis; Lorain, Stéphanie

    2013-08-01

    In the context of future adeno-associated viral (AAV)-based clinical trials for Duchenne myopathy, AAV genome fate in dystrophic muscles is of importance considering the viral capsid immunogenicity that prohibits recurring treatments. We showed that AAV genomes encoding non-therapeutic U7 were lost from mdx dystrophic muscles within 3 weeks after intramuscular injection. In contrast, AAV genomes encoding U7ex23 restoring expression of a slightly shortened dystrophin were maintained endorsing that the arrest of the dystrophic process is crucial for maintaining viral genomes in transduced fibers. Indeed, muscles treated with low doses of AAV-U7ex23, resulting in sub-optimal exon skipping, displayed much lower titers of viral genomes, showing that sub-optimal dystrophin restoration does not prevent AAV genome loss. We also followed therapeutic viral genomes in severe dystrophic dKO mice over time after systemic treatment with scAAV9-U7ex23. Dystrophin restoration decreased significantly between 3 and 12 months in various skeletal muscles, which was correlated with important viral genome loss, except in the heart. Altogether, these data show that the success of future AAV-U7 therapy for Duchenne patients would require optimal doses of AAV-U7 to induce substantial levels of dystrophin to stabilize the treated fibers and maintain the long lasting effect of the treatment.

  14. Identification of Splicing Factors Involved in DMD Exon Skipping Events Using an In Vitro RNA Binding Assay.

    Science.gov (United States)

    Miro, Julie; Bourgeois, Cyril F; Claustres, Mireille; Koenig, Michel; Tuffery-Giraud, Sylvie

    2018-01-01

    Mutation-induced exon skipping in the DMD gene can modulate the severity of the phenotype in patients with Duchenne or Becker Muscular Dystrophy. These alternative splicing events are most likely the result of changes in recruitment of splicing factors at cis-acting elements in the mutated DMD pre-mRNA. The identification of proteins involved can be achieved by an affinity purification procedure. Here, we provide a detailed protocol for the in vitro RNA binding assay that we routinely apply to explore molecular mechanisms underlying splicing defects in the DMD gene. In vitro transcribed RNA probes containing either the wild type or mutated sequence are oxidized and bound to adipic acid dihydrazide-agarose beads. Incubation with a nuclear extract allows the binding of nuclear proteins to the RNA probes. The unbound proteins are washed off and then the specifically RNA-bound proteins are released from the beads by an RNase treatment. After separation by SDS-PAGE, proteins that display differential binding affinities for the wild type and mutant RNA probes are identified by mass spectrometry.

  15. Analysis and Prediction of Exon Skipping Events from RNA-Seq with Sequence Information Using Rotation Forest

    Directory of Open Access Journals (Sweden)

    Xiuquan Du

    2017-12-01

    Full Text Available In bioinformatics, exon skipping (ES event prediction is an essential part of alternative splicing (AS event analysis. Although many methods have been developed to predict ES events, a solution has yet to be found. In this study, given the limitations of machine learning algorithms with RNA-Seq data or genome sequences, a new feature, called RS (RNA-seq and sequence features, was constructed. These features include RNA-Seq features derived from the RNA-Seq data and sequence features derived from genome sequences. We propose a novel Rotation Forest classifier to predict ES events with the RS features (RotaF-RSES. To validate the efficacy of RotaF-RSES, a dataset from two human tissues was used, and RotaF-RSES achieved an accuracy of 98.4%, a specificity of 99.2%, a sensitivity of 94.1%, and an area under the curve (AUC of 98.6%. When compared to the other available methods, the results indicate that RotaF-RSES is efficient and can predict ES events with RS features.

  16. A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population.

    Science.gov (United States)

    Gow, Chien-Hung; Hsieh, Min-Shu; Wu, Shang-Gin; Shih, Jin-Yuan

    2017-01-01

    Recurrent somatic splice-site alterations at MET exon 14 (MET(Δ14)), which result in exon skipping and MET proto-oncogene, receptor tyrosine kinase (MET) activation, have been characterised. However, their demographic features and clinical outcomes in East Asian lung cancer patients have yet to be determined. A one-step reverse transcription-polymerase chain reaction (RT-PCR), using RNA samples from 850 East Asian lung cancer patients, was performed in order to detect MET(Δ14) and five other major driver mutations, including those in the EGFR, KRAS, ALK, HER2, and ROS1 genes. Immunohistochemistry (IHC) was used to confirm the overexpression of MET in patients harbouring the MET(Δ14) mutation. We analysed the demographic data and clinical outcomes of MET(Δ14) mutation positive lung cancer patients and compared them to those of MET(Δ14) mutation negative lung cancer patients. In total, 27 lung adenocarcinoma (ADC) patients and 1 squamous cell carcinoma patient with the MET(Δ14) mutation were identified. The overall incidence was 3.3% for lung cancer and 4.0% for lung ADC. IHC demonstrated that the majority of lung cancer patients harboring a MET(Δ14) mutation exhibited a strong cytoplasmic expression of MET. MET(Δ14) mutation positive patients were generally quite elderly individuals. Stage IV MET(Δ14) mutation positive lung cancer patients receiving no specific anti-MET therapy were observed to have a similar overall survival (OS) compared to patients in the all negative group (P>0.05). In the multivariate analysis, mutation status was found not to be a major risk factor for OS in lung cancer patients without appropriate tyrosine kinase inhibitors treatment. The OS of MET(Δ14) mutation positive lung cancer patients is comparable to that of the major driver gene mutation negative lung cancer patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Ehlers-Danlos syndrome type VII: a single base change that causes exon skipping in the type I collagen alpha 2(I) chain.

    Science.gov (United States)

    Nicholls, A C; Oliver, J; Renouf, D V; McPheat, J; Palan, A; Pope, F M

    1991-06-01

    We have examined the procollagens and collagens produced by skin fibroblasts from a patient with Ehlers-Danlos syndrome type VII. The patient was heterozygous for an abnormal alpha 2(I) chain migrating with the approximate size of pN alpha 2(I) chains after pepsin digestion. Peptide mapping suggested that the abnormality was located at the amino-terminus of the alpha 2(I) chain. Quantitative analysis of the alpha 2(I) mRNA indicated loss of the exon 6 sequences, and subsequent polymerase chain reaction amplification of cDNA demonstrated a deletion of the 54 bp of exon 6 from some of the alpha 2(I) mRNA. Analysis of genomic DNA from the patient revealed a single base change in one COL1A2 allele, substituting an A for a G as the first base of intron 6. This change mutates the obligate GT-dinulceotide splicing signal to AT and leads to exon skipping with splicing from exon 5 to exon 7. Loss of exon 6 sequences results in the loss of the procollagen-N-propeptidase cleavage site and a lysine residue that normally participates in covalent intermolecular crosslinking within collagen fibres.

  18. Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice

    Directory of Open Access Journals (Sweden)

    Mingxing Wang

    2017-12-01

    Full Text Available We investigated a series of Tween 85 modified low molecular weight polyethylenimine (LPEI, 0.8k/1.2k/2.0k-copolymers (Zs through simple formulation and covalent conjugation with phosphorodiamidate morpholino oligomer (PMO for their potential to enhance delivery in vitro and in dystrophic mdx mice. Z polymers significantly enhanced PMO-induced exon-skipping in a GFP reporter-based cell culture system. Application of optimized formulations of Zs with PMO targeted to dystrophin exon 23 demonstrated a significant increase in exon-skipping efficiency in mdx mice. Consistent with our observations in vitro, optimization of molecular size and hydropholic-lipopholic balance (HLB of polymers are important factors to achieve enhanced PMO delivery in vivo. The best formulation of Zs enhanced PMO delivery with 20- and 6-fold over PMO alone in vitro and in vivo, respectively. Further, chemical conjugation of the polymer and PMO exhibits greater benefit than polymer/PMO simple formulation in PMO delivery efficiency. Observed cytotoxicity of the Zs was lower than Endo-porter and PEI 25k in vitro, and no tissue toxicity was clearly detected with the Zs at the dosage tested. These results indicate the potential of the Zs as effective and safe PMO delivery carriers for treating diseases such as muscular dystrophy.

  19. Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice.

    Science.gov (United States)

    Williams, Jason H; Schray, Rebecca C; Sirsi, Shashank R; Lutz, Gordon J

    2008-04-02

    Exon skipping oligonucleotides (ESOs) of 2'O-Methyl (2'OMe) and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD). However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine) (PEI) and poly(ethylene glycol) (PEG) are regarded as effective agents for enhanced delivery of nucleic acids in various applications. We examined whether PEG-PEI copolymers can facilitate ESO-mediated dystrophin expression after intramuscular injections into tibialis anterior (TA) muscles of mdx mice. We utilized a set of PEG-PEI copolymers containing 2 kDa PEI and either 550 Da or 5 kDa PEG, both of which bind 2'OMe ESOs with high affinity and form stable nanoparticulates with a relatively low surface charge. Three weekly intramuscular injections of 5 microg of ESO complexed with PEI2K-PEG550 copolymers resulted in about 500 dystrophin-positive fibers and about 12% of normal levels of dystrophin expression at 3 weeks after the initial injection, which is significantly greater than for injections of ESO alone, which are known to be almost completely ineffective. In an effort to enhance biocompatibility and cellular uptake, the PEI2K-PEG550 and PEI2K-PEG5K copolymers were functionalized by covalent conjugation with nanogold (NG) or adsorbtion of colloidal gold (CG), respectively. Surprisingly, using the same injection and dosing regimen, we found no significant difference in dystrophin expression by Western blot between the NG-PEI2K-PEG550, CG-PEI2K-PEG5K, and non-functionalized PEI2K-PEG550 copolymers. Dose-response experiments using the CG-PEI2K-PEG5K copolymer with total ESO ranging from 3-60 microg yielded a maximum of about 15% dystrophin expression. Further improvements in dystrophin expression up to 20% of normal levels were found at 6 weeks after

  20. Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice

    Directory of Open Access Journals (Sweden)

    Sirsi Shashank R

    2008-04-01

    Full Text Available Abstract Background Exon skipping oligonucleotides (ESOs of 2'O-Methyl (2'OMe and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD. However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine (PEI and poly(ethylene glycol (PEG are regarded as effective agents for enhanced delivery of nucleic acids in various applications. Results We examined whether PEG-PEI copolymers can facilitate ESO-mediated dystrophin expression after intramuscular injections into tibialis anterior (TA muscles of mdx mice. We utilized a set of PEG-PEI copolymers containing 2 kDa PEI and either 550 Da or 5 kDa PEG, both of which bind 2'OMe ESOs with high affinity and form stable nanoparticulates with a relatively low surface charge. Three weekly intramuscular injections of 5 μg of ESO complexed with PEI2K-PEG550 copolymers resulted in about 500 dystrophin-positive fibers and about 12% of normal levels of dystrophin expression at 3 weeks after the initial injection, which is significantly greater than for injections of ESO alone, which are known to be almost completely ineffective. In an effort to enhance biocompatibility and cellular uptake, the PEI2K-PEG550 and PEI2K-PEG5K copolymers were functionalized by covalent conjugation with nanogold (NG or adsorbtion of colloidal gold (CG, respectively. Surprisingly, using the same injection and dosing regimen, we found no significant difference in dystrophin expression by Western blot between the NG-PEI2K-PEG550, CG-PEI2K-PEG5K, and non-functionalized PEI2K-PEG550 copolymers. Dose-response experiments using the CG-PEI2K-PEG5K copolymer with total ESO ranging from 3–60 μg yielded a maximum of about 15% dystrophin expression. Further improvements in dystrophin expression up to 20% of normal

  1. Thousands of exon skipping events differentiate among splicing patterns in sixteen human tissues [v2; ref status: indexed, http://f1000r.es/2dl

    Directory of Open Access Journals (Sweden)

    Liliana Florea

    2013-11-01

    Full Text Available Alternative splicing is widely recognized for its roles in regulating genes and creating gene diversity. However, despite many efforts, the repertoire of gene splicing variation is still incompletely characterized, even in humans. Here we describe a new computational system, ASprofile, and its application to RNA-seq data from Illumina’s Human Body Map project (>2.5 billion reads.  Using the system, we identified putative alternative splicing events in 16 different human tissues, which provide a dynamic picture of splicing variation across the tissues. We detected 26,989 potential exon skipping events representing differences in splicing patterns among the tissues. A large proportion of the events (>60% were novel, involving new exons (~3000, new introns (~16000, or both. When tracing these events across the sixteen tissues, only a small number (4-7% appeared to be differentially expressed (‘switched’ between two tissues, while 30-45% showed little variation, and the remaining 50-65% were not present in one or both tissues compared.  Novel exon skipping events appeared to be slightly less variable than known events, but were more tissue-specific. Our study represents the first effort to build a comprehensive catalog of alternative splicing in normal human tissues from RNA-seq data, while providing insights into the role of alternative splicing in shaping tissue transcriptome differences. The catalog of events and the ASprofile software are freely available from the Zenodo repository (http://zenodo.org/record/7068; doi:10.5281/zenodo.7068 and from our web site http://ccb.jhu.edu/software/ASprofile.

  2. Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping

    DEFF Research Database (Denmark)

    Madsen, Pia Pinholt; Kibæk, Maria; Roca, Xavier

    2006-01-01

    /MS currently lacks sensitivity in detecting SBCADD. Until now, seven mutations in the SBCAD gene have been reported, but only three have been tested experimentally. Here, we identify and characterize an IVS3+3A>G mutation (c.303+3A>G) in the SBCAD gene, and provide evidence that this mutation is disease......>G) induces missplicing only when in the context of non-consensus (weak) 5' splice sites. Statistical analysis of the sequences shows that the wild-type versions of 5' splice sites in which +3A>G mutations cause exon skipping and disease are weaker on average than a random set of 5' splice sites. This finding...... is relevant to the interpretation of the functional consequences of this type of mutation in other disease genes....

  3. Bottom-up design of small molecules that stimulate exon 10 skipping in mutant MAPT pre-mRNA.

    Science.gov (United States)

    Luo, Yiling; Disney, Matthew D

    2014-09-22

    One challenge in chemical biology is to develop small molecules that control cellular protein content. The amount and identity of proteins are influenced by the RNAs that encode them; thus, protein content in a cell could be affected by targeting mRNA. However, RNA has been traditionally difficult to target with small molecules. In this report, we describe controlling the protein products of the mutated microtubule-associated protein tau (MAPT) mature mRNA with a small molecule. MAPT mutations in exon 10 are associated with inherited frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), an incurable disease that is directly caused by increased inclusion of exon 10 in MAPT mRNA. Recent studies have shown that mutations within a hairpin at the MAPT exon 10-intron junction decrease the thermodynamic stability of the RNA, increasing binding to U1 snRNP and thus exon 10 inclusion. Therefore, we designed small molecules that bind and stabilize a mutant MAPT by using Inforna, a computational approach based on information about RNA-small-molecule interactions. The optimal compound selectively bound the mutant MAPT hairpin and thermodynamically stabilized its folding, facilitating exon 10 exclusion. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. First Exon Length Controls Active Chromatin Signatures and Transcription

    Directory of Open Access Journals (Sweden)

    Nicole I. Bieberstein

    2012-07-01

    Full Text Available Here, we explore the role of splicing in transcription, employing both genome-wide analysis of human ChIP-seq data and experimental manipulation of exon-intron organization in transgenic cell lines. We show that the activating histone modifications H3K4me3 and H3K9ac map specifically to first exon-intron boundaries. This is surprising, because these marks help recruit general transcription factors (GTFs to promoters. In genes with long first exons, promoter-proximal levels of H3K4me3 and H3K9ac are greatly reduced; consequently, GTFs and RNA polymerase II are low at transcription start sites (TSSs and exhibit a second, promoter-distal peak from which transcription also initiates. In contrast, short first exons lead to increased H3K4me3 and H3K9ac at promoters, higher expression levels, accuracy in TSS usage, and a lower frequency of antisense transcription. Therefore, first exon length is predictive for gene activity. Finally, splicing inhibition and intron deletion reduce H3K4me3 levels and transcriptional output. Thus, gene architecture and splicing determines transcription quantity and quality as well as chromatin signatures.

  5. Dystrophin rescue by trans-splicing: a strategy for DMD genotypes not eligible for exon skipping approaches.

    Science.gov (United States)

    Lorain, Stéphanie; Peccate, Cécile; Le Hir, Maëva; Griffith, Graziella; Philippi, Susanne; Précigout, Guillaume; Mamchaoui, Kamel; Jollet, Arnaud; Voit, Thomas; Garcia, Luis

    2013-09-01

    RNA-based therapeutic approaches using splice-switching oligonucleotides have been successfully applied to rescue dystrophin in Duchenne muscular dystrophy (DMD) preclinical models and are currently being evaluated in DMD patients. Although the modular structure of dystrophin protein tolerates internal deletions, many mutations that affect nondispensable domains of the protein require further strategies. Among these, trans-splicing technology is particularly attractive, as it allows the replacement of any mutated exon by its normal version as well as introducing missing exons or correcting duplication mutations. We have applied such a strategy in vitro by using cotransfection of pre-trans-splicing molecule (PTM) constructs along with a reporter minigene containing part of the dystrophin gene harboring the stop-codon mutation found in the mdx mouse model of DMD. Optimization of the different functional domains of the PTMs allowed achieving accurate and efficient trans-splicing of up to 30% of the transcript encoded by the cotransfected minigene. Optimized parameters included mRNA stabilization, choice of splice site sequence, inclusion of exon splice enhancers and artificial intronic sequence. Intramuscular delivery of adeno-associated virus vectors expressing PTMs allowed detectable levels of dystrophin in mdx and mdx4Cv, illustrating that a given PTM can be suitable for a variety of mutations.

  6. An Intronic SINE insertion in FAM161A that causes exon-skipping is associated with progressive retinal atrophy in Tibetan Spaniels and Tibetan Terriers.

    Directory of Open Access Journals (Sweden)

    Louise M Downs

    Full Text Available Progressive retinal atrophy (PRA in dogs is characterised by the degeneration of the photoreceptor cells of the retina, resulting in vision loss and eventually complete blindness. The condition affects more than 100 dog breeds and is known to be genetically heterogeneous between breeds. Around 19 mutations have now been identified that are associated with PRA in around 49 breeds, but for the majority of breeds the mutation(s responsible have yet to be identified. Using genome-wide association with 22 Tibetan Spaniel PRA cases and 10 controls, we identified a novel PRA locus, PRA3, on CFA10 (p(raw = 2.01 × 10(-5, p(genome = 0.014, where a 3.8 Mb region was homozygous within 12 cases. Using targeted next generation sequencing, a short interspersed nuclear element insertion was identified near a splice acceptor site in an intron of a provocative gene, FAM161A. Analysis of mRNA from an affected dog revealed that the SINE causes exon skipping, resulting in a frame shift, leading to a downstream premature termination codon and possibly a truncated protein product. This mutation segregates with the disease in 22 out of 35 cases tested (63%. Of the PRA controls, none are homozygous for the mutation, 15% carry the mutation and 85% are homozygous wildtype. This mutation was also identified in Tibetan Terriers, although our results indicate that PRA is genetically heterogeneous in both Tibetan Spaniels and Tibetan Terriers.

  7. An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.

    Science.gov (United States)

    Mosegaard, Signe; Bruun, Gitte Hoffmann; Flyvbjerg, Karen Freund; Bliksrud, Yngve Thomas; Gregersen, Niels; Dembic, Maja; Annexstad, Ellen; Tangeraas, Trine; Olsen, Rikke Katrine Jentoft; Andresen, Brage S

    2017-11-02

    Vitamin B2, riboflavin is essential for cellular function, as it participates in a diversity of redox reactions central to human metabolism, through its role as precursor for the cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are electron carriers. The electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH), uses FAD as cofactor. The ETF and ETFDH are forming the electron transport pathway for many mitochondrial flavoprotein dehydrogenases involved in fatty acid, amino acid and choline metabolism. A variation in either ETF or ETFDH causes multiple acyl-CoA dehydrogenation deficiency (MADD), but genetic variations in the riboflavin metabolism or transportation of riboflavin can also cause MADD. The most common variations are located in the riboflavin transporter 2 (RFVT2) and 3 (RFVT3), that are highly expressed in brain and intestinal tissues, respectively. Deficiency of riboflavin transporter 1 (RFVT1), encoded by the SLC52A1 gene, highly expressed in the placenta, has only been reported once. We here report a case of transient MADD, caused by a heterozygous intronic variation, c.1134+11G>A, in the SLC52A1 gene encoding RFVT1. This variation creates a binding site for the splice inhibitory hnRNP A1 protein and causes exon 4 skipping. Riboflavin deficiency and maternal malnutrition during pregnancy might have been the determining factor in the outcome of this case. Copyright © 2017. Published by Elsevier Inc.

  8. Comparison between gentamycin and exon skipping treatments to restore ryanodine receptor subtype 2 functions in mdx mouse duodenum myocytes.

    Science.gov (United States)

    Dabertrand, Fabrice; Mironneau, Jean; Henaff, Morgana; Macrez, Nathalie; Morel, Jean-Luc

    2010-02-25

    In Duchenne muscular dystrophy, a stop-codon mutation in the dystrophin gene induces an impairment of skeletal and smooth muscles contraction. In duodenum from mdx mouse, the disease model, the decrease of contractility was linked with the decrease of calcium signals encoded by ryanodine receptor subtype 2. Aminoglycoside and antisense oligonucleotide strategies were investigated to restore calcium signalling in the mdx mouse. Mdx mice were treated by intraperitoneal injection of gentamycin or 2-O-methyl antisense ribonucleotide directed against exon 23 of dystrophin for 2 weeks. The efficiency of both therapeutic strategies was determined by the level of dystrophin protein expression. The physiological effects of both treatments on ryanodine receptor expression and function were followed by RT-PCR, western blot and calcium measurements. Fourteen days after injection of gentamycin or anti-dystrophin antisense, the expression of dystrophin was recovered in skeletal muscle from treated mdx mice. In duodenum cells, RT-PCR and western blot indicated that the expression of ryanodine receptor subtype 2 was similar in treated mice than in control mice in association with the recovery of caffeine-induced Ca(2+) response. No significant difference was observed in the ryanodine subtype 3-dependent spontaneous Ca(2+) oscillations in untreated and treated mice. Conclusions - these results may help to explain the efficiency of aminoglycoside and anti-dystrophin antisense treatments in smooth muscle. Both treatments could be an interesting therapeutic option to restore smooth muscle contraction in patients with Duchenne muscular dystrophy.

  9. Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Alberto Malerba

    2012-01-01

    Full Text Available The knockdown of myostatin, a negative regulator of skeletal muscle mass may have important implications in disease conditions accompanied by muscle mass loss like cancer, HIV/AIDS, sarcopenia, muscle atrophy, and Duchenne muscular dystrophy (DMD. In DMD patients, where major muscle loss has occurred due to a lack of dystrophin, the therapeutic restoration of dystrophin expression alone in older patients may not be sufficient to restore the functionality of the muscles. We recently demonstrated that phosphorodiamidate morpholino oligomers (PMOs can be used to re-direct myostatin splicing and promote the expression of an out-of-frame transcript so reducing the amount of the synthesized myostatin protein. Furthermore, the systemic administration of the same PMO conjugated to an octaguanidine moiety (Vivo-PMO led to a significant increase in the mass of soleus muscle of treated mice. Here, we have further optimized the use of Vivo-PMO in normal mice and also tested the efficacy of the same PMO conjugated to an arginine-rich cell-penetrating peptide (B-PMO. Similar experiments conducted in mdx dystrophic mice showed that B-PMO targeting myostatin is able to significantly increase the tibialis anterior (TA muscle weight and when coadministered with a B-PMO targeting the dystrophin exon 23, it does not have a detrimental interaction. This study confirms that myostatin knockdown by exon skipping is a potential therapeutic strategy to counteract muscle wasting conditions and dual myostatin and dystrophin skipping has potential as a therapy for DMD.

  10. Splicing defects in ABCD1 gene leading to both exon skipping and partial intron retention in X-linked adrenoleukodystrophy Tunisian patient.

    Science.gov (United States)

    Kallabi, Fakhri; Hadj Salem, Ikhlass; Ben Chehida, Amel; Ben Salah, Ghada; Ben Turkia, Hadhami; Tebib, Neji; Keskes, Leila; Kamoun, Hassen

    2015-08-01

    X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and adrenal cortex secondary to mutations in the ABCD1 gene that encodes a peroxisomal membrane protein: the adrenoleukodystrophy protein. The disease is characterized by high concentrations of very long-chain fatty acids in plasma, adrenal, testicular and nervous tissues. Various types of mutations have been identified in the ABCD1 gene: point mutations, insertions, and deletions. To date, more than 40 point mutations have been reported at the splice junctions of the ABCD1 gene; only few functional studies have been performed to explore these types of mutations. In this study, we have identified de novo splice site mutation c.1780+2T>G in ABCD1 gene in an X-ALD Tunisian patient. Sequencing analysis of cDNA showed a minor transcript lacking exon 7 and a major transcript with a partial intron 7 retention due to activation of a new intronic cryptic splice site. Both outcomes lead to frameshifts with premature stop codon generation in exon 8 and intron 7 respectively. To the best of our knowledge, the current study demonstrates that a single splicing mutation affects the ABCD1 transcripts and the ALDP protein function. Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  11. A novel point mutation (G[sup [minus]1] to T) in a 5[prime] splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker Muscular Dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Hagiwara, Yoko; Nishio, Hisahide; Kitoh, Yoshihiko; Takeshima, Yasuhiro; Narita, Naoko; Wada, Hiroko; Yokoyama, Mitsuhiro; Nakamura, Hajime; Matsuo, Masafumi (Kobe Univ. School of Medicine (Japan))

    1994-01-01

    The mutations in one-third of Duchenne and Becker muscular dystrophy patients remain unknown, as they do not involve gross rearrangements of the dystrophin gene. The authors now report a defect in the splicing of precursor mRNA (pre-mRNA), resulting from a maternally inherited mutation of the dystrophin gene in a patient with Becker muscular dystrophy. This defect results from a G-to-T transversion at the terminal nucleotide of exon 13, within the 5[prime] splice site of intron 13, and causes complete skipping of exon 13 during processing of dystrophin pre-mRNA. The predicted polypeptide encoded by the aberrant mRNA is a truncated dystrophin lacking 40 amino acids from the amino-proximal end of the rod domain. This is the first report of an intraexon point mutation that completely inactivates a 5[prime] splice donor site in dystrophin pre-mRNA. Analysis of the genomic context of the G[sup [minus]1]-to-T mutation at the 5[prime] splice site supports the exon-definition model of pre-mRNA splicing and contributes to the understanding of splice-site selection. 48 refs., 5 figs.

  12. An Exon-Specific U1snRNA Induces a Robust Factor IX Activity in Mice Expressing Multiple Human FIX Splicing Mutants

    Directory of Open Access Journals (Sweden)

    Dario Balestra

    2016-01-01

    Full Text Available In cellular models we have demonstrated that a unique U1snRNA targeting an intronic region downstream of a defective exon (Exon-specific U1snRNA, ExSpeU1 can rescue multiple exon-skipping mutations, a relevant cause of genetic disease. Here, we explored in mice the ExSpeU1 U1fix9 toward two model Hemophilia B-causing mutations at the 5′ (c.519A > G or 3′ (c.392-8T > G splice sites of F9 exon 5. Hydrodynamic injection of wt-BALB/C mice with plasmids expressing the wt and mutant (hFIX-2G5′ss and hFIX-8G3′ss splicing-competent human factor IX (hFIX cassettes resulted in the expression of hFIX transcripts lacking exon 5 in liver, and in low plasma levels of inactive hFIX. Coinjection of U1fix9, but not of U1wt, restored exon inclusion of variants and in the intrinsically weak FIXwt context. This resulted in appreciable circulating hFIX levels (mean ± SD; hFIX-2G5′ss, 1.0 ± 0.5 µg/ml; hFIX-8G3′ss, 1.2 ± 0.3 µg/ml; and hFIXwt, 1.9 ± 0.6 µg/ml, leading to a striking shortening (from ≃100 seconds of untreated mice to ≃80 seconds of FIX-dependent coagulation times, indicating a hFIX with normal specific activity. This is the first proof-of-concept in vivo that a unique ExSpeU1 can efficiently rescue gene expression impaired by distinct exon-skipping variants, which extends the applicability of ExSpeU1s to panels of mutations and thus cohort of patients.

  13. Alternative splicing regulation of APP exon 7 by RBFox proteins.

    Science.gov (United States)

    Alam, Shafiul; Suzuki, Hitoshi; Tsukahara, Toshifumi

    2014-12-01

    RBFox proteins are well-known alternative splicing regulators. We have shown previously that during neuronal differentiation of P19 cells induced by all-trans retinoic acid and cell aggregation, RBFox1 shows markedly increased temporal expression. To find its key splicing regulation, we examined the effect of RBFox1 on 33 previously reported and validated neuronal splicing events of P19 cells. We observed that alternative splicing of three genes, specifically, amyloid precursor protein (APP), disks large homolog 3 (DLG3), and G protein, alpha activating activity polypeptide O (GNAO1), was altered by transient RBFox1 expression in HEK293 and HeLa cells. Moreover, an RBFox1 mutant (RBFox1FA) that was unable to bind the target RNA sequence ((U)GCAUG) did not induce these splicing events. APP generates amyloid beta peptides that are involved in the pathology of Alzheimer's disease, and therefore we examined APP alternative splicing regulation by RBFox1 and other splicing regulators. Our results indicated that RBFox proteins promote the skipping of APP exon 7, but not the inclusion of exon 8. We made APP6789 minigenes and observed that two (U)GCAUG sequences, located upstream of exon 7 and in exon 7, functioned to induce skipping of exon 7 by RBFox proteins. Overall, RBFox proteins may shift APP from exon 7 containing isoforms, APP770 and APP751, toward the exon 7 lacking isoform, APP695, which is predominant in neural tissues. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome.

    Science.gov (United States)

    Masuda, Akio; Shen, Xin-Ming; Ito, Mikako; Matsuura, Tohru; Engel, Andrew G; Ohno, Kinji

    2008-12-15

    In humans and great apes, CHRNA1 encoding the muscle nicotinic acetylcholine receptor alpha subunit carries an inframe exon P3A, the inclusion of which yields a nonfunctional alpha subunit. In muscle, the P3A(-) and P3A(+) transcripts are generated in a 1:1 ratio but the functional significance and regulation of the alternative splicing remain elusive. An intronic mutation (IVS3-8G>A), identified in a patient with congenital myasthenic syndrome, disrupts an intronic splicing silencer (ISS) and results in exclusive inclusion of the downstream P3A exon. We found that the ISS-binding splicing trans-factor was heterogeneous nuclear ribonucleoprotein (hnRNP) H and the mutation attenuated the affinity of hnRNP for the ISS approximately 100-fold. We next showed that direct placement of hnRNP H to the 3' end of intron 3 silences, and siRNA-mediated downregulation of hnRNP H enhances recognition of exon P3A. Analysis of the human genome suggested that the hnRNPH-binding UGGG motif is overrepresented close to the 3' ends of introns. Pursuing this clue, we showed that alternative exons of GRIP1, FAS, VPS13C and NRCAM are downregulated by hnRNP H. Our findings imply that the presence of the hnRNP H-binding motif close to the 3' end of an intron is an essential but underestimated splicing regulator of the downstream exon.

  15. Stemcell Information: SKIP000190 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000190 ... Diseased GM23717 GM23717 ... 先天性筋ジストロフィー G712 MUSCULAR DYSTROPHY, C...delAG); paternal allele: 7732C>T in exon 55 resulting prematire stop at codon 2578 (R2578X) 先天性筋ジストロフィー

  16. TAT gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II; characterization of a silent exonic transversion that causes complete missplicing by exon 11 skipping

    DEFF Research Database (Denmark)

    Maydan, G; Andresen, Brage Storstein; Madsen, Pia Pinholt

    2006-01-01

    therefore seek prenatal diagnosis, but this is not possible by biochemical assays as tyrosine does not accumulate in amniotic fluid and TAT is not expressed in chorionic villi or amniocytes. Molecular analysis is therefore the only possible approach for prenatal diagnosis and carrier detection. To this end....... Homozygosity for a c.1249C > T (R417X) exon 12 nonsense mutation (previously reported in a French patient) was identified in both patients from the third kindred, enabling successful prenatal diagnosis of an unaffected fetus using chorionic villous tissue....

  17. Gaucher disease: A G[sup +1][yields]A[sup +1] IVS2 splice donor site mutation causing exon 2 skipping in the acid [beta]-glucosidase mRNA

    Energy Technology Data Exchange (ETDEWEB)

    He, Guo-Shun (Mount Siani School of Medicine, New York, NY (United States)); Grabowski, G.A. (Children' s Hospital Medical Center, Cincinnati, OH (United States))

    1992-10-01

    Gaucher disease is the most frequent lysosomal storage disease and the most prevalent Jewish genetic disease. About 30 identified missense mutations are causal to the defective activity of acid [beta]-glucosidase in this disease. cDNAs were characterized from a moderately affected 9-year-old Ashkenazi Jewish Gaucher disease type 1 patient whose 80-years-old, enzyme-deficient, 1226G (Asn[sup 370][yields]Ser [N370S]) homozygous grandfather was nearly asymptomatic. Sequence analyses revealed four populations of cDNAs with either the 1226G mutation, an exact exon 2 ([Delta] EX2) deletion, a deletion of exon 2 and the first 115 bp of exon 3 ([Delta] EX2-3), or a completely normal sequence. About 50% of the cDNAs were the [Delta] EX2, the [Delta] EX2-3, and the normal cDNAs, in a ratio of 6:3:1. Specific amplification and characterization of exon 2 and 5[prime] and 3[prime] intronic flanking sequences from the structural gene demonstrated clones with either the normal sequence or with a G[sup +1][yields]A[sup +1] transition at the exon 2/intron 2 boundary. This mutation destroyed the splice donor consensus site (U1 binding site) for mRNA processing. This transition also was present at the corresponding exon/intron boundary of the highly homologous pseudogene. This new mutation, termed [open quotes]IVS2 G[sup +1],[close quotes] is the first in the Ashkenazi Jewish population. The occurrence of this [open quotes]pseudogene[close quotes]-type mutation in the structural gene indicates the role of acid [beta]-glucosidase pseudogene and structural gene rearrangements in the pathogenesis of this disease. 33 refs., 8 figs., 1 tab.

  18. Exon silencing by UAGG motifs in response to neuronal excitation.

    Directory of Open Access Journals (Sweden)

    Ping An

    2007-02-01

    Full Text Available Alternative pre-mRNA splicing plays fundamental roles in neurons by generating functional diversity in proteins associated with the communication and connectivity of the synapse. The CI cassette of the NMDA R1 receptor is one of a variety of exons that show an increase in exon skipping in response to cell excitation, but the molecular nature of this splicing responsiveness is not yet understood. Here we investigate the molecular basis for the induced changes in splicing of the CI cassette exon in primary rat cortical cultures in response to KCl-induced depolarization using an expression assay with a tight neuron-specific readout. In this system, exon silencing in response to neuronal excitation was mediated by multiple UAGG-type silencing motifs, and transfer of the motifs to a constitutive exon conferred a similar responsiveness by gain of function. Biochemical analysis of protein binding to UAGG motifs in extracts prepared from treated and mock-treated cortical cultures showed an increase in nuclear hnRNP A1-RNA binding activity in parallel with excitation. Evidence for the role of the NMDA receptor and calcium signaling in the induced splicing response was shown by the use of specific antagonists, as well as cell-permeable inhibitors of signaling pathways. Finally, a wider role for exon-skipping responsiveness is shown to involve additional exons with UAGG-related silencing motifs, and transcripts involved in synaptic functions. These results suggest that, at the post-transcriptional level, excitable exons such as the CI cassette may be involved in strategies by which neurons mount adaptive responses to hyperstimulation.

  19. A founder synonymous COL7A1 mutation in three Danish families with dominant dystrophic epidermolysis bullosa pruriginosa identifies exonic regulatory sequences required for exon 87 splicing

    DEFF Research Database (Denmark)

    Covaciu, C; Grosso, F; Pisaneschi, E

    2011-01-01

    shoulders. DEB-Pr is caused by either dominant (DDEB-Pr) or recessive mutations in the COL7A1 gene encoding type VII collagen (COLVII). The full spectrum of COL7A1 mutations in DEB-Pr remains elusive and the genotype-phenotype correlation is largely incomplete. Here, we report and functionally characterize...... a previously unrecognized translationally silent exonic COL7A1 mutation that results in skipping of exon 87 and is associated with DDEB-Pr phenotypes in several members of three apparently unrelated Danish families. A haplotype segregation study suggested a common ancestor in these kindred. Functional splicing...... analysis of the mutant exon by a COL7A1 minigene construct and computational prediction for splicing regulatory cis-sequences prove that the mutation alters the activity of an exonic splicing enhancer (ESE) critical for exon inclusion. These findings substantiate for the first time the involvement...

  20. Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice.

    Science.gov (United States)

    Lu-Nguyen, Ngoc; Malerba, Alberto; Popplewell, Linda; Schnell, Fred; Hanson, Gunnar; Dickson, George

    2017-03-17

    Antisense-mediated exon skipping is a promising approach for the treatment of Duchenne muscular dystrophy (DMD), a rare life-threatening genetic disease due to dystrophin deficiency. Such an approach can restore the disrupted reading frame of dystrophin pre-mRNA, generating a truncated form of the protein. Alternatively, antisense therapy can be used to induce destructive exon skipping of myostatin pre-mRNA, knocking down myostatin expression to enhance muscle strength and reduce fibrosis. We have reported previously that intramuscular or intraperitoneal antisense administration inducing dual exon skipping of dystrophin and myostatin pre-mRNAs was beneficial in mdx mice, a mouse model of DMD, although therapeutic effects were muscle type restricted, possibly due to the delivery routes used. Here, following systemic intravascular antisense treatment, muscle strength and body activity of treated adult mdx mice increased to the levels of healthy controls. Importantly, hallmarks of muscular dystrophy were greatly improved in mice receiving the combined exon-skipping therapy, as compared to those receiving dystrophin antisense therapy alone. Our results support the translation of antisense therapy for dystrophin restoration and myostatin inhibition into the clinical setting for DMD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Stemcell Information: SKIP000838 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... 50-59 Male ... Yes No TPB27(DNAVEC) is iPSC line reprogrammed from a Parkinson disease patient's T-cells, wh... SKIP000838 ... Diseased TPB27 (DNAVEC) TPB27 (DNAVEC) ... 家族性パーキンソン病 ... G20 ... ...ich deleated exon 6 and 7 in parkin gene.DNAVEC: SeV vectors, which were produced by DNAVEC Corp.(Cytotune). パーキンソン

  2. Stemcell Information: SKIP000835 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 50-59 Male ... Yes No TPB4(DNAVEC) is iPSC line reprogrammed from a Parkinson disease patient's T-cells, which... SKIP000835 ... Diseased TPB4 (DNAVEC) TPB4 (DNAVEC) ... 家族性パーキンソン病 ... G20 ... ... deleated exon 6 and 7 in parkin gene.DNAVEC: SeV vectors, which were produced by DNAVEC Corp.(Cytotune). パーキンソン

  3. Stemcell Information: SKIP000836 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 50-59 Male ... Yes No TPB8(DNAVEC) is iPSC line reprogrammed from a Parkinson disease patient's T-cells, which... SKIP000836 ... Diseased TPB8 (DNAVEC) TPB8 (DNAVEC) ... 家族性パーキンソン病 ... G20 ... ... deleated exon 6 and 7 in parkin gene.DNAVEC: SeV vectors, which were produced by DNAVEC Corp.(Cytotune). パーキンソン

  4. Stemcell Information: SKIP000837 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... 50-59 Male ... Yes No TPB11(DNAVEC) is iPSC line reprogrammed from a Parkinson disease patient's T-cells, wh... SKIP000837 ... Diseased TPB11 (DNAVEC) TPB11 (DNAVEC) ... 家族性パーキンソン病 ... G20 ... ...ich deleated exon 6 and 7 in parkin gene.DNAVEC: SeV vectors, which were produced by DNAVEC Corp.(Cytotune). パーキンソン

  5. Exonization of active mouse L1s: a driver of transcriptome evolution?

    Directory of Open Access Journals (Sweden)

    Badge Richard

    2007-10-01

    Full Text Available Abstract Background Long interspersed nuclear elements (LINE-1s, L1s have been recently implicated in the regulation of mammalian transcriptomes. Results Here, we show that members of the three active mouse L1 subfamilies (A, GF and TF contain, in addition to those on their sense strands, conserved functional splice sites on their antisense strands, which trigger multiple exonization events. The latter is particularly intriguing in the light of the strong antisense orientation bias of intronic L1s, implying that the toleration of antisense insertions results in an increased potential for exonization. Conclusion In a genome-wide analysis, we have uncovered evidence suggesting that the mobility of the large number of retrotransposition-competent mouse L1s (~2400 potentially active L1s in NCBIm35 has significant potential to shape the mouse transcriptome by continuously generating insertions into transcriptional units.

  6. Rat tenascin-R gene: structure, chromosome location and transcriptional activity of promoter and exon 1.

    Science.gov (United States)

    Leprini, A; Gherzi, R; Vecchi, E; Borsi, L; Zardi, L; Siri, A

    1998-01-01

    Tenascin-R is an extracellular matrix protein expressed exclusively in the central nervous system where it is thought to play a relevant role in regulating neurite outgrowth. We have i) cloned the cDNA of the rat tenascin-R 5' region; ii) defined its genomic organization, obtaining the sequence of two novel untranslated exons; iii) mapped the gene to rat chromosome 13q23 and suggested a previously unreported synteny between rat chromosome 13q23, human chromosome 1q24, and mouse chromosome 4E; and iv) sequenced and characterized the elements responsible for its neural cell-restricted transcription. We found that two discrete regions of the rat gene (the first in the proximal promoter, the second in the first exon) are independently able to activate to a high degree the transcription of a reporter gene in either human or rat neuroblastoma cell lines but not in other cell lines. Based on this observation, we re-evaluated the arrangement of transcriptionally active regions in the human tenascin-R gene we recently cloned and found that the human gene also contains an exon sequence able to initiate and sustain transcription independently of promoter sequences.

  7. Splicing of designer exons informs a biophysical model for exon definition.

    Science.gov (United States)

    Arias, Mauricio A; Lubkin, Ashira; Chasin, Lawrence A

    2015-02-01

    Pre-mRNA molecules in humans contain mostly short internal exons flanked by longer introns. To explain the removal of such introns, exon recognition instead of intron recognition has been proposed. We studied this exon definition using designer exons (DEs) made up of three prototype modules of our own design: an exonic splicing enhancer (ESE), an exonic splicing silencer (ESS), and a Reference Sequence (R) predicted to be neither. Each DE was examined as the central exon in a three-exon minigene. DEs made of R modules showed a sharp size dependence, with exons shorter than 14 nt and longer than 174 nt splicing poorly. Changing the strengths of the splice sites improved longer exon splicing but worsened shorter exon splicing, effectively displacing the curve to the right. For the ESE we found, unexpectedly, that its enhancement efficiency was independent of its position within the exon. For the ESS we found a step-wise positional increase in its effects; it was most effective at the 3' end of the exon. To apply these results quantitatively, we developed a biophysical model for exon definition of internal exons undergoing cotranscriptional splicing. This model features commitment to inclusion before the downstream exon is synthesized and competition between skipping and inclusion fates afterward. Collision of both exon ends to form an exon definition complex was incorporated to account for the effect of size; ESE/ESS effects were modeled on the basis of stabilization/destabilization. This model accurately predicted the outcome of independent experiments on more complex DEs that combined ESEs and ESSs. © 2015 Arias et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  8. Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2β in development.

    Directory of Open Access Journals (Sweden)

    Sushma Grellscheid

    2011-12-01

    Full Text Available Alternative splicing amplifies the information content of the genome, creating multiple mRNA isoforms from single genes. The evolutionarily conserved splicing activator Tra2β (Sfrs10 is essential for mouse embryogenesis and implicated in spermatogenesis. Here we find that Tra2β is up-regulated as the mitotic stem cell containing population of male germ cells differentiate into meiotic and post-meiotic cells. Using CLIP coupled to deep sequencing, we found that Tra2β binds a high frequency of exons and identified specific G/A rich motifs as frequent targets. Significantly, for the first time we have analysed the splicing effect of Sfrs10 depletion in vivo by generating a conditional neuronal-specific Sfrs10 knock-out mouse (Sfrs10(fl/fl; Nestin-Cre(tg/+. This mouse has defects in brain development and allowed correlation of genuine physiologically Tra2β regulated exons. These belonged to a novel class which were longer than average size and importantly needed multiple cooperative Tra2β binding sites for efficient splicing activation, thus explaining the observed splicing defects in the knockout mice. Regulated exons included a cassette exon which produces a meiotic isoform of the Nasp histone chaperone that helps monitor DNA double-strand breaks. We also found a previously uncharacterised poison exon identifying a new pathway of feedback control between vertebrate Tra2 proteins. Both Nasp-T and the Tra2a poison exon are evolutionarily conserved, suggesting they might control fundamental developmental processes. Tra2β protein isoforms lacking the RRM were able to activate specific target exons indicating an additional functional role as a splicing co-activator. Significantly the N-terminal RS1 domain conserved between flies and humans was essential for the splicing activator function of Tra2β. Versions of Tra2β lacking this N-terminal RS1 domain potently repressed the same target exons activated by full-length Tra2β protein.

  9. PNA-mediated modulation and redirection of Her-2 pre-mRNA splicing: specific skipping of erbB-2 exon 19 coding for the ATP catalytic domain

    DEFF Research Database (Denmark)

    Pankratova, Stanislava; Nielsen, Birgit N; Shiraishi, Takehiko

    2010-01-01

    interference as a means of manipulating erbB-2 expression in a therapeutically relevant fashion, we have studied the effect on mRNA splicing of a series of peptide nucleic acid (PNA) oligomers targeting specific intron-exon junctions in the erbB-2 pre-mRNA. In particular, we are interested in identifying PNA...

  10. The effect of skipping meals and daily activities of university students regarding the body mass index (BMI

    Directory of Open Access Journals (Sweden)

    Selen Ozakar Akca

    2015-10-01

    Full Text Available Background: If we assume that the group of 18-24 years old young people are university students, their proper eating habits present social importance for their own health. With this present study it was aimed to determine the effect of eating habits and daily activity situations of university students regarding obesity. Methods: This descriptive and cross-sectional type study has been carried out in the Health College of the Hitit University. No sample selection was performed, the sample consisted of students visiting the school during the study dates (10- 21.03.2014 and participated voluntarily (n=197 in the study. Questionnaires were used as data collection tool. The data was evaluated with appropriate statistical methods. P < 0.05 has been accepted as statistically significant. Results: 73.1% of the students, participating in the study were female and 26,9% male. The overweight and obesity frequency rate of female students (16% was lower in comparison to male students (17%, whereas the students' BMI average was 22.595+/-3.57. 13.7% of participating students were thin and 8.5% obese. It was seen that 68% of participants in the study skip meals and 28.9% eat 1-2 meals per day. Additionally it was determined that students' skipping meal status is according to the BMI classification statistically significant (p<0.05 Apart from this it was stated that 90.7% of students are doing and #8804;2 hours/week sports. Conclusions: If we assume that one out of every three student is overweight/obese and that the majority do not have a proper nutrition and sport habit, it reveals the importance of BMI screenings and trainings regarding eating habits in school [TAF Prev Med Bull 2015; 14(5.000: 394-400

  11. Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy)

    DEFF Research Database (Denmark)

    Vorwerk, P; Christoffersen, C T; Müller, J

    1999-01-01

    to be compound heterozygotes for mutations in the IR gene. The maternal allele was alternatively spliced in exon 17 due to a point mutation in the -1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase...

  12. MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

    Science.gov (United States)

    Pilotto, Sara; Gkountakos, Anastasios; Carbognin, Luisa; Scarpa, Aldo; Tortora, Giampaolo

    2017-01-01

    The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients’ subgroup, are explored. PMID:28164087

  13. Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants.

    Science.gov (United States)

    Pagenstecher, Constanze; Wehner, Maria; Friedl, Waltraut; Rahner, Nils; Aretz, Stefan; Friedrichs, Nicolaus; Sengteller, Marlies; Henn, Wolfram; Buettner, Reinhard; Propping, Peter; Mangold, Elisabeth

    2006-03-01

    Single base substitutions in DNA mismatch repair genes which are predicted to lead either to missense or silent mutations, or to intronic variants outside the highly conserved splicing region are often found in hereditary nonpolyposis colorectal cancer (HNPCC) families. In order to use the variants for predictive testing in persons at risk, their pathogenicity has to be evaluated. There is growing evidence that some substitutions have a detrimental influence on splicing. We examined 19 unclassified variants (UVs) detected in MSH2 or MLH1 genes in patients suspected of HNPCC for expression at RNA level. We demonstrate that 10 of the 19 UVs analyzed affect splicing. For example, the substitution MLH1,c.2103G > C in the last position of exon 18 does not result in a missense mutation as theoretically predicted (p.Gln701His), but leads to a complete loss of exon 18. The substitution MLH1,c.1038G > C (predicted effect p.Gln346His) leads to complete inactivation of the mutant allele by skipping of exons 10 and 11, and by activation of a cryptic intronic splice site. Similarly, the intronic variant MLH1,c.306+2dupT results in loss of exon 3 and a frameshift mutation due to a new splice donor site 5 bp upstream. Furthermore, we confirmed complete exon skipping for the mutations MLH1,c.1731G > A and MLH1,c.677G > A. Partial exon skipping was demonstrated for the mutations MSH2,c.1275A > G, MLH1,c.588+5G > A, MLH1,c.790+4A > G and MLH1,c.1984A > C. In contrast, five missense mutations (MSH2,c.4G > A, MSH2,c.2123T > A, MLH1,c.464T > G, MLH1,c.875T > C and MLH1,c.2210A > T) were found in similar proportions in the mRNA as in the genomic DNA. We conclude that the mRNA examination should precede functional tests at protein level.

  14. Categorization of 77 dystrophin exons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers.

    Science.gov (United States)

    Malueka, Rusdy Ghazali; Takaoka, Yutaka; Yagi, Mariko; Awano, Hiroyuki; Lee, Tomoko; Dwianingsih, Ery Kus; Nishida, Atsushi; Takeshima, Yasuhiro; Matsuo, Masafumi

    2012-03-31

    Duchenne muscular dystrophy, a fatal muscle-wasting disease, is characterized by dystrophin deficiency caused by mutations in the dystrophin gene. Skipping of a target dystrophin exon during splicing with antisense oligonucleotides is attracting much attention as the most plausible way to express dystrophin in DMD. Antisense oligonucleotides have been designed against splicing regulatory sequences such as splicing enhancer sequences of target exons. Recently, we reported that a chemical kinase inhibitor specifically enhances the skipping of mutated dystrophin exon 31, indicating the existence of exon-specific splicing regulatory systems. However, the basis for such individual regulatory systems is largely unknown. Here, we categorized the dystrophin exons in terms of their splicing regulatory factors. Using a computer-based machine learning system, we first constructed a decision tree separating 77 authentic from 14 known cryptic exons using 25 indexes of splicing regulatory factors as decision markers. We evaluated the classification accuracy of a novel cryptic exon (exon 11a) identified in this study. However, the tree mislabeled exon 11a as a true exon. Therefore, we re-constructed the decision tree to separate all 15 cryptic exons. The revised decision tree categorized the 77 authentic exons into five groups. Furthermore, all nine disease-associated novel exons were successfully categorized as exons, validating the decision tree. One group, consisting of 30 exons, was characterized by a high density of exonic splicing enhancer sequences. This suggests that AOs targeting splicing enhancer sequences would efficiently induce skipping of exons belonging to this group. The decision tree categorized the 77 authentic exons into five groups. Our classification may help to establish the strategy for exon skipping therapy for Duchenne muscular dystrophy.

  15. Is breakfast skipping associated with physical activity among U.S. adolescents? A cross-sectional study of adolescents aged 12-19 years, National Health and Nutrition Examination Survey (NHANES).

    Science.gov (United States)

    Lyerly, Jordan E; Huber, Larissa R; Warren-Findlow, Jan; Racine, Elizabeth F; Dmochowski, Jacek

    2014-04-01

    To examine the association between breakfast skipping and physical activity among US adolescents aged 12-19 years. A cross-sectional study of nationally representative 2007-2008 National Health and Nutrition Examination Survey (NHANES) data. Breakfast skipping was assessed by two 24 h dietary recalls. Physical activity was self-reported by participants and classified based on meeting national recommendations for physical activity for the appropriate age group. Multiple logistic regression analysis was used to model the association between breakfast skipping and physical activity while controlling for confounders. A total of 936 adolescents aged 12-19 years in the USA. After adjusting for family income, there was no association between breakfast skipping and meeting physical activity guidelines for age among adolescents aged 12-19 years (OR = 0.95, 95% CI 0.56, 1.32). Findings from the study differ from previous research findings on breakfast skipping and physical activity. Therefore, further research that uses large, nationally representative US samples and national recommended guidelines for physical activity is needed.

  16. Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene.

    Science.gov (United States)

    Flanigan, Kevin M; Dunn, Diane M; von Niederhausern, Andrew; Soltanzadeh, Payam; Howard, Michael T; Sampson, Jacinda B; Swoboda, Kathryn J; Bromberg, Mark B; Mendell, Jerry R; Taylor, Laura E; Anderson, Christine B; Pestronk, Alan; Florence, Julaine M; Connolly, Anne M; Mathews, Katherine D; Wong, Brenda; Finkel, Richard S; Bonnemann, Carsten G; Day, John W; McDonald, Craig; Weiss, Robert B

    2011-03-01

    Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping. © 2011 Wiley-Liss, Inc.

  17. Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene

    Science.gov (United States)

    Flanigan, Kevin M.; Dunn, Diane M.; von Niederhausern, Andrew; Soltanzadeh, Payam; Howard, Michael T.; Sampson, Jacinda B.; Swoboda, Kathryn J.; Bromberg, Mark B.; Mendell, Jerry R.; Taylor, Laura; Anderson, Christine B.; Pestronk, Alan; Florence, Julaine; Connolly, Anne M.; Mathews, Katherine D.; Wong, Brenda; Finkel, Richard S.; Bonnemann, Carsten G.; Day, John W.; McDonald, Craig; Weiss, Robert B.

    2013-01-01

    Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping. PMID:21972111

  18. Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping▿

    OpenAIRE

    Bell, Matthew L; Buvoli, Massimo; Leinwand, Leslie A.

    2010-01-01

    The ancient MYH7b gene, expressed in striated muscle and brain, encodes a sarcomeric myosin and the intronic microRNA miR-499. We find that skipping of an exon introduces a premature termination codon in the transcript that downregulates MYH7b protein production without affecting microRNA expression. Among other genes, endogenous miR-499 targets the 3′ untranslated region of the transcription factor Sox6, which in turn acts as a repressor of MYH7b transcriptional activity. Thus, concerted tra...

  19. Antisense PMO found in dystrophic dog model was effective in cells from exon 7-deleted DMD patient.

    Science.gov (United States)

    Saito, Takashi; Nakamura, Akinori; Aoki, Yoshitsugu; Yokota, Toshifumi; Okada, Takashi; Osawa, Makiko; Takeda, Shin'ichi

    2010-08-18

    Antisense oligonucleotide-induced exon skipping is a promising approach for treatment of Duchenne muscular dystrophy (DMD). We have systemically administered an antisense phosphorodiamidate morpholino oligomer (PMO) targeting dystrophin exons 6 and 8 to a dog with canine X-linked muscular dystrophy in Japan (CXMD(J)) lacking exon 7 and achieved recovery of dystrophin in skeletal muscle. To date, however, antisense chemical compounds used in DMD animal models have not been directly applied to a DMD patient having the same type of exon deletion. We recently identified a DMD patient with an exon 7 deletion and tried direct translation of the antisense PMO used in dog models to the DMD patient's cells. We converted fibroblasts of CXMD(J) and the DMD patient to myotubes by FACS-aided MyoD transduction. Antisense PMOs targeting identical regions of dog and human dystrophin exons 6 and 8 were designed. These antisense PMOs were mixed and administered as a cocktail to either dog or human cells in vitro. In the CXMD(J) and human DMD cells, we observed a similar efficacy of skipping of exons 6 and 8 and a similar extent of dystrophin protein recovery. The accompanying skipping of exon 9, which did not alter the reading frame, was different between cells of these two species. Antisense PMOs, the effectiveness of which has been demonstrated in a dog model, achieved multi-exon skipping of dystrophin gene on the FACS-aided MyoD-transduced fibroblasts from an exon 7-deleted DMD patient, suggesting the feasibility of systemic multi-exon skipping in humans.

  20. Antisense PMO found in dystrophic dog model was effective in cells from exon 7-deleted DMD patient.

    Directory of Open Access Journals (Sweden)

    Takashi Saito

    Full Text Available BACKGROUND: Antisense oligonucleotide-induced exon skipping is a promising approach for treatment of Duchenne muscular dystrophy (DMD. We have systemically administered an antisense phosphorodiamidate morpholino oligomer (PMO targeting dystrophin exons 6 and 8 to a dog with canine X-linked muscular dystrophy in Japan (CXMD(J lacking exon 7 and achieved recovery of dystrophin in skeletal muscle. To date, however, antisense chemical compounds used in DMD animal models have not been directly applied to a DMD patient having the same type of exon deletion. We recently identified a DMD patient with an exon 7 deletion and tried direct translation of the antisense PMO used in dog models to the DMD patient's cells. METHODOLOGY/PRINCIPAL FINDINGS: We converted fibroblasts of CXMD(J and the DMD patient to myotubes by FACS-aided MyoD transduction. Antisense PMOs targeting identical regions of dog and human dystrophin exons 6 and 8 were designed. These antisense PMOs were mixed and administered as a cocktail to either dog or human cells in vitro. In the CXMD(J and human DMD cells, we observed a similar efficacy of skipping of exons 6 and 8 and a similar extent of dystrophin protein recovery. The accompanying skipping of exon 9, which did not alter the reading frame, was different between cells of these two species. CONCLUSION/SIGNIFICANCE: Antisense PMOs, the effectiveness of which has been demonstrated in a dog model, achieved multi-exon skipping of dystrophin gene on the FACS-aided MyoD-transduced fibroblasts from an exon 7-deleted DMD patient, suggesting the feasibility of systemic multi-exon skipping in humans.

  1. An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers.

    Science.gov (United States)

    Smith, Philip J; Zhang, Chaolin; Wang, Jinhua; Chew, Shern L; Zhang, Michael Q; Krainer, Adrian R

    2006-08-15

    Numerous disease-associated point mutations exert their effects by disrupting the activity of exonic splicing enhancers (ESEs). We previously derived position weight matrices to predict putative ESEs specific for four human SR proteins. The score matrices are part of ESEfinder, an online resource to identify ESEs in query sequences. We have now carried out a refined functional SELEX screen for motifs that can act as ESEs in response to the human SR protein SF2/ASF. The test BRCA1 exon under selection was internal, rather than the 3'-terminal IGHM exon used in our earlier studies. A naturally occurring heptameric ESE in BRCA1 exon 18 was replaced with two libraries of random sequences, one seven nucleotides in length, the other 14. Following three rounds of selection for in vitro splicing via internal exon inclusion, new consensus motifs and score matrices were derived. Many winner sequences were demonstrated to be functional ESEs in S100-extract-complementation assays with recombinant SF2/ASF. Motif-score threshold values were derived from both experimental and statistical analyses. Motif scores were shown to correlate with levels of exon inclusion, both in vitro and in vivo. Our results confirm and extend our earlier data, as many of the same motifs are recognized as ESEs by both the original and our new score matrix, despite the different context used for selection. Finally, we have derived an increased specificity score matrix that incorporates information from both of our SF2/ASF-specific matrices and that accurately predicts the exon-skipping phenotypes of deleterious point mutations.

  2. Modulating Calcium Signals to Boost AON Exon Skipping for DMD

    Science.gov (United States)

    2016-10-01

    acids + 1% pen/strep) in 6-well plates ( Corning ) pre-coated for 1 hour with 0.1% gelatin (sigma). The following day, 5μM 4OH-tamoxifen (Sigma...resuspended in ethanol) was added in fibroblast growth media for 24 hours. On day 3, cells were washed in 1 x Phosphate Buffered Saline (PBS; Invitrogen

  3. Stemcell Information: SKIP001121 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available lines(C3) using transcription activator-like effector nuclease (TALEN; Fig. 3a ). TALENを用いてゲノム編集したiPS細胞... SKIP001121 ... Normal C-3-1-3M C-3-1-3M ... -- Female ... -- No Isogenic iPS cell...(C3) human ES-like Research Grade Plasmid ... -- ... Yes Differentiation of iPS cells into foreb...0.1038/nature13716 Synaptic dysregulation in a human iPS cell model of mental disorders. Wen Z, Nguyen HN, G

  4. Exon exchange approach to repair Duchenne dystrophin transcripts.

    Directory of Open Access Journals (Sweden)

    Stéphanie Lorain

    Full Text Available BACKGROUND: Trans-splicing strategies for mRNA repair involve engineered transcripts designed to anneal target mRNAs in order to interfere with their natural splicing, giving rise to mRNA chimeras where endogenous mutated exons have been replaced by exogenous replacement sequences. A number of trans-splicing molecules have already been proposed for replacing either the 5' or the 3' part of transcripts to be repaired. Here, we show the feasibility of RNA surgery by using a double trans-splicing approach allowing the specific substitution of a given mutated exon. METHODOLOGY/PRINCIPAL FINDINGS: As a target we used a minigene encoding a fragment of the mdx dystrophin gene enclosing the mutated exon (exon 23. This minigene was cotransfected with a variety of exon exchange constructions, differing in their annealing domains. We obtained accurate and efficient replacement of exon 23 in the mRNA target. Adding up a downstream intronic splice enhancer DISE in the exon exchange molecule enhanced drastically its efficiency up to 25-45% of repair depending on the construction in use. CONCLUSIONS/SIGNIFICANCE: These results demonstrate the possibility to fix up mutated exons, refurbish deleted exons and introduce protein motifs, while keeping natural untranslated sequences, which are essential for mRNA stability and translation regulation. Conversely to the well-known exon skipping, exon exchange has the advantage to be compatible with almost any type of mutations and more generally to a wide range of genetic conditions. In particular, it allows addressing disorders caused by dominant mutations.

  5. Exon Exchange Approach to Repair Duchenne Dystrophin Transcripts

    Science.gov (United States)

    Lorain, Stéphanie; Peccate, Cécile; Le Hir, Maëva; Garcia, Luis

    2010-01-01

    Background Trans-splicing strategies for mRNA repair involve engineered transcripts designed to anneal target mRNAs in order to interfere with their natural splicing, giving rise to mRNA chimeras where endogenous mutated exons have been replaced by exogenous replacement sequences. A number of trans-splicing molecules have already been proposed for replacing either the 5′ or the 3′ part of transcripts to be repaired. Here, we show the feasibility of RNA surgery by using a double trans-splicing approach allowing the specific substitution of a given mutated exon. Methodology/Principal Findings As a target we used a minigene encoding a fragment of the mdx dystrophin gene enclosing the mutated exon (exon 23). This minigene was cotransfected with a variety of exon exchange constructions, differing in their annealing domains. We obtained accurate and efficient replacement of exon 23 in the mRNA target. Adding up a downstream intronic splice enhancer DISE in the exon exchange molecule enhanced drastically its efficiency up to 25–45% of repair depending on the construction in use. Conclusions/Significance These results demonstrate the possibility to fix up mutated exons, refurbish deleted exons and introduce protein motifs, while keeping natural untranslated sequences, which are essential for mRNA stability and translation regulation. Conversely to the well-known exon skipping, exon exchange has the advantage to be compatible with almost any type of mutations and more generally to a wide range of genetic conditions. In particular, it allows addressing disorders caused by dominant mutations. PMID:20531943

  6. Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice.

    Science.gov (United States)

    Wein, Nicolas; Vulin, Adeline; Falzarano, Maria S; Szigyarto, Christina Al-Khalili; Maiti, Baijayanta; Findlay, Andrew; Heller, Kristin N; Uhlén, Mathias; Bakthavachalu, Baskar; Messina, Sonia; Vita, Giuseppe; Passarelli, Chiara; Brioschi, Simona; Bovolenta, Matteo; Neri, Marcella; Gualandi, Francesca; Wilton, Steve D; Rodino-Klapac, Louise R; Yang, Lin; Dunn, Diane M; Schoenberg, Daniel R; Weiss, Robert B; Howard, Michael T; Ferlini, Alessandra; Flanigan, Kevin M

    2014-09-01

    Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. We confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5' exons of DMD.

  7. CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes.

    Science.gov (United States)

    Reindl, Carola; Quentmeier, Hilmar; Petropoulos, Konstantin; Greif, Philipp A; Benthaus, Tobias; Argiropoulos, Bob; Mellert, Gudrun; Vempati, Sridhar; Duyster, Justus; Buske, Christian; Bohlander, Stefan K; Humphries, Keith R; Hiddemann, Wolfgang; Spiekermann, Karsten

    2009-04-01

    CBL is a negative regulator of activated receptor tyrosine kinases (RTK). In this study, we determined the frequency of CBL mutations in acute leukemias and evaluated the oncogenic potential of mutant CBL. The cDNA of 300 acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and 82 human leukemic cell lines was screened for aberrations in the linker and RING finger domain of CBL. The oncogenic potential of identified mutants was evaluated in hematopoietic cells. We identified 3 of 279 AML/MDS patients expressing CBL exon 8/9 deletion mutants. Three of four cases at diagnosis expressed deleted transcripts missing exon 8 or exon 8/9. In remission samples a weak or no expression of mutant CBL was detected. No aberrations were found in normal hematopoietic tissues. One of 116 sequenced AML/MDS cases carried a R420G missense mutation. All AML/MDS patients with identified CBL mutants belonged to the core binding factor and 11q deletion AML subtypes. Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. Expression of CBLDeltaexon8 and CBLDeltaexon8+9 in FLT3-WT-Ba/F3 cells induced growth factor-independent proliferation associated with autophosphorylation of FLT3 and activated the downstream targets signal transducer and activator of transcription 5 (STAT5) and protein kinase B (AKT). FLT3 ligand-dependent hyperproliferation of CBL mutant cells could be abrogated by treatment with the FLT3 PTK inhibitor PKC412 (midostaurin). CBL exon8/9 mutants occur in genetically defined AML/MDS subtypes and transform hematopoietic cells by constitutively activating the FLT3 pathway. This phenotype resembles the one of mutated RTKs and suggests that CBL mutant AML patients might benefit from treatment with FLT3 PTK inhibitors.

  8. Deep intronic mutation and pseudo exon activation as a novel muscular hypertrophy modifier in cattle.

    Directory of Open Access Journals (Sweden)

    Claire Bouyer

    Full Text Available Myostatin is essential for proper regulation of myogenesis, and inactivation of Myostatin results in muscle hypertrophy. Here, we identified an unexpected mutation in the myostatin gene which is almost fixed in Blonde d'Aquitaine cattle. In skeletal muscle, the mutant allele was highly expressed leading to an abnormal transcript consisting of a 41-bp inclusion and premature termination codons and to residual levels of a correctly spliced transcript. This expression pattern, caused by a leaky intronic mutation with regard to spliceosome activity and its apparent stability with regard to surveillance mechanisms, could contribute to the moderate muscle hypertrophy in this cattle breed. This finding is of importance for genetic counseling for meat quantity and quality in livestock production and possibly to manipulate myostatin pre-mRNA in human muscle diseases.

  9. Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease

    NARCIS (Netherlands)

    E. van der Wal (Erik); A.J. Bergsma (Atze); J. Pijnenburg (Joon); A.T. van der Ploeg (Ans); W.W.M.P. Pijnappel (Pim)

    2017-01-01

    textabstractThe most common variant causing Pompe disease is c.-32-13T>G (IVS1) in the acid α-glucosidase (GAA) gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild-type splicing, leading to a childhood/adult

  10. Rodent-specific alternative exons are more frequent in rapidly evolving genes and in paralogs

    Directory of Open Access Journals (Sweden)

    Mironov Andrey A

    2009-06-01

    Full Text Available Abstract Background Alternative splicing is an important mechanism for generating functional and evolutionary diversity of proteins in eukaryotes. Here, we studied the frequency and functionality of recently gained, rodent-specific alternative exons. Results We projected the data about alternative splicing of mouse genes to the rat, human, and dog genomes, and identified exons conserved in the rat genome, but missing in more distant genomes. We estimated the frequency of rodent-specific exons while controlling for possible residual conservation of spurious exons. The frequency of rodent-specific exons is higher among predominantly skipped exons and exons disrupting the reading frame. Separation of all genes by the rate of sequence evolution and by gene families has demonstrated that rodent-specific cassette exons are more frequent in rapidly evolving genes and in rodent-specific paralogs. Conclusion Thus we demonstrated that recently gained exons tend to occur in fast-evolving genes, and their inclusion rate tends to be lower than that of older exons. This agrees with the theory that gain of alternative exons is one of the major mechanisms of gene evolution.

  11. Diverse splicing patterns of exonized Alu elements in human tissues.

    Directory of Open Access Journals (Sweden)

    Lan Lin

    2008-10-01

    Full Text Available Exonization of Alu elements is a major mechanism for birth of new exons in primate genomes. Prior analyses of expressed sequence tags show that almost all Alu-derived exons are alternatively spliced, and the vast majority of these exons have low transcript inclusion levels. In this work, we provide genomic and experimental evidence for diverse splicing patterns of exonized Alu elements in human tissues. Using Exon array data of 330 Alu-derived exons in 11 human tissues and detailed RT-PCR analyses of 38 exons, we show that some Alu-derived exons are constitutively spliced in a broad range of human tissues, and some display strong tissue-specific switch in their transcript inclusion levels. Most of such exons are derived from ancient Alu elements in the genome. In SEPN1, mutations of which are linked to a form of congenital muscular dystrophy, the muscle-specific inclusion of an Alu-derived exon may be important for regulating SEPN1 activity in muscle. Realtime qPCR analysis of this SEPN1 exon in macaque and chimpanzee tissues indicates human-specific increase in its transcript inclusion level and muscle specificity after the divergence of humans and chimpanzees. Our results imply that some Alu exonization events may have acquired adaptive benefits during the evolution of primate transcriptomes.

  12. Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease

    Directory of Open Access Journals (Sweden)

    Erik van der Wal

    2017-06-01

    Full Text Available The most common variant causing Pompe disease is c.-32-13T>G (IVS1 in the acid α-glucosidase (GAA gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild-type splicing, leading to a childhood/adult phenotype. We hypothesized that cis-acting splicing motifs may exist that could be blocked using antisense oligonucleotides (AONs to promote exon inclusion. To test this, a screen was performed in patient-derived primary fibroblasts using a tiling array of U7 small nuclear RNA (snRNA-based AONs. This resulted in the identification of a splicing regulatory element in GAA intron 1. We designed phosphorodiamidate morpholino oligomer-based AONs to this element, and these promoted exon 2 inclusion and enhanced GAA enzyme activity to levels above the disease threshold. These results indicate that the common IVS1 GAA splicing variant in Pompe disease is subject to negative regulation, and inhibition of a splicing regulatory element using AONs is able to restore canonical GAA splicing and endogenous GAA enzyme activity.

  13. Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease.

    Science.gov (United States)

    van der Wal, Erik; Bergsma, Atze J; Pijnenburg, Joon M; van der Ploeg, Ans T; Pijnappel, W W M Pim

    2017-06-16

    The most common variant causing Pompe disease is c.-32-13T>G (IVS1) in the acid α-glucosidase (GAA) gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild-type splicing, leading to a childhood/adult phenotype. We hypothesized that cis-acting splicing motifs may exist that could be blocked using antisense oligonucleotides (AONs) to promote exon inclusion. To test this, a screen was performed in patient-derived primary fibroblasts using a tiling array of U7 small nuclear RNA (snRNA)-based AONs. This resulted in the identification of a splicing regulatory element in GAA intron 1. We designed phosphorodiamidate morpholino oligomer-based AONs to this element, and these promoted exon 2 inclusion and enhanced GAA enzyme activity to levels above the disease threshold. These results indicate that the common IVS1 GAA splicing variant in Pompe disease is subject to negative regulation, and inhibition of a splicing regulatory element using AONs is able to restore canonical GAA splicing and endogenous GAA enzyme activity. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  14. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... to A to Z list Skip directly to navigation Skip directly to page options Skip directly to ... Statistics Facts About Physical Activity Data, Trends and Maps Surveillance Systems Resources & Publications Reports Adults Need More ...

  15. 3′ Splice Site Sequences of Spinal Muscular Atrophy Related SMN2 Pre-mRNA Include Enhancers for Nearby Exons

    Directory of Open Access Journals (Sweden)

    Sunghee Cho

    2014-01-01

    Full Text Available Spinal muscular atrophy (SMA is a human genetic disease which occurs because of the deletion or mutation of SMN1 gene. SMN1 gene encodes the SMN protein which plays a key role in spliceosome assembly. Although human patients contain SMN2, a duplicate of SMN1, splicing of SMN2 produces predominantly exon 7 skipped isoform. In order to understand the functions of splice site sequences on exon 7 and 8, we analyzed the effects of conserved splice site sequences on exon 7 skipping of SMN2 and SMN1 pre-mRNA. We show here that conserved 5′ splice site sequence of exon 7 promoted splicing of nearby exons and subsequently reduced splicing of distant exons. However, to our surprise, conserved 3′ splice site sequence of exon 7 and 8 did not promote splicing of nearby exons. By contrast, the mutation inhibited splicing of nearby exons and subsequently promoted splicing of distant exons. Our study shows that 3′ splice sites of exon 7 and 8 contain enhancer for their splice site selection, in addition to providing cleavage sites.

  16. Blau syndrome-associated mutations in exon 4 of the caspase activating recruitment domain 15 (CARD 15) gene are not found in ethnic Danes with sarcoidosis.

    Science.gov (United States)

    Milman, Nils; Nielsen, Finn Cilius; Hviid, Thomas Vauvert F; Hansen, Thomas van Overeem

    2007-12-01

    Distinct mutations of the caspase activating recruitment domain 15 (CARD15) gene (also known as nucleotide-binding oligomerisation domain protein 2) on chromosome 16q are associated with the chronic granulomatous disease called Blau syndrome. Sarcoidosis is a systemic granulomatous disease, which has features in common with Blau syndrome. The aim of this study was to evaluate whether ethnic Danes with sarcoidosis have CARD15 mutations associated with Blau syndrome. Analysis of exon 4 of the CARD15 gene containing mutations associated with Blau syndrome was performed by polymerase chain reaction and sequencing of genomic DNA from 52 patients with histologically verified sarcoidosis. None of the patients had mutations in CARD15 associated with Blau syndrome. Eight other variations were found in exon 4: single nucleotide polymorphism (SNP)6 in 40% of the 104 alleles examined, SNP7 in 26%, c. 1833 C > T and SNP8 in 4%, c. 2107 C > T in 2%, and c. 931 C > T, c. 1292 C > T and c. 2377 G > A in 1%. One variation was found in intron 4 (IVS4 + 10 A > C) in 3% of the alleles. The frequencies of the variations in sarcoidosis patients were not statistically significant compared with frequencies in a control group of 103 healthy subjects. The course of disease was not significantly different in patients with or without variations in CARD15 or in the 46 patients with SNP6 and/or SNP7. Danish sarcoidosis patients have frequent variations in CARD15 exon 4, but do not present any mutation associated with Blau syndrome. The variations found had no influence on the course of disease.

  17. Stemcell Information: SKIP000721 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000721 ... polydactylous human fingers 指 Normal Yub631 Yub631 ... -- -- ... -- No JCRB1156 fin...ite proliferation. Cell line established from polydactylous human fingers (finger).

  18. Stemcell Information: SKIP000720 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000720 ... polydactylous human fingers 指 Normal Yub625 Yub625 ... -- -- ... -- No JCRB1155 fin...ite proliferation. ... 指由来, 有限増殖 fibroblast-like -- Retrovirus ... Yes -- ... poweredby10. W

  19. Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction.

    Directory of Open Access Journals (Sweden)

    Barbara Wappenschmidt

    Full Text Available Screening for pathogenic mutations in breast and ovarian cancer genes such as BRCA1/2, CHEK2 and RAD51C is common practice for individuals from high-risk families. However, test results may be ambiguous due to the presence of unclassified variants (UCV in the concurrent absence of clearly cancer-predisposing mutations. Especially the presence of intronic or exonic variants within these genes that possibly affect proper pre-mRNA processing poses a challenge as their functional implications are not immediately apparent. Therefore, it appears necessary to characterize potential splicing UCV and to develop appropriate classification tools. We investigated 30 distinct BRCA1 variants, both intronic and exonic, regarding their spliceogenic potential by commonly used in silico prediction algorithms (HSF, MaxEntScan along with in vitro transcript analyses. A total of 25 variants were identified spliceogenic, either causing/enhancing exon skipping or activation of cryptic splice sites, or both. Except from a single intronic variant causing minor effects on BRCA1 pre-mRNA processing in our analyses, 23 out of 24 intronic variants were correctly predicted by MaxEntScan, while HSF was less accurate in this cohort. Among the 6 exonic variants analyzed, 4 severely impair correct pre-mRNA processing, while the remaining two have partial effects. In contrast to the intronic alterations investigated, only half of the spliceogenic exonic variants were correctly predicted by HSF and/or MaxEntScan. These data support the idea that exonic splicing mutations are commonly disease-causing and concurrently prone to escape in silico prediction, hence necessitating experimental in vitro splicing analysis.

  20. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500 U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic...... evaluation revealed a deletion of exon 26 of the dystrophin gene in both. This is the first description of patients with a exon 26 deletion of the dystrophin gene. Assuming the proband's comorbidity is unrelated, exon 26 deletion results in a very mild phenotype. This might be of interest in planning exon...

  1. 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.

  2. Occurrence of a 2-bp (AT) deletion allele and a nonsense (G-to-T) mutant allele at the E2 (DBT) locus of six patients with maple syrup urine disease: Multiple-exon skipping as a secondary effect of the mutations

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, C.W.; Fisher, C.R.; Chuang, J.L.; Lau, K.S.; Chuang, D.T.; Cox, R.P. (Univ. of Texas, Dallas (United States))

    1993-02-01

    The authors have identified two novel mutant alleles in the transacylase (E2) gene of the human branched-chain [alpha]-keto acid dehydrogenase (BCKAD) complex in 6 of 38 patients with maple syrup urine disease (MSUD). One mutation, a 2-bp (AT) deletion in exon 2 of the E2 gene, causes a frameshift downstream of residue ([minus]26) in the mitochondrial targeting presequence. The second mutation, a G-to-T transversion in exon 6 of the E2 gene, produces a premature stop codon at Glu-163 (E163*). Transfection of constructs harboring the E163* mutation into an E2-deficient MSUD cell line produced a truncated E2 subunit. However, this mutant E2 chain is unable to assemble into a 24-mer cubic structure and is degraded in the cell. The 2-bp (AT) deletion and the E163* mutant alleles occur in either the homozygous or compound-heterozygous state in the 6 of 38 unrelated MSUD patients studied. Moreover, an array of precise single- and multiple-exon deletions were observed in many amplified E2 mutant cDNAs. The latter results appear to represent secondary effects on RNA processing that are associated with the MSUD mutations at the E2 locus. 30 refs., 8 figs.

  3. Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity.

    Science.gov (United States)

    Pantazatos, S P; Huang, Y-Y; Rosoklija, G B; Dwork, A J; Arango, V; Mann, J J

    2017-05-01

    Brain gene expression profiling studies of suicide and depression using oligonucleotide microarrays have often failed to distinguish these two phenotypes. Moreover, next generation sequencing approaches are more accurate in quantifying gene expression and can detect alternative splicing. Using RNA-seq, we examined whole-exome gene and exon expression in non-psychiatric controls (CON, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9) of sudden death medication-free individuals post mortem. Using small RNA-seq, we also examined miRNA expression (nine samples per group). DeSeq2 identified 35 genes differentially expressed between groups and surviving adjustment for false discovery rate (adjusted Pdepression, altered genes include humanin-like-8 (MTRNRL8), interleukin-8 (IL8), and serpin peptidase inhibitor, clade H (SERPINH1) and chemokine ligand 4 (CCL4), while exploratory gene ontology (GO) analyses revealed lower expression of immune-related pathways such as chemokine receptor activity, chemotaxis and cytokine biosynthesis, and angiogenesis and vascular development in (adjusted Psuicide and depression, and provisional evidence for altered DNA-dependent ATPase expression in suicide only. DEXSEq analysis identified differential exon usage in ATPase, class II, type 9B (adjusted Pdepression. Differences in miRNA expression or structural gene variants were not detected. Results lend further support for models in which deficits in microglial, endothelial (blood-brain barrier), ATPase activity and astrocytic cell functions contribute to MDD and suicide, and identify putative pathways and mechanisms for further study in these disorders.

  4. The effect of skipping meals and daily activities of university students regarding the body mass index (BMI)

    OpenAIRE

    Selen Ozakar Akca; Filiz Selen

    2015-01-01

    Background: If we assume that the group of 18-24 years old young people are university students, their proper eating habits present social importance for their own health. With this present study it was aimed to determine the effect of eating habits and daily activity situations of university students regarding obesity. Methods: This descriptive and cross-sectional type study has been carried out in the Health College of the Hitit University. No sample selection was performed, the sample cons...

  5. Unusual intron conservation near tissue-regulated exons found by splicing microarrays.

    Directory of Open Access Journals (Sweden)

    Charles W Sugnet

    2006-01-01

    Full Text Available Alternative splicing contributes to both gene regulation and protein diversity. To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome. In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40% of the 6,216 alternative events we could detect. Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle. A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons. By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation. Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5' splice site of exons included in muscle. Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern. While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families.

  6. Skipping breakfast and associated factors among Brazilian adolescents

    Directory of Open Access Journals (Sweden)

    Rosemeyre França de Paula FIUZA

    Full Text Available ABSTRACT Objective To analyze the prevalence and factors associated with breakfast skipping among adolescents. Methods Cross-sectional study, with adolescents aged 10-17 years, evaluated between 2009 and 2011, belonging to a cohort study in the Central-West region of Brazil. Breakfast skipping was considered as not having breakfast every day. Demographic, socioeconomic, and lifestyle factors were evaluated through a questionnaire. Anthropometric assessment included measurement of weight and height, which were used to classify weight status using body mass index. Poisson regression was used to assess the association of breakfast skipping with demographic and socioeconomic variables, lifestyle factors, and weight status. Results Among 1,716 Brazilian adolescents evaluated, 36.2% reported not consuming breakfast every day, with the highest prevalence among girls (p=0.03. After adjusting for age and economic class, breakfast skipping was associated with not consuming breakfast with parents and morning shift at school, in both genders, and with obesity only in boys. Lifestyle factors such as alcohol consumption, physical activity, diet quality, and smoking were not associated with skipping breakfast. Conclusion The omission of breakfast was observed in more than a third of adolescents, being associated with demographic and lifestyle factors. In the public health perspective, the importance of encouraging the consumption of this meal is highlighted, with actions involving the school environment and the family.

  7. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1 1/2 years old. He had no complaints of muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....

  8. Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation.

    Science.gov (United States)

    Bashyam, M D; Chaudhary, A K; Kiran, M; Reddy, V; Nagarajaram, H A; Dalal, A; Bashyam, L; Suri, D; Gupta, A; Gupta, N; Kabra, M; Puri, R D; RamaDevi, R; Kapoor, S; Danda, S

    2014-12-01

    Farber lipogranulomatosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene. In the largest ever study, we identified and characterized ASAH1 mutations from 11 independent Farber disease (FD) families. A total of 13 different mutations were identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven mutations were exclusive to the Indian population. The IVS6+4A>G splice and IVS5-16delTTTTC PPT deletion mutations resulted in skipping of exon 6 precluding thereby the region responsible for cleavage of enzyme precursor. A missense mutation (p.V198A) resulted in skipping of exon 8 due to inactivation of an exonic splicing enhancer (ESE) element. This is the first report of mutations affecting PPT and ESE in the ASAH1 gene resulting in FD. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences.

    Science.gov (United States)

    Günther, Katharina; Rust, Mareike; Leers, Joerg; Boettger, Thomas; Scharfe, Maren; Jarek, Michael; Bartkuhn, Marek; Renkawitz, Rainer

    2013-03-01

    The heterogeneous collection of nucleosome remodelling and deacetylation (NuRD) complexes can be grouped into the MBD2- or MBD3-containing complexes MBD2-NuRD and MBD3-NuRD. MBD2 is known to bind to methylated CpG sequences in vitro in contrast to MBD3. Although functional differences have been described, a direct comparison of MBD2 and MBD3 in respect to genome-wide binding and function has been lacking. Here, we show that MBD2-NuRD, in contrast to MBD3-NuRD, converts open chromatin with euchromatic histone modifications into tightly compacted chromatin with repressive histone marks. Genome-wide, a strong enrichment for MBD2 at methylated CpG sequences is found, whereas CpGs bound by MBD3 are devoid of methylation. MBD2-bound genes are generally lower expressed as compared with MBD3-bound genes. When depleting cells for MBD2, the MBD2-bound genes increase their activity, whereas MBD2 plus MBD3-bound genes reduce their activity. Most strikingly, MBD3 is enriched at active promoters, whereas MBD2 is bound at methylated promoters and enriched at exon sequences of active genes.

  10. Stemcell Information: SKIP000291 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000291 ... Normal C4 C4 ... -- Female ... -- No Healthy control lin...e for LRRK2 patient #2. Isogenic parent line of C4+G2019S, Subclone of C4 with inserted G2019S mutation. Healthy

  11. Stemcell Information: SKIP000855 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000855 ... Diseased HPS0255 HPS0255 ... アルツハイマー病 G309 Alzheimer disease 104300... ... -- -- Japanese Japanese No No Disease specific iPS cell line derived from a patient with Alzheimer disease アルツハイマー

  12. Stemcell Information: SKIP000854 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000854 ... Diseased HPS0254 HPS0254 ... アルツハイマー病 G309 Alzheimer disease 104300... ... -- -- Japanese Japanese No No Disease specific iPS cell line derived from a patient with Alzheimer disease アルツハイマー

  13. Stemcell Information: SKIP000856 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000856 ... Diseased HPS0256 HPS0256 ... アルツハイマー病 G309 Alzheimer disease 104300... ... -- -- ... No No Disease specific iPS cell line derived from a patient with Alzheimer disease アルツハイマー

  14. Stemcell Information: SKIP000327 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available cal School ... 23836290 10.1007/s00401-013-1149-y Modeling key pathological features of frontotemporal dementia... SKIP000327 ... Diseased Carrier2 #11 Carrier2 #11 ... 前頭側頭型認知症 G310 FrontoTemporal

  15. Stemcell Information: SKIP000324 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available School ... 23836290 10.1007/s00401-013-1149-y Modeling key pathological features of frontotemporal dementia... SKIP000324 ... Diseased Carrier1 #5 Carrier1 #5 ... 前頭側頭型認知症 G310 FrontoTemporal D

  16. Stemcell Information: SKIP000326 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 0.1007/s00401-013-1149-y Modeling key pathological features of frontotemporal dementia... SKIP000326 ... Diseased Carrier2 #1 Carrier2 #1 ... 前頭側頭型認知症 G310 FrontoTemporal D

  17. Stemcell Information: SKIP000325 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available School ... 23836290 10.1007/s00401-013-1149-y Modeling key pathological features of frontotemporal dementia... SKIP000325 ... Diseased Carrier1 #6 Carrier1 #6 ... 前頭側頭型認知症 G310 FrontoTemporal D

  18. Stemcell Information: SKIP000282 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000282 ... Diseased HPS0272 HPS0272 ... アトピー性皮膚炎 L209 Atopic dermatitis 603165... ... -- -- Japanese Japanese Yes No Disease specific iPS cell line derived from a patient : Atopic derm

  19. Stemcell Information: SKIP000236 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000236 ... Diseased HPS0271 HPS0271 ... アトピー性皮膚炎 L210 Atopic dermatitis 603166... ... -- -- ... Yes No iPS cell line derived from Atopic dermatitis patient. Same patient as HPS0270| アトピー

  20. Stemcell Information: SKIP000235 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000235 ... Diseased HPS0270 HPS0270 ... アトピー性皮膚炎 L209 Atopic dermatitis 603165... ... -- -- ... Yes No iPS cell line derived from Atopic dermatitis patient. Same patient as HPS0271| アトピー

  1. Stemcell Information: SKIP000598 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000598 ... Diseased PDB4F-4 PDB4F-4 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  2. Stemcell Information: SKIP000940 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000940 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP04.1 SP04.1 ... パーキンソン病 G20 Parkinson...ic phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  3. Stemcell Information: SKIP000965 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000965 ... Diseased PDB1lox-17Puro-33 PDB1lox-17Puro-33 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  4. Stemcell Information: SKIP000606 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000606 ... Diseased PDD4F-5 PDD4F-5 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  5. Stemcell Information: SKIP000958 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000958 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP13.4 SP13.4 ... パーキンソン病 G20 Parkinson...ls of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimen

  6. Stemcell Information: SKIP000762 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000762 ... Diseased PDB2lox-5 PDB2lox-5 ... パーキンソン病 G20 Parkinson disease 1686...71 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced pluripotent stem cells free of vir

  7. Stemcell Information: SKIP000972 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000972 ... Diseased PDB1lox-21Puro-26 PDB1lox-21Puro-26 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  8. Stemcell Information: SKIP000597 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000597 ... Diseased PDB4F-3 PDB4F-3 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  9. Stemcell Information: SKIP000771 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available e PARK6 600116 ... -- -- ... Yes No iPS cell line derived from a patient with Parkinson's disease, Familial type, PARK6. 家族性パーキンソン... SKIP000771 ... Diseased PKA13 PKA13 ... 家族性パーキンソン病 G20 familial parkinson's diseas

  10. Stemcell Information: SKIP000966 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000966 ... Diseased PDB1lox-21GFP-19 PDB1lox-21GFP-19 ... パーキンソン病 G20 Parkinson...Jaenisch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  11. Stemcell Information: SKIP000764 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000764 ... Diseased PDB2lox-21 PDB2lox-21 ... パーキンソン病 G20 Parkinson disease 16...9371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced pluripotent stem cells free of v

  12. Stemcell Information: SKIP000765 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000765 ... Diseased PDB2lox-22 PDB2lox-22 ... パーキンソン病 G20 Parkinson disease 16...9371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced pluripotent stem cells free of v

  13. Stemcell Information: SKIP000590 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000590 ... Diseased PDB3F-1 PDB3F-1 ... パーキンソン病 G20 Parkinson disease 168600 ... ...e ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived in

  14. Stemcell Information: SKIP000955 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000955 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP12.3 SP12.3 ... パーキンソン病 G20 Parkinson...ls of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimen

  15. Stemcell Information: SKIP000594 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000594 ... Diseased PDB3F-d12 PDB3F-d12 ... パーキンソン病 G20 Parkinson disease 1686...he Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced

  16. Stemcell Information: SKIP000962 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000962 ... Diseased PDB1lox-17Puro-10 PDB1lox-17Puro-10 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  17. Stemcell Information: SKIP000961 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000961 ... Diseased PDB1lox-17Puro-5 PDB1lox-17Puro-5 ... パーキンソン病 G20 Parkinson... Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  18. Stemcell Information: SKIP000605 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000605 ... Diseased PDD4F-4 PDD4F-4 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  19. Stemcell Information: SKIP000953 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000953 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP06.1 SP06.1 ... パーキンソン病 G20 Parkinson...om human iPS-based models of genetic and sporadic Parkinson's disease. Sanchez-Da

  20. Stemcell Information: SKIP000600 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000600 ... Diseased PDC3F-1 PDC3F-1 ... パーキンソン病 G20 Parkinson disease 168600 ... ...titute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived

  1. Stemcell Information: SKIP000596 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000596 ... Diseased PDB4F-2 PDB4F-2 ... パーキンソン病 G20 Parkinson disease 168600 ... ...f Jaenisch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkins...on's disease patient-derived induced pluripotent stem ce

  2. Stemcell Information: SKIP000959 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000959 ... Diseased PDB1lox-17GFP-29 PDB1lox-17GFP-29 ... パーキンソン病 G20 Parkinson...Jaenisch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  3. Stemcell Information: SKIP000591 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000591 ... Diseased PDB3F-5 PDB3F-5 ... パーキンソン病 G20 Parkinson disease 168600 ... ...dolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  4. Stemcell Information: SKIP000608 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000608 ... Diseased PDD4F-9 PDD4F-9 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  5. Stemcell Information: SKIP000970 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000970 ... Diseased PDB1lox-21Puro-18 PDB1lox-21Puro-18 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  6. Stemcell Information: SKIP000609 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000609 ... Diseased PDE3F-3 PDE3F-3 ... パーキンソン病 G20 Parkinson disease 168600 ... ...69371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced plur

  7. Stemcell Information: SKIP000601 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000601 ... Diseased PDD3F-1 PDD3F-1 ... パーキンソン病 G20 Parkinson disease 168600 ... ...19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced p

  8. Stemcell Information: SKIP000943 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000943 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP08.2 SP08.2 ... パーキンソン病 G20 Parkinson...ific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  9. Stemcell Information: SKIP000945 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000945 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP10.1 SP10.1 ... パーキンソン病 G20 Parkinson...e neurons from human iPS-based models of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-

  10. Stemcell Information: SKIP000770 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available PARK6 600116 ... -- -- ... Yes No iPS cell line derived from a patient with Parkinson's disease, Familial type, PARK6. 家族性パーキンソン... SKIP000770 ... Diseased PKA5 PKA5 ... 家族性パーキンソン病 G20 familial parkinson's disease

  11. Stemcell Information: SKIP000971 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000971 ... Diseased PDB1lox-21Puro-20 PDB1lox-21Puro-20 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  12. Stemcell Information: SKIP000952 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000952 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP05.2 SP05.2 ... パーキンソン病 G20 Parkinson...fic phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  13. Stemcell Information: SKIP000950 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000950 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP16.3 SP16.3 ... パーキンソン病 G20 Parkinson...ific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  14. Stemcell Information: SKIP000963 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000963 ... Diseased PDB1lox-17Puro-12 PDB1lox-17Puro-12 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  15. Stemcell Information: SKIP000949 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000949 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP16.2 SP16.2 ... パーキンソン病 G20 Parkinson...s of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimene

  16. Stemcell Information: SKIP000946 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000946 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP10.2 SP10.2 ... パーキンソン病 G20 Parkinson...sease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinso

  17. Stemcell Information: SKIP000960 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000960 ... Diseased PDB1lox-17GFP-55 PDB1lox-17GFP-55 ... パーキンソン病 G20 Parkinson...Jaenisch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  18. Stemcell Information: SKIP000610 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000610 ... Diseased PDE3F-4 PDE3F-4 ... パーキンソン病 G20 Parkinson disease 168600 ... ...69371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced plur

  19. Stemcell Information: SKIP000603 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000603 ... Diseased PDD3F-7 PDD3F-7 ... パーキンソン病 G20 Parkinson disease 168600 ... ...19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced p

  20. Stemcell Information: SKIP000593 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000593 ... Diseased PDB3F-9 PDB3F-9 ... パーキンソン病 G20 Parkinson disease 168600 ... ... ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induc

  1. Stemcell Information: SKIP000968 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000968 ... Diseased PDB1lox-21Puro-12 PDB1lox-21Puro-12 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  2. Stemcell Information: SKIP000937 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000937 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP01.4 SP01.4 ... パーキンソン病 G20 Parkinson...ific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  3. Stemcell Information: SKIP000969 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000969 ... Diseased PDB1lox-21Puro-13 PDB1lox-21Puro-13 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  4. Stemcell Information: SKIP000265 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000265 ... Diseased HPS0264 HPS0264 ... パーキンソン病 G20 Parkinson disease ... ... ... 40-49 Male ... Yes No iPS cell line derived from Parkinson disease patient. パーキンソン病患者由来| human ES-like -- Re

  5. Stemcell Information: SKIP000967 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000967 ... Diseased PDB1lox-21Puro-5 PDB1lox-21Puro-5 ... パーキンソン病 G20 Parkinson... Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  6. Stemcell Information: SKIP000939 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000939 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP02.2 SP02.2 ... パーキンソン病 G20 Parkinson...ic phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  7. Stemcell Information: SKIP000607 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000607 ... Diseased PDD4F-8 PDD4F-8 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  8. Stemcell Information: SKIP000951 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000951 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP05.1 SP05.1 ... パーキンソン病 G20 Parkinson... of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimenez

  9. Stemcell Information: SKIP000944 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000944 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP08.3 SP08.3 ... パーキンソン病 G20 Parkinson....1002/emmm.201200215 Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  10. Stemcell Information: SKIP000942 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000942 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP08.1 SP08.1 ... パーキンソン病 G20 Parkinson...s of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimene

  11. Stemcell Information: SKIP000936 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000936 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP01.1 SP01.1 ... パーキンソン病 G20 Parkinson...s of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimene

  12. Stemcell Information: SKIP000602 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000602 ... Diseased PDD3F-4 PDD3F-4 ... パーキンソン病 G20 Parkinson disease 168600 ... ...19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced p

  13. Stemcell Information: SKIP000599 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000599 ... Diseased PDB4F-5 PDB4F-5 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  14. Stemcell Information: SKIP000974 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000974 ... Diseased PDB1lox-21GFP-41 PDB1lox-21GFP-41 ... パーキンソン病 G20 Parkinson...Jaenisch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  15. Stemcell Information: SKIP000763 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000763 ... Diseased PDB2lox-17 PDB2lox-17 ... パーキンソン病 G20 Parkinson disease 16...9371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived induced pluripotent stem cells free of v

  16. Stemcell Information: SKIP000589 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000589 ... Diseased PDA3F-5 PDA3F-5 ... パーキンソン病 G20 Parkinson disease 168600 ... ...Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkins...on's disease patient-derived induced pluripotent stem cells free of viral reprogram

  17. Stemcell Information: SKIP000595 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000595 ... Diseased PDB4F-1 PDB4F-1 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  18. Stemcell Information: SKIP000592 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000592 ... Diseased PDB3F-8 PDB3F-8 ... パーキンソン病 G20 Parkinson disease 168600 ... ...ute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patient-derived

  19. Stemcell Information: SKIP000956 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000956 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP12.4 SP12.4 ... パーキンソン病 G20 Parkinson...cific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  20. Stemcell Information: SKIP000973 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000973 ... Diseased PDB1lox-21Puro-28 PDB1lox-21Puro-28 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  1. Stemcell Information: SKIP000964 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000964 ... Diseased PDB1lox-17Puro-31 PDB1lox-17Puro-31 ... パーキンソン病 G20 Parkinson...ch Rudolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  2. Stemcell Information: SKIP000604 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000604 ... Diseased PDD4F-1 PDD4F-1 ... パーキンソン病 G20 Parkinson disease 168600 ... ...head Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson's disease patie

  3. Stemcell Information: SKIP000957 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000957 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP13.2 SP13.2 ... パーキンソン病 G20 Parkinson...cific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  4. Stemcell Information: SKIP000542 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000542 ... Diseased PDA3F-1 PDA3F-1 ... パーキンソン病 G20 Parkinson disease 168600 ... ...udolf Jaenisch Available The Whitehead Institute The Whitehead Institute ... 19269371 10.1016/j.cell.2009.02.013 Parkinson

  5. Stemcell Information: SKIP000954 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000954 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP06.2 SP06.2 ... パーキンソン病 G20 Parkinson... of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimenez

  6. Stemcell Information: SKIP000948 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000948 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP14.2 SP14.2 ... パーキンソン病 G20 Parkinson...ic phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson

  7. Stemcell Information: SKIP000294 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000294 ... Normal C1-1 C1-1 ... -- Female ... -- No Healthy control... line for L1-1,2Mut. Born in 1959 Healthy control line for L1-1,2Mut. Born in 1959 -- Research Grade Lentivi

  8. Stemcell Information: SKIP001118 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001118 ... Diseased D3-2 D3-2 ... 大うつ病 F33.3 major depression 605210 ... ...-- Male ... Yes No iPS cells derived from fibroblasts of a patient in which a frameshift mutation of disrupted in major depression

  9. Stemcell Information: SKIP001117 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001117 ... Diseased D3-1 D3-1 ... 大うつ病 F33.3 major depression 605210 ... ...-- Male ... Yes No iPS cells derived from fibroblasts of a patient in which a frameshift mutation of disrupted in major depression

  10. Stemcell Information: SKIP000245 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000245 ... Diseased HPS0164 HPS0164 ... デュシェンヌ型筋ジストロフィー G710 Duchenne Muscular... Dystrophy 310200 ... -- -- ... Yes No intractable disease-specific iPSC derived from Duchenne Muscular Dystrophy. デュシェンヌ型筋ジストロフィー

  11. Stemcell Information: SKIP000181 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000181 ... Diseased GM23225 GM23225 ... ハンチントン病 G10 Huntington disease 143100 ... ... 20 20-29 Female ... Yes No iPSCs derived from GM04281 Fibroblast. HTT CAG repeats are 17 and 72. 遺伝性ハンチントン

  12. Stemcell Information: SKIP000317 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000317 ... Diseased HD180i.5 HD180i.5 ... ハンチントン病 G10 Huntington's Disease 143...nduced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated p

  13. Stemcell Information: SKIP000828 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000828 ... Diseased HPS0263 HPS0263 ... ハンチントン病 G10 Huntington disease 143100 ... ... -- Unknown Japanese Japanese Yes No Disease specific iPS cell line derived from a patient,Huntington disease. ハンチントン

  14. Stemcell Information: SKIP000316 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000316 ... Diseased HD60i.4 HD60i.4 ... ハンチントン病 G10 Huntington's Disease 14310....04.027 Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-ass

  15. Stemcell Information: SKIP000315 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000315 ... Diseased HD33i.8 HD33i.8 ... ハンチントン病 G10 Huntington's Disease 14310...rtium ... 22748968 10.1016/j.stem.2012.04.027 Induced pluripotent stem cells from patients with Huntington'

  16. Stemcell Information: SKIP000253 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 21490598 10.1038/nature09915 Modelling schizophrenia using human induced pluripo... SKIP000253 ... Diseased GM23760 GM23760 ... 統合失調症 F20 Schizophrenia 181500 ... ...(SCZD) .episodes of agitatation, delusions of persecutation, fear of assassination, father also affected. 統合失調症

  17. Stemcell Information: SKIP000284 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000284 ... mesenchymal stem cell 間葉系幹細胞 Umbilical cord blood 臍帯血 Normal UCB302MS...chymal stem cells. ... finite and slow proliferation 臍帯血由来間葉系幹細胞(有限増殖, 増殖はきわめて遅い) fibroblast-like -- -- ... Yes --

  18. Stemcell Information: SKIP000285 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000285 ... mesenchymal stem cell 間葉系幹細胞 Umbilical cord blood 臍帯血 Normal UCBTERT-...nchymal stem cells. Immortalized by hTERT 臍帯血由来間葉系幹細胞 hTERTによる不死化 fibroblast-like -- Retrovirus recombinant

  19. Stemcell Information: SKIP000287 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000287 ... mesenchymal stem cell 間葉系幹細胞 Umbilical cord blood 臍帯血 Normal UCB408E7...senchymal stem cells with transgenic HPV E7. finite proliferation 臍帯血由来間葉系幹細胞 (有限増殖) fibroblast-like -- Retr

  20. Stemcell Information: SKIP000241 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000241 ... Diseased HPS0183 HPS0183 ... 封入体筋炎 G724 Inclusion body myositis 147...421 ... -- -- ... Yes No intractable disease-specific iPSC derived from Inclution body myositis. 封入体筋炎患者由

  1. Stemcell Information: SKIP000914 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000914 ... Diseased IR-M3 IR-M3 GM20034 GM20034 ドナヒュー症候群 E348 Donohue Syndro...me 246200 ... 0-9 Male ... Yes No Specific disease iPS cell line from patient with Donohue Syndrome ドナヒュー症候群

  2. Stemcell Information: SKIP001066 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001066 ... Diseased LQT3 LQT3 ... QT延長症候群 I45.81 Long QT Syndrome 192500 ... ... ... -- Unknown ... Yes No Specific disease iPS cell line from patient with Long QT Syndrom QT延長症候群患者由来iPS細胞 hu

  3. Stemcell Information: SKIP000738 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000738 ... Diseased GM25305 GM25305 ... QT延長性症候群 I490 LONG QT SYNDROME 2 61368...8 ... 48 40-49 Female Chinese Chinese Yes No LONG QT SYNDROME 2 hiPSC derived from fibroblast QT延長症候群患者線

  4. Stemcell Information: SKIP000912 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000912 ... Diseased IR-M1 IR-M1 Minn1 Minn1 ドナヒュー症候群 E348 Donohue Syndrome 2...46200 ... 0-9 Female ... Yes No Specific disease iPS cell line from patient with Donohue Syndrome ドナヒュー症候群

  5. Stemcell Information: SKIP000279 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000279 ... Diseased HPS0192 HPS0192 ... 杉花粉症 J301 Allergic rhinitis (Pollen allergy) 607154 食物...アレルギー(カニ) T781 food allergy (crab) ... -- -- Japanese Japanese No No Disease specific iPS

  6. Stemcell Information: SKIP000296 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000296 ... Normal C2 C2 ... -- Female ... -- No Healthy control lin...e for L2-1,2,3Mut. Born in 1931 Healthy control line for L2-1,2,3Mut. Born in 1931 -- -- -- ... -- ... Yes I

  7. Stemcell Information: SKIP000175 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available le Black Black -- No Apparently healthy iPSCs from fetal lung fibroblast cell culture (GM06114) 健常胎児肺線維芽細胞(GM06114)由来iPS細胞... SKIP000175 ... Lung Fibroblast 肺線維芽細胞 Normal GM23392 GM23392 ... 0-9 Ma

  8. Stemcell Information: SKIP001141 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001141 ... cardiac fibroblast 心臓線維芽細胞 Normal ATCC-CYS0105 ATCC-CYS0105 ... ...mary cardiac fibroblasts obtained from a healthy donor. ... 健常人の心臓線維芽細胞由来iPS細胞。 human ES-like Research Grade Se

  9. Stemcell Information: SKIP000888 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000888 ... T cells T細胞 Normal 24HM 24HM ... 24 20-29 Male Japanese 日本人 -- No iPS cell...s from healthy human T cells ヒト健常人由来iPS細胞 human ES-like Research Grade Plasmid OCT4,SOX2,KL

  10. Stemcell Information: SKIP000582 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000582 ... Diseased HCM 512519 HCM 512519 HCM 2 HCM 2 肥大型心筋症 I422 Hypertrophic cardiomyopathy...ces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripot...MXs-Oct4, pMXs-Sox2, pMXs-Klf4, and pMXs-c-Myc encoding (mouse) reprogramming fac

  11. Stemcell Information: SKIP000186 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000186 ... Diseased iPS-WT iPS-WT GM23241 GM23241 脊髄性筋委縮症Ⅰ型 G120 Infantile spinal muscular atrophy...tem cells from a spinal muscular atrophy patient. Ebert, A.D. and Svendsen, C.N.--Ebert AD, Yu J, Rose FF Jr

  12. Stemcell Information: SKIP000555 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000555 ... Diseased HPS0191 HPS0191 ... ベルナール・スーリエ症候群 D69.1 Bernard-Soulier syndrome... 231200 ... -- -- ... No No Disease specific iPS cell line derived from Bernard-Soulier syndrome patient ベルナール·スーリエ症候群

  13. Stemcell Information: SKIP000239 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000239 ... Diseased HPS0214 HPS0214 ... エーラース・ダンロス症候群 Q796 Ehlers-Danlos syndrome... 130000 ... -- -- ... Yes No intractable disease-specific iPSC derived from Ehlers-Danlos syndrome, ne

  14. Stemcell Information: SKIP000735 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000735 ... Unknown 不明 Diseased GM24683 GM24683 ... 嚢胞性線維症 E849 CYSTIC FIBROSIS 2...19700 ... 13 10-19 Male ... Yes No CYSTIC FIBROSIS hiPSC derived from parental fibroblast GM01014 囊胞性線維症患者

  15. Stemcell Information: SKIP000298 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... 23472874 10.1016/j.stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinsoni... SKIP000298 ... Diseased L2-2Mut L2-2Mut ... パーキンソン病 G20 Parkinson's disease 607060

  16. Stemcell Information: SKIP000301 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... Information Only ... 23472874 10.1016/j.stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinson... SKIP000301 ... Diseased L2-2GC L2-2GC ... パーキンソン病 G20 Parkinson's disease 607060 ...

  17. Stemcell Information: SKIP000293 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... 23472874 10.1016/j.stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinson... SKIP000293 ... Diseased L1-1GC2 L1-1GC2 ... パーキンソン病 G20 Parkinson's disease 607060

  18. Stemcell Information: SKIP000290 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 1016/j.stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegene... SKIP000290 ... Diseased L1-1Mut L1-1Mut ... パーキンソン病 G20 Parkinson's disease 607060

  19. Stemcell Information: SKIP000299 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... 23472874 10.1016/j.stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinsoni... SKIP000299 ... Diseased L2-3Mut L2-3Mut ... パーキンソン病 G20 Parkinson's disease 607060

  20. Stemcell Information: SKIP000300 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... 23472874 10.1016/j.stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinson... SKIP000300 ... Diseased L2-1GC L2-1GC ... パーキンソン病 G20 Parkinson's disease 607060 ...

  1. Stemcell Information: SKIP000292 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration ... SKIP000292 ... Diseased L1-2Mut L1-2Mut ... パーキンソン病 G20 Parkinson's disease 607060

  2. Stemcell Information: SKIP000302 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... Information Only ... 23472874 10.1016/j.stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinso... SKIP000302 ... Diseased L2-3GC L2-3GC ... パーキンソン病 G20 Parkinson's disease 607060 ...

  3. Stemcell Information: SKIP000297 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available j.stem.2013.01.008 Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneratio... SKIP000297 ... Diseased L2-1Mut L2-1Mut ... パーキンソン病 G20 Parkinson's disease 607060

  4. Stemcell Information: SKIP000815 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000815 ... Diseased ACH-8857-1 ACH-8857-1 ... 軟骨無形成症 Q774 Achondroplasia 10080...0 ... 34 30-39 Male Japanese Japanese Yes No Achondroplasia(GM08857)-specific iPSC.GM08857 is from the father of GM08859. 軟骨無形成症

  5. Stemcell Information: SKIP000739 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000739 ... Unknown 不明 Diseased GM25318 GM25318 ... 結節性硬化症 Q85.1 TUBEROUS SCLEROSIS... 2 613254 ... 26 20-29 Female ... Yes No TUBEROUS SCLEROSIS 2 hiPSC line derived from fibroblast GM06102 結節性硬化

  6. Stemcell Information: SKIP000626 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000626 ... Diseased CiRA00021 CiRA00021 HP0327 HP0327 筋萎縮性側索硬化症 G122 Amyotro...rived from a patient : Amyotrophic lateral sclerosis. HPS0290 and HPS0291 are derived from the same patient. 筋萎縮性側索硬化

  7. Stemcell Information: SKIP000809 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000809 ... Diseased HPS0148 HPS0148 ... 孤発性筋萎縮性側索硬化症 (bulbar, with UMN) ... Amyot...ng the Sendai virus vector. Order Form to RIKEN BRC: C-0042, C-0057, C-0007 or C-0007p. 孤発性筋萎縮性側索硬化症 (bulbar

  8. Stemcell Information: SKIP000806 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000806 ... Diseased HPS0059 HPS0059 ... 筋萎縮性側索硬化症 G12.2 Amyotrophic lateral sc...otrophic lateral sclerosis with TDP-43 mutation. Order Form to Riken BioResouce Center (C-0042, C-0057, C-00

  9. Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable - Molecular pathology of mutations in PAH exon 11

    DEFF Research Database (Denmark)

    Heintz, Caroline; Dobrowolski, Steven F.; Andersen, Henriette Skovgaard

    2012-01-01

    distributed throughout the exon. Finally, we identified a pseudoexon in intron 11, which would have pathogenic consequences if activated by mutations or improved splicing conditions. Exonic mutations that disrupt splicing are unlikely to facilitate response to BH(4) and may lead to inconsistent genotype......In about 20-30% of phenylketonuria (PKU) patients, phenylalanine (Phe) levels can be controlled by cofactor 6R-tetrahydrobiopterin (BH(4)) administration. The phenylalanine hydroxylase (PAH) genotype has a predictive value concerning BH(4)-response and therefore a correct assessment of the mutation...... molecular pathology is important. Mutations that disturb the splicing of exons (e.g. interplay between splice site strength and regulatory sequences like exon splicing enhancers (ESEs)/exon splicing silencers (ESSs)) may cause different severity of PKU. In this study, we identified PAH exon 11...

  10. Characteristics of transposable element exonization within human and mouse.

    Directory of Open Access Journals (Sweden)

    Noa Sela

    Full Text Available Insertion of transposed elements within mammalian genes is thought to be an important contributor to mammalian evolution and speciation. Insertion of transposed elements into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization. Elucidation of the evolutionary constraints that have shaped fixation of transposed elements within human and mouse protein coding genes and subsequent exonization is important for understanding of how the exonization process has affected transcriptome and proteome complexities. Here we show that exonization of transposed elements is biased towards the beginning of the coding sequence in both human and mouse genes. Analysis of single nucleotide polymorphisms (SNPs revealed that exonization of transposed elements can be population-specific, implying that exonizations may enhance divergence and lead to speciation. SNP density analysis revealed differences between Alu and other transposed elements. Finally, we identified cases of primate-specific Alu elements that depend on RNA editing for their exonization. These results shed light on TE fixation and the exonization process within human and mouse genes.

  11. Exonic remnants of whole-genome duplication reveal cis-regulatory function of coding exons.

    Science.gov (United States)

    Dong, Xianjun; Navratilova, Pavla; Fredman, David; Drivenes, Øyvind; Becker, Thomas S; Lenhard, Boris

    2010-03-01

    Using a comparative genomics approach to reconstruct the fate of genomic regulatory blocks (GRBs) and identify exonic remnants that have survived the disappearance of their host genes after whole-genome duplication (WGD) in teleosts, we discover a set of 38 candidate cis-regulatory coding exons (RCEs) with predicted target genes. These elements demonstrate evolutionary separation of overlapping protein-coding and regulatory information after WGD in teleosts. We present evidence that the corresponding mammalian exons are still under both coding and non-coding selection pressure, are more conserved than other protein coding exons in the host gene and several control sets, and share key characteristics with highly conserved non-coding elements in the same regions. Their dual function is corroborated by existing experimental data. Additionally, we show examples of human exon remnants stemming from the vertebrate 2R WGD. Our findings suggest that long-range cis-regulatory inputs for developmental genes are not limited to non-coding regions, but can also overlap the coding sequence of unrelated genes. Thus, exonic regulatory elements in GRBs might be functionally equivalent to those in non-coding regions, calling for a re-evaluation of the sequence space in which to look for long-range regulatory elements and experimentally test their activity.

  12. NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity.

    Science.gov (United States)

    Chamieh, Hala; Ballut, Lionel; Bonneau, Fabien; Le Hir, Hervé

    2008-01-01

    Nonsense-mediated mRNA decay (NMD) eliminates mRNAs containing a premature translation termination codon through the recruitment of the conserved NMD factors UPF1, UPF2 and UPF3. In humans, a dynamic assembly pathway allows UPF1 to join UPF2 and UPF3 recruited to the mRNA by the exon-junction complex (EJC). Here we show that the recombinant EJC core is sufficient to reconstitute, with the three UPF proteins, a stable heptameric complex on RNA. The EJC proteins MAGOH, Y14 and eIF4AIII provide a composite binding site for UPF3b that serves as a bridge to UPF2 and UPF1. In the UPF trimeric complex, UPF2 and UPF3b cooperatively stimulate both ATPase and RNA helicase activities of UPF1. This work demonstrates that the EJC core is sufficient to stably anchor the UPF proteins to mRNA and provides insights into the regulation of its central effector, UPF1.

  13. Stemcell Information: SKIP000733 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available https://catalog.coriell.org ... 22278060 10.1038/nature10821 Probing sporadic and familial Alzheimer's disea... SKIP000733 ... Diseased GM24666 GM24666 sAD2 sAD2 アルツハイマー病 G309 ALZHEIMER DISEAS...E 104300 ... 83 80-89 Male ... Yes Yes ALZHEIMER DISEASE(Sporadic AD) hiPSC derived from fibroblast アルツハイマー

  14. Stemcell Information: SKIP000048 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000048 ... Diseased A000010#3-4 A000010#3-4 ... 家族性筋委縮性側索硬化症 G122 (amyotrophic... lateral sclerosis) 105400 ... -- -- ... Yes No intractable disease-specific iPSC, Familial ALS 難病性疾患克服事業iPS細胞バンク 家族

  15. Stemcell Information: SKIP001079 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001079 ... Fibroblast 線維芽細胞 Diseased ND35670 ND35670 NDS00074 NDS00074 筋萎縮性側索硬...t. SOD1 V148G mutation ALS 患者由来 (線維芽細胞) SOD1 V148G変異 human ES-like Research Grade Retrovirus Oct4, Sox2, Klf

  16. Stemcell Information: SKIP001077 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001077 ... Fibroblast 線維芽細胞 Diseased ND35668 ND35668 ... 筋萎縮性側索硬化症 G122 amyotrop...1 E49K mutation ALS 由来 (ND39026 線維芽細胞) SOD1 E49K 変異 ... human ES-like Research Grade Retrovirus Oct4, Sox2, Klf

  17. Stemcell Information: SKIP000938 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000938 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP02.1 SP02.1 ... パーキンソン病 G20 Parkinson...of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimenez-...0215 Disease-specific phenotypes in dopamine neurons from human iPS-based models

  18. Stemcell Information: SKIP000947 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000947 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP14.1 SP14.1 ... パーキンソン病 G20 Parkinson...of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimenez-...0215 Disease-specific phenotypes in dopamine neurons from human iPS-based models

  19. Stemcell Information: SKIP000941 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000941 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP04.2 SP04.2 ... パーキンソン病 G20 Parkinson...of genetic and sporadic Parkinson's disease. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimenez-...0215 Disease-specific phenotypes in dopamine neurons from human iPS-based models

  20. Stemcell Information: SKIP000189 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000189 ... Diseased GM23404 GM23404 ... フリードライヒ運動失調症 G111 Friedreich ataxia (a....2010.09.014 Friedreich's ataxia induced pluripotent stem cells model intergenera... (GM04078/GM04079) is similarly affected; homozygous for the GAATTC expansion in the 1st intron in frataxin gene. フリードライヒ運動失調

  1. Stemcell Information: SKIP001076 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001076 ... Fibroblast 線維芽細胞 Diseased ND35666 ND35666 ... 筋萎縮性側索硬化症 G122 amyotrop...mutation. Same subject as ND20522 (LCL) ALS 由来 (ND29509線維芽細胞) SOD1 D91A変異 LCL (ND20522)有 human ES-like Resea

  2. Stemcell Information: SKIP001116 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001116 ... Diseased D2-2 D2-2 ... 統合失調症 F209 schizophrenia ... 605210 ... 39 ...30-39 Female ... Yes No iPS cells derived from fibroblasts of a patient in which a frameshift mutation of disrupted in schizophrenia... 1 ( DISC1 ) 統合失調症患者由来iPS細胞 human ES-like Research Grade Plasmid OCT4,SOX2,KLF4,c-MYC,

  3. Stemcell Information: SKIP001115 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001115 ... Diseased D2-1 D2-1 ... 統合失調症 F209 schizophrenia ... 605210 ... 39 ...30-39 Female ... Yes No iPS cells derived from fibroblasts of a patient in which a frameshift mutation of disrupted in schizophrenia... 1 ( DISC1 ) 統合失調症患者由来iPS細胞 human ES-like Research Grade Plasmid OCT4,SOX2,KLF4,c-MYC,

  4. Stemcell Information: SKIP000261 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available Sample_Detail.aspx?Ref=GM23762&PgId=166 ... 21490598 10.1038/nature09915 Modelling schizophrenia using human... SKIP000261 ... Diseased GM23762 GM23762 ... 統合失調症 F20 Schizophrenia 181500 ... ...cally affected with Shizophrenia(SCZD) . 統合失調症患者線維芽細胞(GM02497)由来iPS細胞株。 | human ES-like -- Retrovirus Oct4,

  5. Stemcell Information: SKIP000260 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available x?Ref=GM23761&PgId=166 ... 21490598 10.1038/nature09915 Modelling schizophrenia using human induced pluripot... SKIP000260 ... Diseased GM23761 GM23761 ... 統合失調症 F20 Schizophrenia 181500 ... ...h Shizophrenia(SCZD) . | 統合失調症患者線維芽細胞(GM01835)由来iPS細胞株| human ES-like -- Lentivirus Oct4, Sox2, Klf4, c-Myc,

  6. Stemcell Information: SKIP000182 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000182 ... Diseased GM23226 GM23226 ... 1型糖尿病 E10 diabetes (mellitus), juvenil...roblast. Multifactorial Defect 遺伝性若年発症I型糖尿病患者線維芽細胞(GM02416)由来iPS細胞 多因子の異常 human ES-like -- Retrovirus Oct4,

  7. Stemcell Information: SKIP000793 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000793 ... Diseased LQT1 PIII-2a LQT1 PⅢ-2a ... 遺伝性QT延長症候群1型 I45.81 long-QT sy...r Long-QT Syndrome type1 QT 延長症候群 1 型患者由来iPS細胞 human ES-like Research Grade Retrovirus OCT3/4 SOX2 KLF4 c-MY

  8. Stemcell Information: SKIP000264 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000264 ... Diseased HPS0156 HPS0156 ... ローレンス・ムーン症候群(バルデー・ビードル症候群) Q878 Lauren...me patient. Bardet-Biedls症候群患者由来iPS細胞。| human ES-like -- Sendai virus SeV18+HS-OCT3/4/TSdeltaF, SeV18+HS-SOX

  9. Stemcell Information: SKIP000283 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000283 ... Diseased HPS0082 HPS0082 iPWS5 iPWS5 プラダー・ウィリー症候群 Q871 Prader Wil...patient of Prader Willi syndrome(RCB1560 PWS-Yamaguchi). del(15) was found in lymphocytes of the patient. 疾患特異的iPS細胞株。プラダー·ウィリー症候群症候群

  10. Stemcell Information: SKIP000333 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000333 ... mesenchymal stem cell 間葉系幹細胞 polydactylous human fingers 指 Normal Yub...ター研究所 ... Not Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cell... 10F Yub 10F JCRB1116 JCRB1116 ... -- -- ... -- No JCRB1116 mesenchymal stem cell finite proliferatio

  11. Stemcell Information: SKIP000332 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000332 ... mesenchymal stem cell 間葉系幹細胞 polydactylous human fingers 指 Normal Yub...ー研究所 ... Not Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cell...623 Yub623 JCRB1115 JCRB1115 ... -- -- ... -- No JCRB1115 mesenchymal stem cell. finite proliferation

  12. Stemcell Information: SKIP000176 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available male Black Black -- No Apparently healthy iPSCs from APPARENTLY HEALTHY FETAL lung fibroblast cell culture (GM06112) 健常胎児肺線維芽細胞... SKIP000176 ... Lung Fibroblast 肺線維芽細胞 Normal GM23413 GM23413 ... 0-9 Fe...(GM06112)由来iPS細胞株 human ES-like -- Retrovirus Oct4, Sox2, Klf, c-Myc, retroviral vectors

  13. Stemcell Information: SKIP001078 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001078 ... Fibroblast 線維芽細胞 Diseased ND35669 ND35669 NDS00076 NDS00076 筋萎縮性側索硬...(SNP, no amino acid change) ... ALS 患者由来 (線維芽細胞) FIG4 27C>T (SNP アミノ酸置換なし) ... human ES-like Research Grade Retrov

  14. Stemcell Information: SKIP000766 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ed pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy... SKIP000766 ... Diseased ARVC-iPSC ARVC-iPSC ... 不整脈源性右室心筋症 I428 arrhythmogenic right ventricular cardiomyop...athy 609040 ... 30 30-39 Male Chinese ... Yes No Disease specific iPS cell from ARVC. ... 不整脈源性右室心筋症

  15. Stemcell Information: SKIP000792 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 欠陥多動障害 F900 attention deficit-hyperactivity disorder 143465 ... 8 0-9 Male ... Yes No Pa... SKIP000792 ... Diseased LQT1 PII-2a LQT1 PⅡ-2a ... 遺伝性QT延長症候群1型 I45.81 long-QT syndrome type 1 192500 注意

  16. Stemcell Information: SKIP000791 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000791 ... Diseased 7643-32 7643-32 ... ティモシー症候群 I45.8 Timothy syndrome 601005... ... -- -- ... Yes No Human iPSCs.The Timothy syndrome iPSCs preserved the Timothy syndrome mutation. 疾患特異的iPS細胞。ティモシー症候群... investigate cardiac phenotypes in Timothy syndrome. Yazawa M, Hsueh B, Jia X, Pa

  17. Stemcell Information: SKIP000038 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000038 ... Diseased A000006#4-3 A000006#4-3 ... 遠位型筋ジストロフィー G710 Muscular dyst...rophy ... -- -- ... Yes No intractable disease-specific iPSC 難病性疾患克服事業iPS細胞バンク 三好型筋ジストロフィー human ES-like

  18. Stemcell Information: SKIP000273 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000273 ... Diseased HPS0133 HOS0133 ... 三好型筋ジストロフィー G710 Muscular dystrophy, M... derived from a patient: Muscular dystrophy, Miyoshi type (Miyoshi myopathy). ... 疾患特異的iPS細胞株。三好型筋ジストロフィー患者由来。セ

  19. Stemcell Information: SKIP000556 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000556 ... Diseased HPS0200 HPS0200 ... 肢体型筋ジストロフィー G71.0 Muscular dystrophy, ...y, Limb-girdle type patient 肢帯型筋ジストロフィー患者由来疾患特異的iPS細胞株 human ES-like Research Grade Sendai virus SeV18+HS-OC

  20. Stemcell Information: SKIP000037 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000037 ... Diseased A000006#4-2 A000006#4-2 ... 遠位型筋ジストロフィー G710 Muscular dyst...rophy ... -- -- ... Yes No intractable disease-specific iPSC 難病性疾患克服事業iPS細胞バンク 三好型筋ジストロフィー human ES-like

  1. Stemcell Information: SKIP000183 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000183 ... Diseased GM23230 GM23230 ... ベッカー型筋ジストロフィー G710 Muscular dystrophy,... showed no detectable mutations. ... ベッカー型筋ジストロフィー患者線維芽細胞(GM04569) 由来。 22歳発症。 責任変異不明 human ES-like -- Retroviru

  2. Stemcell Information: SKIP000270 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000270 ... Diseased HPS0087 HPS0087 iOCT4 iOCT4 オルニチントランスカルバミナーゼ欠損症 E724 Orn...ine derived from a patient: Ornithinetranscarbamylase deficiency (RCB0492 OTCD1TKB). ... 疾患特異的iPS細胞株。オルニチントランスカ

  3. Stemcell Information: SKIP000035 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000035 ... Diseased A000054# 4 A000054# 4 ... オルニチントランスカルバミラーゼ欠損症 E724 ornithi...ific iPS cell line derived from a patient: Ornithinetranscarbamylase deficiency ... 難病性疾患克服事業iPS細胞バンク|オルニチントランス

  4. Stemcell Information: SKIP000052 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000052 ... Diseased A000023#7 A000023#7 ... 孤発性筋委縮性側索硬化症 G122 (amyotrophic lat...eral sclerosis) 105400 ... -- -- ... Yes No intractable disease-specific iPSC, sporadic ALS, bulbar, with UMN| 難病性疾患孤発性筋委縮性側索硬化

  5. Stemcell Information: SKIP000614 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000614 ... Diseased HPS0142 HPS0142 ... 家族性筋萎縮性側索硬化症 G122 Amyotrophic lateral ... a patient.Amyotrophic lateral sclerosis, Familial type. ... 疾患特異的iPS細胞株。家族性筋萎縮性側索硬化症患者由来。 human ES-like Resear

  6. Stemcell Information: SKIP000775 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000775 ... Unknown 不明 Diseased FALS-e54 FALS-e54 ... 筋萎縮性脊索硬化症 G122 (amyotrophic...ype, FUS mutation. 家族性筋萎縮性脊索硬化症(FUS遺伝子変異)患者由来iPS細胞株 human ES-like Research Grade Plasmid episomal plasmid ve

  7. Stemcell Information: SKIP000272 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000272 ... Diseased HPS0129 HPS0129 ... 孤発性筋萎縮性側索硬化症 ... (classical, with UMN) G1...assical, with UMN). ... 疾患特異的iPS細胞株。孤発性筋萎縮性側索硬化症 (classical, with UMN)患者由来。センダイウイルスベ

  8. Stemcell Information: SKIP000776 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000776 ... Unknown 不明 Diseased FALS-e46 FALS-e46 ... 筋萎縮性脊索硬化症 G122 (amyotrophic...ype, FUS mutation. 家族性筋萎縮性脊索硬化症(FUS遺伝子変異)患者由来iPS細胞株 human ES-like Research Grade Plasmid episomal plasmid ve

  9. Stemcell Information: SKIP000774 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000774 ... Diseased FALS-2e2 FALS-2e2 ... 筋萎縮性脊索硬化症 G122 (amyotrophic lateral ...e, FUS mutation. 家族性筋萎縮性脊索硬化症(FUS遺伝子変異)患者由来iPS細胞株 human ES-like Research Grade Plasmid episomal plasmid vect

  10. Stemcell Information: SKIP000232 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000232 ... Diseased CiRA00026 CiRA00026 HPS0294 HPS0294 筋萎縮性側索硬化症 G122 Amyot...rived from skin fibroblast. TDP-43 mutation Same patient as CiRA00024, CiRA00025. 筋萎縮性側索硬化症(TDP-43遺伝子変異) iPS

  11. Stemcell Information: SKIP000040 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000040 ... Diseased A000007#5 A000007#5 ... 孤発性筋委縮性側索硬化症 G122 (amyotrophic lat...euritic without UMN| 難病性疾患克服事業iPS細胞バンク 孤発性ALS psuedo-polyneuritic without UMN|孤発性筋委縮性側索硬化症 (pseudo-polyneuri

  12. Stemcell Information: SKIP000777 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000777 ... Unknown 不明 Diseased FALS-e48 FALS-e48 ... 筋萎縮性脊索硬化症 G122 (amyotrophic...ype, FUS mutation. 家族性筋萎縮性脊索硬化症(FUS遺伝子変異)患者由来iPS細胞株 human ES-like Research Grade Plasmid episomal plasmid ve

  13. Stemcell Information: SKIP000613 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000613 ... Diseased HPS0140 HPS0140 ... 家族性筋萎縮性側索硬化症 G122 Amyotrophic lateral ... a patient.Amyotrophic lateral sclerosis, Familial type. ... 疾患特異的iPS細胞株。家族性筋萎縮性側索硬化症患者由来。 human ES-like Resear

  14. Stemcell Information: SKIP000772 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000772 ... Diseased FALS-2e3 FALS-2e3 ... 筋萎縮性脊索硬化症 G122 (amyotrophic lateral ...e, FUS mutation. 家族性筋萎縮性脊索硬化症(FUS遺伝子変異)患者由来iPS細胞株 human ES-like Research Grade Plasmid episomal plasmid vect

  15. Stemcell Information: SKIP000615 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000615 ... Diseased HPS0147 HPS0147 ... 孤発性筋萎縮性側索硬化症(bulbar, with UMN) G122 Am...cell line derived from a patient : Amyotrophic lateral sclerosis, Sporadic type (bulbar, with UMN) 疾患特異的iPS細胞株。孤発性筋萎縮性側索硬化

  16. Stemcell Information: SKIP000230 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000230 ... Diseased CiRA00024 CiRA00024 HPS0292 HPS0292 筋萎縮性側索硬化症 G122 Amyot...erived from skin fibroblast. TDP-43 mutation Same patient as CiRA00025, CiRA00026. 筋萎縮性側索硬化症(TDP-43遺伝子変異) iP

  17. Stemcell Information: SKIP000853 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000853 ... Diseased HPS0249 ... HPS0249 ... 筋萎縮性側索硬化症 G122 Amyotrophic lateral s...ic lateral sclerosis. ... 筋萎縮性側索硬化症(TDP-43遺伝子変異)患者由来疾患特異的iPS細胞株。ガラス化法保存。 human ES-like Research Grade Plasmid e

  18. Stemcell Information: SKIP000773 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000773 ... Diseased FALS-2e23 FALS-2e23 ... 筋萎縮性脊索硬化症 G122 (amyotrophic latera...ype, FUS mutation. 家族性筋萎縮性脊索硬化症(FUS遺伝子変異)患者由来iPS細胞株 human ES-like Research Grade Plasmid episomal plasmid ve

  19. Stemcell Information: SKIP000228 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000228 ... Diseased CiRA00022 CiRA00022 HP0290 HP0290 筋萎縮性側索硬化症 G122 Amyotro...d from skin fibroblast. TDP43 mitation. Same patient as CiRA00023. 筋萎縮性側索硬化症(TDP-43遺伝子変異) iPS細胞。CiRA00023 HP

  20. Stemcell Information: SKIP000231 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000231 ... Diseased CiRA00025 CiRA00025 HPS0293 HPS0293 筋萎縮性側索硬化症 G122 Amyot...erived from skin fibroblast. TDP-43 mutation Same patient as CiRA00024, CiRA00026. 筋萎縮性側索硬化症(TDP-43遺伝子変異) iP

  1. Stemcell Information: SKIP000046 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000046 ... Diseased A000010#1-8 A000010#1-8 ... 家族性筋委縮性側索硬化症 G122 (amyotrophic... lateral sclerosis) 105400 ... -- -- ... Yes No intractable disease-specific iPSC, Familial ALS| 難病性疾患克服事業iPS細胞バンク |家族性筋委縮性側索硬化

  2. Stemcell Information: SKIP000229 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000229 ... Diseased CiRA00023 CiRA00023 HP0291 HP0291 筋萎縮性側索硬化症 G122 Amyotro...d from skin fibroblast. TDP-43 mutation Same patient as CiRA00022. 筋萎縮性側索硬化症(TDP-43遺伝子変異) iPS細胞。CiRA00022 HP

  3. Stemcell Information: SKIP001190 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001190 ... blood mononuclear cell 血中単核細胞 Diseased HPS0414 HPS0414 ... 原発性側索硬化症 G...m a patient :Primary lateral sclerosis (PLS). ... 原発性側索硬化症由来iPS細胞株。 human ES-like Research Grade Other Oct3/4,

  4. Structural insights into the exon junction complex.

    Science.gov (United States)

    Le Hir, Hervé; Andersen, Gregers Rom

    2008-02-01

    In higher eukaryotes, the exon junction complex is loaded onto spliced mRNAs at a precise position upstream of exon junctions, where it remains during nuclear export and cytoplasmic localisation until it is removed during the first translation round. The exon junction core complex consists of four proteins that form a dynamic binding platform for a variety of peripheral factors involved in mRNA metabolism. In the complex, mRNA binding is mediated by the DEAD-box protein eIF4AIII, and inhibition of its ATPase activity forms the mechanistic basis for the long-term stability of the complex. Recent crystal structures of the exon junction complex and eIF4AIII have provided the structural framework for investigating the function of the eIF4AIII ATPase and for localisation of surface patches involved in binding peripheral factors. Additionally, by comparison with the structure of a second DEAD-box protein also bound to RNA and ATP, general principles for the ATPase and unwinding/mRNP remodelling activities for this important group of enzymes can be proposed on the basis of atomic structures.

  5. Lifestyle and socioeconomic correlates of breakfast skipping in Hong Kong primary 4 schoolchildren.

    Science.gov (United States)

    Tin, Sze Pui Pamela; Ho, Sai Yin; Mak, Kwok Hang; Wan, Ka Leung; Lam, Tai Hing

    2011-01-01

    Although breakfast is associated with different benefits, breakfast skipping is increasingly common among children. This study aimed to identify lifestyle and socioeconomic correlates of breakfast skipping in Hong Kong schoolchildren. 68,606 primary 4 participants of the Department of Health Student Health Service in 1998-2000 reported breakfast habit and other lifestyle characteristics using a standardized questionnaire. Height and weight were measured by trained SHS nurses. Socioeconomic data were reported by parents. In cross-sectional analysis, multivariate logistic regression was used to identify lifestyle and socioeconomic correlates of breakfast skipping. 3,598 subjects (5.2%) usually skipped breakfast. Breakfast skipping was associated with being overweight (Odds ratio=1.59, 95% CI: 1.46 to 1.73) and obese (2.06, 1.80 to 2.36), and unhealthy dietary habits including more frequent junk food (1.23, 1.14 to 1.33) but less frequent fruit/vegetable (1.23, 1.13 to 1.34) and milk (1.98, 1.80 to 2.16) intake. Breakfast skippers tended to skip lunch, do less extra-curricular physical activity, watch more television and have less educated parents. Breakfast skipping was significantly related to various health-compromising lifestyle characteristics and lower parental education. Breakfast habit can be a potential lifestyle indicator. Education programmes aimed at specific target groups should encourage regular breakfast consumption. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Leptin Level and Skipping Breakfast: The National Health and Nutrition Examination Survey III (NHANES III)

    Science.gov (United States)

    Asao, Keiko; Marekani, Amandine Sambira; VanCleave, Jessica; Rothberg, Amy E.

    2016-01-01

    Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988–1994. We defined breakfast as any food or beverage consumed between 5:00 a.m. and 10:00 a.m. using a single 24-h recall. Skipped breakfast was seen in 13.1%. In the logistic regression models with and without adjusting for adiposity and sex, leptin levels were not associated with skipping breakfast. After adjusting for age, race/ethnicity, and time of venipuncture, the association remained insignificant. After further adjusting for potential confounders: physical activity, alcohol intake, smoking and diabetes and after further adjusting for: dietary factors, insulin and glucose levels, there was a 9% and 11%–12%, respectively, statistically significantly higher likelihood of skipping breakfast if the leptin level was more than 50% greater. Further investigation into the biological reasons for skipping breakfast may be useful for promoting healthy lifestyles. PMID:26927164

  7. Loss of exon identity is a common mechanism of human inherited disease.

    Science.gov (United States)

    Sterne-Weiler, Timothy; Howard, Jonathan; Mort, Matthew; Cooper, David N; Sanford, Jeremy R

    2011-10-01

    It is widely accepted that at least 10% of all mutations causing human inherited disease disrupt splice-site consensus sequences. In contrast to splice-site mutations, the role of auxiliary cis-acting elements such as exonic splicing enhancers (ESE) and exonic splicing silencers (ESS) in human inherited disease is still poorly understood. Here we use a top-down approach to determine rates of loss or gain of known human exonic splicing regulatory (ESR) sequences associated with either disease-causing mutations or putatively neutral single nucleotide polymorphisms (SNPs). We observe significant enrichment toward loss of ESEs and gain of ESSs among inherited disease-causing variants relative to neutral polymorphisms, indicating that exon skipping may play a prominent role in aberrant gene regulation. Both computational and biochemical approaches underscore the relevance of exonic splicing enhancer loss and silencer gain in inherited disease. Additionally, we provide direct evidence that both SRp20 (SRSF3) and possibly PTB (PTBP1) are involved in the function of a splicing silencer that is created de novo by a total of 83 different inherited disease mutations in 67 different disease genes. Taken together, we find that ~25% (7154/27,681) of known mis-sense and nonsense disease-causing mutations alter functional splicing signals within exons, suggesting a much more widespread role for aberrant mRNA processing in causing human inherited disease than has hitherto been appreciated.

  8. Antisense Oligonucleotide-mediated Exon Skipping as a Systemic Therapeutic Approach for Recessive Dystrophic Epidermolysis Bullosa : Exon Skipping as Systemic Therapy for RDEB

    NARCIS (Netherlands)

    Bremer, Jeroen; Bornert, Olivier; Nyström, Alexander; Gostynski, Antoni; Jonkman, Marcel F; Aartsma-Rus, Annemieke; van den Akker, Peter C; Pasmooij, Anna MG

    2016-01-01

    The "generalized severe" form of recessive dystrophic epidermolysis bullosa (RDEB-gen sev) is caused by bi-allelic null mutations in COL7A1, encoding type VII collagen. The absence of type VII collagen leads to blistering of the skin and mucous membranes upon the slightest trauma. Because most

  9. Stemcell Information: SKIP001105 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001105 ... Diseased APP1E111 APP1E111 ... 家族性アルツハイマー病 G309 Alzheimer's disease... F693 ... -- -- ... Yes No Disease specific iPS cells from a patient of Alzheimer's disease. 疾患特異的iPS細胞株。APP-E693Δ変異家族性アルツハイマー...93 10.1016/j.stem.2013.01.009 Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated w

  10. Stemcell Information: SKIP000734 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available riell Institute Coriell Institute https://catalog.coriell.org ... 22278060 10.1038/nature10821 Probing sporadic and familial Alzheime... SKIP000734 ... Diseased GM24675 GM24675 APPDp2 APPDp2 アルツハイマー病 G309 ALZHEIMER DI... hiPSC derived from fibroblast 家族性アルツハイマー病患者(APP遺伝子重複)維芽細胞由来iPS細胞 human ES-like Research Grade Retrovirus OC

  11. Stemcell Information: SKIP000269 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000269 ... Diseased HPS0070 HPS0070 ... ミトコンドリア病 E888 Mitochondrial myopathy, ...ease specific iPS cell line derived from a patient: Mitochondrial myopathy, Encephalopathy, Lactic acidosis,... and Stroke-like episodes. 疾患特異的iPS細胞株。ミトコンドリア病患者由来。センダイウイルスベクターを用いて4因子(Oct3/4, S

  12. Stemcell Information: SKIP000748 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available B1345. Ph1 chromosome-positive human acute lymphoblastic leukemia cell line. Single Ph1 chromosome observed. 白血病... SKIP000748 ... acute lymphoblastic leukemia cell line 急性リンパ芽球 ... Diseased PALL-2 PALL...c and molecular analysis of Ph1-chromosome-positive acute lymphoblastic leukemia cell lines. Miyagi T, Ohyas...-2 JCRB1345 JCRB1345 急性リンパ性白血病 C910 Acute lymphoblastic leukaemia [ALL] 613065 ... -- Male ... Yes No JCR

  13. Stemcell Information: SKIP000280 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000280 ... Diseased HPS0209 HPS0209 ... 肺性高血圧症 I270 Pulmonary hypertension 178...600 ... -- -- Japanese Japanese Yes No Disease specific iPS cell line derived from a patient: Pulmonary hypertension.... ... 疾患特異的iPS細胞株。肺性高血圧症患者由来。 human ES-like -- Sendai virus SeV18+HS-OCT3/4/TSΔF, SeV18+HS-SOX2/TS

  14. Stemcell Information: SKIP000992 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ISEASE 8, AUTOSOMAL DOMINANT; PARK8 607060 ... 66 60-69 Female ... Yes No iPS cells from familial Parkinson... SKIP000992 ... Diseased PARK8-LA11 PARK8-LA11 ... 遺伝性パーキンソン病:PARK8 G20 PARKINSON D...'s disease patient ... 遺伝性パーキンソン病患者由来iPS細胞 human ES-like Research Grade Lentivirus Klf4, Sox2, Oct4, c-Myc ... Ye

  15. Stemcell Information: SKIP001136 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001136 ... Diseased ATCC-DYS0530 ATCC-DYS0530 ... パーキンソン病 G20 Parkinson's dise...kinson disease, asthma, depression 疾患由来iPS細胞株(パーキンソン病、喘息、うつ病) human ES-like Researc...ase 605543 喘息 J45 Asthma 600807 うつ病 F209 Depression 181500 63 60-69 Male ... No No Disease iPS cell lines derived from patient with Par

  16. Stemcell Information: SKIP000991 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available EASE 8, AUTOSOMAL DOMINANT; PARK8 607060 ... 66 60-69 Female ... Yes No iPS cells from familial Parkinson's disease patient ... 遺伝性パーキ... SKIP000991 ... Diseased PARK8-LA5 PARK8-LA5 ... 遺伝性パーキンソン病:PARK8 G20 PARKINSON DIS...ンソン病患者由来iPS細胞 human ES-like Research Grade Lentivirus Klf4, Sox2, Oct4, c-Myc ... Yes

  17. Stemcell Information: SKIP001068 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available DISEASE, PARK4 605543 ... 42 40-49 Male ... Yes No Disease specific iPS cell lines derived from patient with Parkinson...rsity Stanford University ... 22110584 10.1371/journal.pone.0026159 SNCA triplication Parkinson... SKIP001068 ... Diseased Trpl17 Trpl17 ... 家族性パーキンソン病 PARK4 G20 Familial PARKINSON ... disease (PARK4) パーキンソン病(PARK4)患者由来iPS細胞 human ES-like Research Grade Retrovirus KLF4,SOX2,OCT4,

  18. Stemcell Information: SKIP000845 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000845 ... unknown 不明 Diseased Sporadic PD-1 Sporadic PD-1 10005.117.01 10005.117.01 パーキンソン病 G20 Parkin...son Disease 168600 ... 65 60-69 Female ... No No Transgene-free iPS cells from Sporadic Parkinson...lrep.2014.10.023 iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson... Disease patient.Using CytoTune iPS Sendai reprogramming protocol (Life Technologies). 孤発性パーキンソン

  19. Stemcell Information: SKIP000993 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ISEASE 8, AUTOSOMAL DOMINANT; PARK8 607060 ... 78 70-79 Female ... Yes No iPS cells from familial Parkinson... SKIP000993 ... Diseased PARK8-LB16 PARK8-LB16 ... 遺伝性パーキンソン病:PARK8 G20 PARKINSON D...'s disease patient ... 遺伝性パーキンソン病患者由来iPS細胞 human ES-like Research Grade Lentivirus Klf4, Sox2, Oct4, c-Myc ... Ye

  20. Stemcell Information: SKIP000617 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000617 ... Diseased HPS0097 HPS0097 ... 家族性パーキンソン病 PARK2 G20 Parkinson's disea...se, Familial type, PARK2 600116 ... -- -- Japanese Japanese No No Disease specific iPS cell line derived from a patient: Parkins...on's disease, Familial type, PARK2. 疾患特異的iPS細胞株。家族性パーキンソン病 PARK2患者由来。レトロウイルスベクターにより

  1. Stemcell Information: SKIP000994 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ISEASE 8, AUTOSOMAL DOMINANT; PARK8 607060 ... 78 70-79 Female ... Yes No iPS cells from familial Parkinson... SKIP000994 ... Diseased PARK8-LB21 PARK8-LB21 ... 遺伝性パーキンソン病:PARK8 G20 PARKINSON D...'s disease patient ... 遺伝性パーキンソン病患者由来iPS細胞 human ES-like Research Grade Lentivirus Klf4, Sox2, Oct4, c-Myc ... Ye

  2. Stemcell Information: SKIP001095 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line derived from a neonate.(1439 KURABO)| 新生児皮膚繊維芽細胞(1439 KURABO)由来iPS細胞 human ES-like Research ...on, Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Research and Application,Kyoto University 京都大学iPS細胞... SKIP001095 ... Normal WT-1-#1 WT-1-#1 ... 0-9 Male ... -- No Nomal human iPS cell...ling type II collagenopathy skeletal dysplasia by directed conversion and induced pluripotent stem cell

  3. Stemcell Information: SKIP000262 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000262 ... Diseased GM23913 GM23913 ... フリードライヒ運動失調症 G111 Friedreich ataxia 22...9300 ... 30 30-39 Male ... Yes No iPS cell line derived from GM04078 fibroblast. Clinically affected with Friedreich ataxia...3 10.1016/j.stem.2010.09.014 Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA-... 541 and 420 repeats. フリードライヒ運動失調症患者由来iPS細胞株。GM04078 由来 Homozygous for thr GAA ex

  4. Stemcell Information: SKIP001110 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ibroblasts a control individual outside of the pedigree as an additional control (ATCC(CRL-2097)) 血縁関係のない正常な個人由来のiPS細胞... SKIP001110 ... Normal C1-2 C1-2 ... 0-9 Male ... -- No iPS cells from f...assay Yes Teratoma formation Yes Differentiation of iPS cells into forebrain-specific neural progenitors and...n Song 宋红军 Information Only ... 25132547 10.1038/nature13716 Synaptic dysregulation in a human iPS cell

  5. Stemcell Information: SKIP001109 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ibroblasts a control individual outside of the pedigree as an additional control (ATCC(CRL-2097)) 血縁関係のない正常な個人由来のiPS細胞... SKIP001109 ... Normal C1-1 C1-1 ... 0-9 Male ... -- No iPS cells from f...assay Yes Teratoma formation Yes Differentiation of iPS cells into forebrain-specific neural progenitors and...n Song 宋红军 Information Only ... 25132547 10.1038/nature13716 Synaptic dysregulation in a human iPS cell

  6. Stemcell Information: SKIP001114 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ed from fibroblasts of unaffected members without the mutation ... 非保因者(遺伝子変異の見られない血縁者)由来iPS細胞 human ES-like Re... SKIP001114 ... Normal C3-2 C3-2 ... -- Female ... -- No iPS cells deriv...ech) ... Yes Immunostaining Yes Embryoid body assay Yes Teratoma formation Yes Differentiation of iPS cell...25132547 10.1038/nature13716 Synaptic dysregulation in a human iPS cell model of

  7. Stemcell Information: SKIP000910 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000910 ... Peripheral Blood 末梢血 Diseased Alex2 Alex2 ... アレキサンダー病 E752 Alexander... disease 203450 ... 10 10-19 Female ... Yes No iPSCs derived from Alexander's disease patient by using TS-...l.pone.0113052 Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of ast...京都大学iPS細胞研究所 http://www.cira.kyoto-u.ac.jp/ ... 27402089--25479600 10.1186/s40478-016-0337-0--10.1371/journa

  8. Stemcell Information: SKIP000188 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000188 ... Diseased R306C-iPS R306C-iPS GM23298 GM23298 レット症候群 F842 Rett syn...cal symptoms. ... MECP2 916C>T (R306C) mutation Coriell ID:GM23298 レット症候群患者線維芽細胞(GM11270) 由来。典型的な症状。MECP2 遺伝子変異

  9. Stemcell Information: SKIP000388 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000388 ... Diseased HPS0207 HPS0207 ... X連鎖アルファ-サラセミア・精神遅滞(ATR-X)症候群 ... Alpha-Th...l line derived from a patient :Alpha-Thalassemia/Mental Retardation Syndrome, X-Linked; ATRX. ... 疾患特異的iPS細胞株。X...連鎖アルファ-サラセミア·精神遅滞(ATR-X)症候群患者由来。 human ES-like Research Grade Sendai virus SeV18+

  10. Stemcell Information: SKIP000380 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000380 ... Diseased HPS0157 HPS0157 ... ローレンス・ムーン症候群(バルデー・ビードル症候群) Q878 Lauren...ved from Bardet-Biedl Syndrome patient. HPS0156 is derived from the same patient. Bardet-Biedls症候群患者由来iPS細胞。疾患特異的iPS細胞株。バルデー·ビードル症候群

  11. Stemcell Information: SKIP000331 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000331 ... mesenchymal stem cell 間葉系幹細胞 polydactylous human fingers 指 Normal Yub...t Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3527 ... ...622 Yub622 JCRB1114 JCRB1114 ... -- -- ... -- No JCRB1114 mesenchymal stem cell finite proliferation

  12. Stemcell Information: SKIP000329 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000329 ... mesenchymal stem cell 間葉系幹細胞 polydactylous human fingers 指 Normal Yub... Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3376 ... ...621b Yub621b JCRB1112 JCRB1112 ... -- -- ... -- No JCRB1112 bone-derived mesenchymal stem cell. finit

  13. Stemcell Information: SKIP001097 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line derived from a neonate.(1439 KURABO)| 新生児皮膚繊維芽細胞(1439 KURABO)由来iPS細胞 human ES-like Research ...n, Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Research and Application,Kyoto University 京都大学iPS細胞... SKIP001097 ... Normal WT-1-#3 WT-1-#3 ... 0-9 Male ... -- No Nomal human iPS cell...ing type II collagenopathy skeletal dysplasia by directed conversion and induced pluripotent stem cell

  14. Stemcell Information: SKIP001096 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line derived from a neonate.(1439 KURABO)| 新生児皮膚繊維芽細胞(1439 KURABO)由来iPS細胞 human ES-like Research ...n, Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Research and Application,Kyoto University 京都大学iPS細胞... SKIP001096 ... Normal WT-1-#2 WT-1-#2 ... 0-9 Male ... -- No Nomal human iPS cell...ing type II collagenopathy skeletal dysplasia by directed conversion and induced pluripotent stem cell

  15. Stemcell Information: SKIP000706 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000706 ... mesenchymal stem cell 間葉系幹細胞 placenta 胎盤 Normal PL502 PL502 ... ... ... -- -- ... -- No JCRB1125 mesenchymal stem cell. finite prolieferation 胎盤由来間葉系幹細胞(有限増殖) fibroblast-like -...lable National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3548 ...

  16. Stemcell Information: SKIP000328 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000328 ... mesenchymal stem cell 間葉系幹細胞 polydactylous human fingers 指 Normal Yub... ... Not Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3375 ... ...621c Yub621c JCRB1111 JCRB1111 ... -- -- ... -- No JCRB1111 cartilige-derived messenchymal stem cell.

  17. Stemcell Information: SKIP000172 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000172 ... Diseased HPS0118 HPS0118 ... CINCA症候群 ... CINCA syndrome 607115 ... ... ... -- Male ... Yes No iPSC from CINCA syndrome patient with mutaion 1709A>G (Y570C) in NLRP3 as somatic mosaicism iPSC from CINCA syndr...12-03-417881 Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic m...ome(CINCA症候群) patient with mutaion 1709A>G (Y570C) in NLRP3 as somatic mosaicism hu

  18. Stemcell Information: SKIP000267 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000267 ... Diseased HPS0083 HPS0083 iCK2 iCK2 コケイン症候群 Q871 Cockayne's syndrome... 216400 ... -- Female japanese japanese No No Disease specific iPS cell line derived from a patient of Cockayne's syndrome.... コケイン症候群患者由来細胞(RCB0397 NCU-F10)に4因子(Oct3/4, Sox2, Klf4, c-Myc)を導入。|| human ES-like --

  19. Stemcell Information: SKIP000790 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000790 ... Diseased 9862-61 9862-61 ... ティモシー症候群 I45.8 Timothy syndrome 601005... ... -- -- ... Yes No Human iPSCs.The Timothy syndrome iPSCs preserved the Timothy syndrome mutation. 疾患特異的iPS細胞。ティモシー症候群...induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome....--Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Yazawa M,

  20. Stemcell Information: SKIP000787 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000787 ... Diseased 7643-5 7643-5 ... ティモシー症候群 I45.8 Timothy syndrome 601005 ... ... ... -- -- ... Yes No Human iPSCs.The Timothy syndrome iPSCs preserved the Timothy syndrome mutation. 疾患特異的iPS細胞。ティモシー症候群...duced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome....--Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Yazawa M, Hs

  1. Stemcell Information: SKIP000107 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000107 ... Diseased A000180#6 A000180#6 ... エーラース・ダンロス症候群 Q796 Ehlers-Danlos syndrome... 130000 ... -- -- ... Yes No intractable disease-specific iPSC, Ehlers-Danlos syndrome, new varien...t 難病性疾患克服事業iPS細胞バンク 新型エーラース・ダンロス症候群 human ES-like -- Sendai virus Sendai Virus (DNAVEC: CytoTuneTM-iPS Cat.

  2. Stemcell Information: SKIP000106 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000106 ... Diseased A000180#5 A000180#5 ... エーラース・ダンロス症候群 Q796 Ehlers-Danlos syndrome... 130000 ... -- -- ... Yes No intractable disease-specific iPSC, Ehlers-Danlos syndrome, new varien...t 難病性疾患克服事業iPS細胞バンク 新型エーラース・ダンロス症候群 human ES-like -- Sendai virus Sendai Virus (DNAVEC: CytoTuneTM-iPS Cat.

  3. Stemcell Information: SKIP001067 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available Q98.0 Klinefelter syndrome ... 25 20-29 Male ... Yes No Specific disease iPS cell line from patient with Klinefelter syndro...213-9 Derivation of integration-free iPSCs from a Klinefelter syndrome patient. Shimizu T, Shiohara M, Tai T...me クラインフェルター症候群患者由来iPS細胞 ... human ES-like Research Grade Sendai virus KLF4,SOX2,OCT4... SKIP001067 ... Testicular fibroblast Testicular fibroblast Diseased KS KS ... クラインフェルター症候群

  4. Stemcell Information: SKIP000105 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000105 ... Diseased A000180#2 A000180#2 ... エーラース・ダンロス症候群 Q796 Ehlers-Danlos syndrome... 130000 ... -- -- ... Yes No intractable disease-specific iPSC, Ehlers-Danlos syndrome, new varien...t 難病性疾患克服事業iPS細胞バンク 新型エーラース・ダンロス症候群 human ES-like -- Sendai virus Sendai Virus (DNAVEC: CytoTuneTM-iPS Cat.

  5. Stemcell Information: SKIP000187 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000187 ... Diseased GM23262 GM23262 ... ベッカー型筋ジストロフィー G710 Muscular dystrophy,... 45-52 in the DMD gene. ベッカー型筋ジストロフィー患者線維芽細胞(GM04981) 由来。 DMD遺伝子エクソン45-52欠失 human ES-like -- Retrovirus Oct4

  6. Stemcell Information: SKIP000275 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000275 ... Diseased HPS0146 HPS0146 ... 孤発性筋萎縮性側索硬化症 (bulbar, with UMN) G122 ... ...th UMN) 疾患特異的iPS細胞株。孤発性筋萎縮性側索硬化症 (bulbar, with UMN)患者由来。センダイウイルスベクターを用いて4因子(Oct3/

  7. Stemcell Information: SKIP001127 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001127 ... Diseased HPS0248 HPS0248 ... 筋萎縮性側索硬化症 G122 Amyotrophic lateral scl...teral sclerosis. Order Form (C-0042, C-0057, C-0007). 疾患特異的iPS細胞株。筋萎縮性側索硬化症患者由来。エピソーマルベクター ( pCXLE )によりヒト6因子

  8. Stemcell Information: SKIP000808 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000808 ... Diseased HPS0136 HPS0136 ... 孤発性筋萎縮性側索硬化症 (pseudo-polyneuritic, w/o...07p). 疾患特異的iPS細胞株。孤発性筋萎縮性側索硬化症 (pseudo-polyneuritic, w/o UMN)患者由来。HPS0134と同一人由来センダイウイルスベクターを用いて樹立。ガラス化法(Vitr

  9. Stemcell Information: SKIP001126 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001126 ... Diseased HPS0247 HPS0247 ... 筋萎縮性側索硬化症 G122 Amyotrophic lateral scl...teral sclerosis. Order Form (C-0042, C-0057, C-0007). 疾患特異的iPS細胞株。筋萎縮性側索硬化症患者由来。エピソーマルベクター ( pCXLE )によりヒト6因子

  10. Stemcell Information: SKIP000032 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000032 ... Diseased A000005#2 A000005#2 ... 孤発性筋委縮性側索硬化症 G122 (amyotrophic lat...h UMN| 難病性疾患克服事業iPS細胞バンク 孤発性ALS classical with UMN|孤発性筋委縮性側索硬化症 (classical, with UMN)患者由来。 human ES-like --

  11. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....... showed dystrophic changes. He had comorbidity with dystonia, slight mental retardation, low stature and neuropathy. The brother of the proband's mother came to medical attention when he was 43 years old. He complained about muscle pain. On examination, a MRC grade 4+ hip extention palsy and a discrete...

  12. Comparative analysis of antisense oligonucleotide sequences targeting exon 53 of the human DMD gene: Implications for future clinical trials.

    Science.gov (United States)

    Popplewell, Linda J; Adkin, Carl; Arechavala-Gomeza, Virginia; Aartsma-Rus, Annemieke; de Winter, Christa L; Wilton, Steve D; Morgan, Jennifer E; Muntoni, Francesco; Graham, Ian R; Dickson, George

    2010-02-01

    Duchenne muscular dystrophy (DMD) is caused by the lack of functional dystrophin protein, most commonly as a result of a range of out-of-frame mutations in the DMD gene. Modulation of pre-mRNA splicing with antisense oligonucleotides (AOs) to restore the reading frame has been demonstrated in vitro and in vivo, such that truncated but functional dystrophin is expressed. AO-induced skipping of exon 51 of the DMD gene, which could treat 13% of DMD patients, has now progressed to clinical trials. We describe here the methodical, cooperative comparison, in vitro (in DMD cells) and in vivo (in a transgenic mouse expressing human dystrophin), of 24 AOs of the phosphorodiamidate morpholino oligomer (PMO) chemistry designed to target exon 53 of the DMD gene, skipping of which could be potentially applicable to 8% of patients. A number of the PMOs tested should be considered worthy of development for clinical trial. Copyright 2009 Elsevier B.V. All rights reserved.

  13. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....... calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500 U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic...

  14. Skip segment Hirschsprung disease and Waardenburg syndrome

    Directory of Open Access Journals (Sweden)

    Erica R. Gross

    2015-04-01

    Full Text Available Skip segment Hirschsprung disease describes a segment of ganglionated bowel between two segments of aganglionated bowel. It is a rare phenomenon that is difficult to diagnose. We describe a recent case of skip segment Hirschsprung disease in a neonate with a family history of Waardenburg syndrome and the genetic profile that was identified.

  15. A putative novel transcription factor, AtSKIP, is involved in abscisic acid signalling and confers salt and osmotic tolerance in Arabidopsis.

    Science.gov (United States)

    Lim, Gah-Hyun; Zhang, Xia; Chung, Moon-Soo; Lee, Dong Ju; Woo, Young-Min; Cheong, Hyeon-Sook; Kim, Cheol Soo

    2010-01-01

    We identified and functionally characterized the AtSKIP gene (At1g77180), an Arabidopsis homologue of SNW/SKIP, under abiotic stresses. Although the SNW/SKIP protein has been implicated as a critical transcription cofactor, its biological functions have yet to be reported in any plant. Recently, we have isolated Salt-tolerance genes (SATs) via the overexpression screening of yeast with a maize cDNA library. One of the selected genes (SAT2) appeared to confer elevated tolerance to salt. Maize SAT2 cDNA encodes a homologue of the human SNW/SKIP transcriptional coregulator. Treatment with salt, mannitol and abscisic acid induced AtSKIP expression. Ectopic expression of the AtSKIP gene modulated the induction of salt tolerance, dehydration resistance and insensitivity towards abscisic acid under stress conditions. By contrast, atskip antisense lines displayed reduced tolerance to abiotic stresses during germination. Moreover, a decrease in AtSKIP expression resulted in an abnormal phenotype. We further determined that the AtSKIP protein activated the transcription of a reporter gene in yeast. Green fluorescent protein-tagged AtSKIP was localized in the nuclei of both onion cells and transgenic Arabidopsis cells. Taken together, these results suggest that AtSKIP functions as both a positive regulator and putative potential transcription factor in the abiotic stress signalling pathway.

  16. A study on single nucleotide polymorphism of exon 7 T/C (locus 593 of platelet-activating factor acetylhydrolase gene in healthy Han population in the Shanghai region

    Directory of Open Access Journals (Sweden)

    Tian-bao XIA

    2012-08-01

    Full Text Available Objective To investigate the distribution of single nucleotide polymorphism (SNP in platelet-activating factor acetylhydrolase (PAF-AH gene exon 7 T/C (locus 593 in healthy Han population in Shanghai region and the features different from other races. Methods The SNP in PAF-AH gene exon 7 T/C (locus 593 was detected and analyzed by PCR and sequencing in 110 healthy Han people from Shanghai areas. The genotype and allele frequency were then calculated and compared with that in other races in combination with review of relevant literature. Results The amplified product of the SNP in PAF-AH gene exon 7 T/C (locus 593 was 240 bp in 110 healthy Han people, of whom 97 were with TT genotype and 13 with TC genotype, but no CC genotype was found. As to the allele frequency distribution, T type allele took the highest position, and C type followed. The genotype frequency of TT and TC was 88.2% and 11.8%, respectively, and they were markedly different from that in German population (0.95%, while not statistically significant different from that in British population (7.67%. Conclusions There exists SNP in PAF-AH gene exon 7 T/C (position 593 in healthy Han people in Shanghai region, with a higher frequency of T→C mutation. The mutational genotype frequency is found to be located at the locus 593 is 11.81%, and it is markedly different from that in German population, but not significantly different from that in British population.

  17. Occipital horn syndrome and classical Menkes syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon

    DEFF Research Database (Denmark)

    Yasmeen, Saiqa; Lund, Katrine; De Paepe, Anne

    2014-01-01

    in the ATP7A gene can be identified in 95-98% of the Menkes disease patients by standard screening techniques. Investigation of RNA isolated from the fibroblasts of eleven patients with no identified mutations was performed, and revealed inclusion of new pseudo-exons into the ATP7A mRNA from three unrelated...... mechanism, which has hitherto been overlooked.European Journal of Human Genetics advance online publication, 4 September 2013; doi:10.1038/ejhg.2013.191....

  18. Intron-exon organization of the active human protein S gene PS. alpha. and its pseudogene PS. beta. : Duplication and silencing during primate evolution

    Energy Technology Data Exchange (ETDEWEB)

    Ploos van Amstel, H.; Reitsma, P.H.; van der Logt, C.P.; Bertina, R.M. (University Hospital, Leiden (Netherlands))

    1990-08-28

    The human protein S locus on chromosome 3 consists of two protein S genes, PS{alpha} and PS{beta}. Here the authors report the cloning and characterization of both genes. Fifteen exons of the PS{alpha} gene were identified that together code for protein S mRNA as derived from the reported protein S cDNAs. Analysis by primer extension of liver protein S mRNA, however, reveals the presence of two mRNA forms that differ in the length of their 5{prime}-noncoding region. Both transcripts contain a 5{prime}-noncoding region longer than found in the protein S cDNAs. The two products may arise from alternative splicing of an additional intron in this region or from the usage of two start sites for transcription. The intron-exon organization of the PS{alpha} gene fully supports the hypothesis that the protein S gene is the product of an evolutional assembling process in which gene modules coding for structural/functional protein units also found in other coagulation proteins have been put upstream of the ancestral gene of a steroid hormone binding protein. The PS{beta} gene is identified as a pseudogene. It contains a large variety of detrimental aberrations, viz., the absence of exon I, a splice site mutation, three stop codons, and a frame shift mutation. Overall the two genes PS{alpha} and PS{beta} show between their exonic sequences 96.5% homology. Southern analysis of primate DNA showed that the duplication of the ancestral protein S gene has occurred after the branching of the orangutan from the African apes. A nonsense mutation that is present in the pseudogene of man also could be identified in one of the two protein S genes of both chimpanzee and gorilla. This implicates that silencing of one of the two protein S genes must have taken place before the divergence of the three African apes.

  19. Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease

    Directory of Open Access Journals (Sweden)

    Lorena Suarez-Artiles

    2018-01-01

    Full Text Available Mutations in the OCRL gene are associated with both Lowe syndrome and Dent-2 disease. Patients with Lowe syndrome present congenital cataracts, mental disabilities and a renal proximal tubulopathy, whereas patients with Dent-2 disease exhibit similar proximal tubule dysfunction but only mild, or no additional clinical defects. It is not yet understood why some OCRL mutations cause the phenotype of Lowe syndrome, while others develop the milder phenotype of Dent-2 disease. Our goal was to gain new insights into the consequences of OCRL exonic mutations on pre-mRNA splicing. Using predictive bioinformatics tools, we selected thirteen missense mutations and one synonymous mutation based on their potential effects on splicing regulatory elements or splice sites. These mutations were analyzed in a minigene splicing assay. Results of the RNA analysis showed that three presumed missense mutations caused alterations in pre-mRNA splicing. Mutation c.741G>T; p.(Trp247Cys generated splicing silencer sequences and disrupted splicing enhancer motifs that resulted in skipping of exon 9, while mutations c.2581G>A; p.(Ala861Thr and c.2581G>C; p.(Ala861Pro abolished a 5′ splice site leading to skipping of exon 23. Mutation c.741G>T represents the first OCRL exonic variant outside the conserved splice site dinucleotides that results in alteration of pre-mRNA splicing. Our results highlight the importance of evaluating the effects of OCRL exonic mutations at the mRNA level.

  20. Stemcell Information: SKIP000414 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available bba ... Fetus Male ... -- No MRC-iPS-01|MRC5(a 14-week male foetal lung tissue)-derived iPS cells| MRC5(14週男性胎児胚線維芽細胞)由来iPS細胞... SKIP000414 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-1 MRC-iPS-1 Bubba Bu...10.1016/j.yexcr.2009.06.016--10.1371/journal.pone.0013017 Lectin microarray analysis of pluripotent and multipotent stem cell...s.--DNA methylation dynamics in human induced pluripotent stem cell...s over time.--Mesenchymal to embryonic incomplete transition of human cells by chimeric OCT4/3 (POU5F1) w

  1. Stemcell Information: SKIP000494 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available eyes Snake eyes ... Fetus Unknown ... -- No MRC-iPS-83|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-... SKIP000494 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-83 MRC-iPS-83 Snake ....2010.01459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cell...s.--DNA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue ....gov/pubmed/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  2. Stemcell Information: SKIP000478 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available g ... Fetus Unknown ... -- No MRC-iPS-66|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like Research ... SKIP000478 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-66 MRC-iPS-66 Tug Tu...-10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells.--DNA met...hylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, Itakura Y, ...155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  3. Stemcell Information: SKIP000277 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available l1 retrotransposition in the neuronal genome in schizophrenia. Bundo M, Toyoshima... SKIP000277 ... Diseased KO-001-25 KO-001-25 ... 統合失調症 F209 Schizophrenia 181500 ... ... |HCV : |その他の感染症 : 梅毒 陰性(梅毒定性RPR(ラテックス比濁法)、梅毒定性TP抗体(ラテックス比濁法)|病歴・治療歴等 : 28歳時、注意力の低下、記憶障害、独語、空笑、幻聴などの精神病症状が亜急性に出現。|        精神科受診し統合失調症

  4. Stemcell Information: SKIP001098 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line derived from a neonate.(789013 KURABO)| 新生児皮膚繊維芽細胞(789013 KURABO)由来iPS細胞 human ES-like Res...ication, Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Research and Application,Kyoto University 京都大学iPS細胞... SKIP001098 ... Normal WT-2-#31 WT-2-#31 ... 0-9 Male ... -- No Nomal human iPS cell... Modeling type II collagenopathy skeletal dysplasia by directed conversion and in...duced pluripotent stem cells. Okada M, Ikegawa S, Morioka M, Yamashita A, Saito A, Sawai H, Murotsuki J, Oha

  5. Stemcell Information: SKIP001175 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available plication (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information Only ... 18035408 10.1016/j.cell... line derived from a healthy individual dermal fibroblasts. 健常人の皮膚線維芽細胞由来のヒトiPS細胞株。 human ES-like Rese... iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and Ap... SKIP001175 ... Normal 253F4 253F4 ... 36 30-39 Female ... -- No Human iPS cell....2007.11.019 Induction of pluripotent stem cells from adult human fibrob

  6. Stemcell Information: SKIP001162 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information Only ... 18035408 10.1016/j.cell... line derived from a healthy individual dermal fibroblasts. 健常人の皮膚線維芽細胞由来のヒトiPS細胞株。 human ES-like Rese...山中 伸弥 Center for iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell... SKIP001162 ... Normal 201B3 201B3 ... 36 30-39 Female ... -- No Human iPS cell....2007.11.019 Induction of pluripotent stem cells from ad

  7. Stemcell Information: SKIP000288 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000288 ... mesenchymal stem cell 間葉系幹細胞 Umbilical cord blood 臍帯血 Normal UCB408E6...d-derived mesenchymal stem cells with transgenic hTERT, HPV E6 and E7. Immortalized ... 臍帯血由来間葉系幹細胞, ... 不死化細胞株 fi...evelopment 国立成育医療研究センター研究所 ... Not Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cell...bank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID...=3374 ... 15647378 ... Immortalization of human fetal cells: the life span of umbilical cord blood-derived cell

  8. Stemcell Information: SKIP000474 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available Gideon ... Fetus Unknown ... -- No MRC-iPS-62|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like Res... SKIP000474 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-62 MRC-iPS-62 Gideon...459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells.--D...NA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, Itaku...med/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  9. Stemcell Information: SKIP000498 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available y Diggity ... Fetus Unknown ... -- No MRC-iPS-86|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like R... SKIP000498 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-86 MRC-iPS-86 Diggit...01459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells.-...-DNA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, Ita...ubmed/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  10. Stemcell Information: SKIP000457 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available s Jimmies ... Fetus Unknown ... -- No MRC-iPS-45|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like R... SKIP000457 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-45 MRC-iPS-45 Jimmie...01459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells.-...-DNA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, Ita...ubmed/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  11. Stemcell Information: SKIP000433 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available pper Gobstopper ... Fetus Unknown ... -- No MRC-iPS-21|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-... SKIP000433 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-21 MRC-iPS-21 Gobsto....2010.01459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cell...s.--DNA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue ....gov/pubmed/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  12. Stemcell Information: SKIP000437 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available c ... Fetus Unknown ... -- No MRC-iPS-25|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like Research ... SKIP000437 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-25 MRC-iPS-25 Tic Ti...-10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells.--DNA met...hylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, Itakura Y, ...155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  13. Stemcell Information: SKIP001176 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available plication (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information Only ... 18035408 10.1016/j.cell... line derived from a healthy individual dermal fibroblasts. 健常人の皮膚線維芽細胞由来のヒトiPS細胞株。 human ES-like Rese... iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and Ap... SKIP001176 ... Normal 253F5 253F5 ... 36 30-39 Female ... -- No Human iPS cell....2007.11.019 Induction of pluripotent stem cells from adult human fibrob

  14. Stemcell Information: SKIP001192 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001192 ... blood mononuclear cell 血中単核細胞 Diseased HPS0429 HPS0429 CiRA00142 Ci...d from a patient :Charcot-Marie-Tooth disease . ... シャルコー·マリー·トゥース病患者由来iPS細胞株。 human ES-like Research Grade Pla...ll Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and Applicati...on (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Available RIKEN Bi...RA00142 シャルコー・マリー・トゥース病 G600 Charcot-Marie-Tooth disease 118210 ... -- -- ... Yes No iPS cell line derive

  15. Stemcell Information: SKIP001166 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available plication (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information Only ... 18035408 10.1016/j.cell... line derived from a healthy individual dermal fibroblasts. 健常人の皮膚線維芽細胞由来のヒトiPS細胞株。 human ES-like Rese... iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and Ap... SKIP001166 ... Normal 246B3 246B3 ... 36 30-39 Female ... -- No Human iPS cell....2007.11.019 Induction of pluripotent stem cells from adult human fibrob

  16. Stemcell Information: SKIP000709 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3572 ... ... finite proliferation 胎盤由来間葉系幹細胞(有限増殖) fibroblast-like -- -- ... Yes -- ... Plusoid-M. When... SKIP000709 ... placenta 胎盤 Normal PL507 PL507 ... -- -- ... -- No JCRB1130 mesenchymal stem cell... the cultures reached subconfluence, the cells were harvested with 0.25% trypsin and 1mM EDTA and replated w...ith one-quarter of harvested cells. ... 5% ... Umezawa, Akihiro 梅澤

  17. Stemcell Information: SKIP001194 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001194 ... blood mononuclear cell 血中単核細胞 Diseased HPS0508 HPS0508 CiRA00161 Ci... line derived from a patient :Charcot-Marie-Tooth disease . ... シャルコー·マリー·トゥース病患者由来iPS細胞株。 huma...ya 山中 伸弥 Center for iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS C...ell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shiny...RA00161 シャルコー・マリー・トゥース病 G600 Charcot-Marie-Tooth disease 118210 ... -- -- Japanese 日本人 Yes No Disease specific iPS cell

  18. Stemcell Information: SKIP001169 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available plication (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information Only ... 18035408 10.1016/j.cell... line derived from a healthy individual dermal fibroblasts. 健常人の皮膚線維芽細胞由来のヒトiPS細胞株。 human ES-like Rese... iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and Ap... SKIP001169 ... Normal 246B4 246B4 ... 36 30-39 Female ... -- No Human iPS cell....2007.11.019 Induction of pluripotent stem cells from adult human fibrob

  19. Stemcell Information: SKIP000286 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000286 ... mesenchymal stem cell 間葉系幹細胞 Umbilical cord blood 臍帯血 Normal UCB408E6...医療研究センター研究所 ... Not Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cell...s with transgenic HPV E6 and E7. finite proliferation 臍帯血由来間葉系幹細胞(有限増殖) fibroblast-li...E7-31 UCB408E6E7-31 JCRB1108 JCRB1108 ... -- -- ... -- No JCRB1108 ... Human umbilical cord blood-derived mesenchymal stem cell...378 ... Immortalization of human fetal cells: the life span of umbilical cord blood-derived cells can be prolon

  20. Stemcell Information: SKIP001100 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line derived from a neonate.(789013 KURABO)| 新生児皮膚繊維芽細胞(789013 KURABO)由来iPS細胞 human ES-like Res...ication, Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Research and Application,Kyoto University 京都大学iPS細胞... SKIP001100 ... Normal WT-2-#33 WT-2-#33 ... 0-9 Male ... -- No Nomal human iPS cell... Modeling type II collagenopathy skeletal dysplasia by directed conversion and in...duced pluripotent stem cells. Okada M, Ikegawa S, Morioka M, Yamashita A, Saito A, Sawai H, Murotsuki J, Oha

  1. Stemcell Information: SKIP001144 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available l line derived from a healthy individual cord blood. ... 健常人の臍帯血由来のヒトiPS細胞株。 human ES-...for iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and... Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Available RIKEN BioResource Center ... SKIP001144 ... cord blood 臍帯血 Normal HPS0331 HPS0331 610B1 610B1 ... -- Male ... -- No Human iPS cel...理化学研究所 バイオリソースセンター ... http://www2.brc.riken.jp/lab/cell/detail.cgi?cell_no=HPS0331&

  2. Stemcell Information: SKIP001159 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... 0-9 Male ... -- No Human iPS cell lines derived from BJ human foreskin fibroblasts. 新生児包皮から得た線維芽細胞由来のヒトiPS細胞... SKIP001159 ... BJ Human Foreskin Fibroblasts 新生児包皮由来の線維芽細胞 Unknown 246G6 246G6 ... ... Shinya 山中 伸弥 Center for iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for ...iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information On...ly ... 18035408--22146343 10.1016/j.cell.2007.11.019--10.1038/mt.2011.266 Indu

  3. Stemcell Information: SKIP001165 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available plication (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information Only ... 18035408 10.1016/j.cell... line derived from a healthy individual dermal fibroblasts. 健常人の皮膚線維芽細胞由来のヒトiPS細胞株。 human ES-like Rese... iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and Ap... SKIP001165 ... Normal 246B2 246B2 ... 36 30-39 Female ... -- No Human iPS cell....2007.11.019 Induction of pluripotent stem cells from adult human fibrob

  4. Stemcell Information: SKIP000822 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line, derived from fibloblast(Cell applications Inc. Lot1388). Lot1388線維芽細胞由来iPS細胞。エピソーマルベクターによる樹立、導入細胞...Yes G-band ... Yes ... Keisuke Okita 沖田 圭介 Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞...研究所 Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研...究所 Shinya Yamanaka 山中伸弥 Information Only Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞... SKIP000822 ... Normal 414C-2 414C-2 ... 36 30-39 Female ... -- No Human iPS cell

  5. Stemcell Information: SKIP000708 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000708 ... mesenchymal stem cell 間葉系幹細胞 placenta 胎盤 Normal PL505 PL505 ... ... ... -- -- ... -- No JCRB1128 mesenchymal stem cell finite proliferation 胎盤由来間葉系幹細胞(有限増殖) fibroblast-like -- ...opment 国立成育医療研究センター研究所 ... Not Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞...バンク http://cellbank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3558 ...

  6. Stemcell Information: SKIP000823 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line, derived from fibloblast(JCRB TIG114). TIG114線維芽細胞由来iPS細胞。エピゾーマルベクターによる樹立、導入細胞には...suke Okita 沖田 圭介 Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研究所 Center for iPS ...Cell Research and Application, Kyoto University 京都大学iPS細胞研究所 Shinya Yamanaka 山中伸弥... Information Only Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研究所 http://www.cir... SKIP000823 ... Normal 418C-1 418C-1 ... 36 30-39 Male Japanese Japanese -- No Human iPS cell

  7. Stemcell Information: SKIP001168 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available plication (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information Only ... 18035408 10.1016/j.cell... line derived from a healthy individual dermal fibroblasts. 健常人の皮膚線維芽細胞由来のヒトiPS細胞株。 human ES-like Rese... iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and Ap... SKIP001168 ... Normal 246B6 246B6 ... 36 30-39 Female ... -- No Human iPS cell....2007.11.019 Induction of pluripotent stem cells from adult human fibrob

  8. Stemcell Information: SKIP001173 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available plication (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Information Only ... 18035408 10.1016/j.cell... line derived from a healthy individual dermal fibroblasts. 健常人の皮膚線維芽細胞由来のヒトiPS細胞株。 human ES-like Rese... iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research and Ap... SKIP001173 ... Normal 253F2 253F2 ... 36 30-39 Female ... -- No Human iPS cell....2007.11.019 Induction of pluripotent stem cells from adult human fibrob

  9. Stemcell Information: SKIP001156 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ... 0-9 Male ... -- No Human iPS cell lines derived from BJ human foreskin fibroblasts. 新生児包皮から得た線維芽細胞由来のヒトiPS細胞... SKIP001156 ... BJ Human Foreskin Fibroblasts 新生児包皮由来の線維芽細胞 Unknown 246G3 246G3 ... ...amanaka Shinya 山中 伸弥 Center for iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Cent...er for iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Informa...tion Only ... 18035408--22146343 10.1016/j.cell.2007.11.019--10.1038/mt.2011.2

  10. Stemcell Information: SKIP000821 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line, derived from fibloblast(Cell applications Inc. Lot1388). Lot1388線維芽細胞由来iPS細胞。エピゾーマルベクターによる樹立、導入細胞...No ... No ... Keisuke Okita 沖田 圭介 Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研究所 ...Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研究所 Shiny...a Yamanaka 山中伸弥 Information Only Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研究所... SKIP000821 ... Normal 404C-2 404C-2 ... 36 30-39 Female ... -- No Human iPS cell

  11. Stemcell Information: SKIP000713 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cellbank/cgi-bin/se...inant retroviruses expressing the E6, E7, and hTERT. 骨芽細胞様株, 間葉系幹細胞の性質を持つとされる, (C3H/He mouse) fibroblast-lik... SKIP000713 ... Normal UE6E7TC-4 UE6E7TC-4 ... -- -- ... -- No JCRB1137 ... Osteoblast-like cell... like. Human bone marrow-derived mesenchymal stem cells which were infected with recomb...oweredby10. When the cultures reached subconfluence, the cells were harvested with 0.25% trypsin and 1mM EDT

  12. Stemcell Information: SKIP000707 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available 胎盤由来間葉系幹細胞 fibroblast-like -- -- ... -- ... When the cultures reached subconfluence, the cell...evelopment 国立成育医療研究センター研究所 ... Not Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cell... SKIP000707 ... placenta 胎盤 Normal PL504 PL504 ... -- -- ... -- No JCRB1126 mesenchymal stem cell...s were harvested with 0.25% trypsin and 1mM EDTA and replated with one-quarter of harvested cells ... 5% ... ...bank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3549 ...

  13. Stemcell Information: SKIP000171 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000171 ... Diseased CiRA086Ai-m1 CiRA086Ai-m1 HPS0117 HPS0117 CINCA症候群 ... CINCA syndrome... 607115 ... -- Male ... Yes No iPSC from CINCA syndrome patient with mutaion 1709A>G (Y570C) in...il.cgi?cell_no=HPS0117&type=1 ... 22723549 10.1182/blood-2012-03-417881 Induced pluripotent stem cells from CINCA syndrome... NLRP3 as somatic mosaicism|Riken BRC:HPS0117 疾患特異的iPS細胞株。慢性乳児神経皮膚関節炎症候群(CINCA症候群)患者由来。 human ES-like -- Ret

  14. Stemcell Information: SKIP000876 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000876 ... Diseased Perry syndrome patient iPSCs Perry syndrome patient iPSCs ... ペリー症候群 G20 Perry synd...rome 168605 ... 61 60-69 Male ... Yes No ... Induced pluripotent stem cells (iPSCs) from a Perry syndrome...016.06.007 Cytoplasmic aggregates of dynactin in iPSC-derived tyrosine hydroxylase-positive neurons from a patient with Perry syndrom... patient with F52L mutation in DCTN1. DCTN1にF52L遺伝子変異をもつPerry症候群患者1名から作製したiPS細胞 human E

  15. Stemcell Information: SKIP000173 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000173 ... Diseased CiRA188Ai-M1 CiRA188Ai-M1 HPS0119 HPS0119 CINCA症候群 ... CINCA syndrome... 607115 ... -- Male ... Yes No iPSC from CINCA syndrome patient with mutaion 919G >A (G307S) in.../lab/cell/detail.cgi?cell_no=HPS0119&type=1 ... 22723549 10.1182/blood-2012-03-417881 Induced pluripotent stem cells from CINCA syndr... NLRP3 as somatic mosaicism|Riken BRC:HPS0119 疾患特異的iPS細胞株。慢性乳児神経皮膚関節炎症候群(CINCA症候群)患者由来。HPS0120と同一人由来。 human ...ome patients as a model for dissecting somatic mosaicism and drug discovery Tanaka

  16. Stemcell Information: SKIP000174 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000174 ... Diseased CiRA188Ai-W1 CiRA188Ai-W1 HPS0120 HPS0120 CINCA症候群 ... CINCA syndrome... 607115 ... -- Male ... Yes No iPSC from CINCA syndrome patient with mutaion 919G>A ... (G307S) in.../lab/cell/detail.cgi?cell_no=HPS0120&type=1 ... 22723549 10.1182/blood-2012-03-417881 Induced pluripotent stem cells from CINCA syndr... NLRP3 as somatic mosaicism|Riken BRC:HSP0120 疾患特異的iPS細胞株。慢性乳児神経皮膚関節炎症候群(CINCA症候群)患者由来。HPS0119と同一人由来。 human ...ome patients as a model for dissecting somatic mosaicism and drug discovery Tanaka

  17. Potential applications of skip SMV with thrust engine

    Science.gov (United States)

    Wang, Weilin; Savvaris, Al

    2016-11-01

    This paper investigates the potential applications of Space Maneuver Vehicles (SMV) with skip trajectory. Due to soaring space operations over the past decades, the risk of space debris has considerably increased such as collision risks with space asset, human property on ground and even aviation. Many active debris removal methods have been investigated and in this paper, a debris remediation method is first proposed based on skip SMV. The key point is to perform controlled re-entry. These vehicles are expected to achieve a trans-atmospheric maneuver with thrust engine. If debris is released at altitude below 80 km, debris could be captured by the atmosphere drag force and re-entry interface prediction accuracy is improved. Moreover if the debris is released in a cargo at a much lower altitude, this technique protects high value space asset from break up by the atmosphere and improves landing accuracy. To demonstrate the feasibility of this concept, the present paper presents the simulation results for two specific mission profiles: (1) descent to predetermined altitude; (2) descent to predetermined point (altitude, longitude and latitude). The evolutionary collocation method is adopted for skip trajectory optimization due to its global optimality and high-accuracy. This method is actually a two-step optimization approach based on the heuristic algorithm and the collocation method. The optimal-control problem is transformed into a nonlinear programming problem (NLP) which can be efficiently and accurately solved by the sequential quadratic programming (SQP) procedure. However, such a method is sensitive to initial values. To reduce the sensitivity problem, genetic algorithm (GA) is adopted to refine the grids and provide near optimum initial values. By comparing the simulation data from different scenarios, it is found that skip SMV is feasible in active debris removal and the evolutionary collocation method gives a truthful re-entry trajectory that satisfies the

  18. Efficient use of a translation start codon in BDNF exon I.

    Science.gov (United States)

    Koppel, Indrek; Tuvikene, Jürgen; Lekk, Ingrid; Timmusk, Tõnis

    2015-09-01

    The brain-derived neurotrophic factor (BDNF) gene contains a number of 5' exons alternatively spliced with a common 3' exon. BDNF protein is synthesized from alternative transcripts as a prepro-precursor encoded by the common 3' exon IX, which has a translation start site 21 bp downstream of the splicing site. BDNF mRNAs containing exon I are an exception to this arrangement as the last three nucleotides of this exon constitute an in-frame AUG. Here, we show that this AUG is efficiently used for translation initiation in PC12 cells and cultured cortical neurons. Use of exon I-specific AUG produces higher levels of BDNF protein than use of the common translation start site, resulting from a higher translation rate. No differences in protein degradation, constitutive or regulated secretion were detected between BDNF isoforms with alternative 5' termini. As the BDNF promoter preceding exon I is known to be highly regulated by neuronal activity, our results suggest that the function of this translation start site may be efficient stimulus-dependent synthesis of BDNF protein. The brain-derived neurotrophic factor (BDNF) gene contains multiple untranslated 5' exons alternatively spliced to one common protein-coding 3' exon. However, exon I contains an in-frame ATG in a favorable translation context. Here, we show that use of this ATG is associated with more efficient protein synthesis than the commonly used ATG in exon IX. © 2015 International Society for Neurochemistry.

  19. Decoding of exon splicing patterns in the human RUNX1-RUNX1T1 fusion gene.

    Science.gov (United States)

    Grinev, Vasily V; Migas, Alexandr A; Kirsanava, Aksana D; Mishkova, Olga A; Siomava, Natalia; Ramanouskaya, Tatiana V; Vaitsiankova, Alina V; Ilyushonak, Ilia M; Nazarov, Petr V; Vallar, Laurent; Aleinikova, Olga V

    2015-11-01

    The t(8;21) translocation is the most widespread genetic defect found in human acute myeloid leukemia. This translocation results in the RUNX1-RUNX1T1 fusion gene that produces a wide variety of alternative transcripts and influences the course of the disease. The rules of combinatorics and splicing of exons in the RUNX1-RUNX1T1 transcripts are not known. To address this issue, we developed an exon graph model of the fusion gene organization and evaluated its local exon combinatorics by the exon combinatorial index (ECI). Here we show that the local exon combinatorics of the RUNX1-RUNX1T1 gene follows a power-law behavior and (i) the vast majority of exons has a low ECI, (ii) only a small part is represented by "exons-hubs" of splicing with very high ECI values, and (iii) it is scale-free and very sensitive to targeted skipping of "exons-hubs". Stochasticity of the splicing machinery and preferred usage of exons in alternative splicing can explain such behavior of the system. Stochasticity may explain up to 12% of the ECI variance and results in a number of non-coding and unproductive transcripts that can be considered as a noise. Half-life of these transcripts is increased due to the deregulation of some key genes of the nonsense-mediated decay system in leukemia cells. On the other hand, preferred usage of exons may explain up to 75% of the ECI variability. Our analysis revealed a set of splicing-related cis-regulatory motifs that can explain "attractiveness" of exons in alternative splicing but only when they are considered together. Cis-regulatory motifs are guides for splicing trans-factors and we observed a leukemia-specific profile of expression of the splicing genes in t(8;21)-positive blasts. Altogether, our results show that alternative splicing of the RUNX1-RUNX1T1 transcripts follows strict rules and that the power-law component of the fusion gene organization confers a high flexibility to this process. Copyright © 2015 Elsevier Ltd. All rights

  20. Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy)

    DEFF Research Database (Denmark)

    Vorwerk, P; Christoffersen, C T; Müller, J

    1999-01-01

    The insulin receptor (IR) in two brothers with a rare syndrome of congenital muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. By direct sequencing of Epstein-Barr virus-transformed lymphocytes both patients were found...... domain. In the correct spliced variant, the point mutation is silent and results in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were present in the lymphocytes of the patients. Purified IR from 293 cells overexpressing...... to be compound heterozygotes for mutations in the IR gene. The maternal allele was alternatively spliced in exon 17 due to a point mutation in the -1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase...

  1. Mutations in Exons 9 and 13 of KIT Gene Are Rare Events in Gastrointestinal Stromal Tumors

    Science.gov (United States)

    Lasota, Jerzy; Wozniak, Agnieszka; Sarlomo-Rikala, Maarit; Rys, Janusz; Kordek, Radzislaw; Nassar, Aziza; Sobin, Leslie H.; Miettinen, Markku

    2000-01-01

    Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases. PMID:11021812

  2. New skips and coal handling systems for mine hoisting

    Energy Technology Data Exchange (ETDEWEB)

    Solomentsev, A.I.

    1984-10-01

    The im. M.M. Fedorov All-Union Research Scientific Institute for Rock Strata Mechanics (VNIIGM) in cooperation with Dongiprouglemash and the MakNII Institute has developed a modernized design of skips and handling systems for coal mines in the USSR. Design of the modernized skip is shown in a scheme. The following elements are evaluated: skip structure, suspension gear, skip measuring pocket. Equipment for coal handling, unloading from a coal hopper, weighing and loading into a skip is described. The PAZ automatic control system for skips developed by the VNIIGM Institute is described (elements of the system, performance, reliability, accuracy).

  3. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500 U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic......With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1 1/2 years old. He had no complaints of muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy...

  4. Reading skill and word skipping: Implications for visual and linguistic accounts of word skipping.

    Science.gov (United States)

    Eskenazi, Michael A; Folk, Jocelyn R

    2015-11-01

    We investigated whether high-skill readers skip more words than low-skill readers as a result of parafoveal processing differences based on reading skill. We manipulated foveal load and word length, two variables that strongly influence word skipping, and measured reading skill using the Nelson-Denny Reading Test. We found that reading skill did not influence the probability of skipping five-letter words, but low-skill readers were less likely to skip three-letter words when foveal load was high. Thus, reading skill is likely to influence word skipping when the amount of information in the parafovea falls within the word identification span. We interpret the data in the context of visual-based (extended optimal viewing position model) and linguistic based (E-Z Reader model) accounts of word skipping. The models make different predictions about how and why a word and skipped; however, the data indicate that both models should take into account the fact that different factors influence skipping rates for high- and low-skill readers. (c) 2015 APA, all rights reserved).

  5. Reading Skill and Word Skipping: Implications for Visual and Linguistic Accounts of Word Skipping

    Science.gov (United States)

    Eskenazi, Michael A.; Folk, Jocelyn R.

    2015-01-01

    We investigated whether high-skill readers skip more words than low-skill readers as a result of parafoveal processing differences based on reading skill. We manipulated foveal load and word length, two variables that strongly influence word skipping, and measured reading skill using the Nelson-Denny Reading Test. We found that reading skill did…

  6. Stemcell Information: SKIP000218 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available および253G1(HPS0002)と同一人由来。エピゾーマルベクターによる樹立、導入細胞には導入遺伝子は残っていない。 human ES-like -- Plasmid Episomal vector pCXLE, ... ... Shinya Yamanaka 山中伸弥 Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研究所 ... Ava... SKIP000218 ... Normal 409B2 409B2 HPS0076 HPS0076 ... 36 30-39 Female ... -- No Human iPS cell...Oct3/4, Sox2, Klf4, L-Myc, Lin28, p53 shRNA ... Yes SNL 76/7 (X-rays:5000R or MMC) 1.5-2.5x10^(6) cell...ilable RIKEN BRC 理化学研究所バイオリソースセンター http://www2.brc.riken.jp/lab/cell/detail.cgi?cell

  7. Stemcell Information: SKIP001101 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001101 ... o induced chondrogenic (iChon) cells ダイレクトリプログラミングで作製した軟骨細胞 ... Normal ...man Dermal Fibroblasts(1439 KURABO). 新生児皮膚繊維芽細胞(1439 KURABO)をダイレクトリプログラミングにより軟骨細胞へと誘導(iChon細胞) Other Researc... Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Research ...and Application,Kyoto University 京都大学iPS細胞研究所 CiRA https://www.cira.kyoto-u.ac.jp/e/index.html ... 25187577 ...WT-1-iChon WT-1-iChon ... 0-9 Male ... -- No Direct iInduction of Chondrogenic(iChon) cells from Hu

  8. Stemcell Information: SKIP001103 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001103 ... induced chondrogenic (iChon) cells ダイレクトリプログラミングで作製した軟骨細胞 ... Diseased ...s have elevated ER stress and undergo apoptosis. 軟骨無発症患者線維芽細胞(GM07892)をダイレクトリプログラミングにより軟骨細胞...へと誘導(iChon細胞)。|小胞体ストレスが生じ、過度のアポトーシスが引き起こされていた。 Other Research Grade Retrovirus c-MYC, KLF4... ... Minoru Okada 岡田 稔 Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研究所... ... Information Only Center for iPS Cell Research and Application,Kyoto University 京都大学iPS細胞研究所 CiRA https:

  9. Stemcell Information: SKIP000219 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available l line. ヒトiPS細胞。歯髄細胞由来。 human ES-like -- Plasmid Episomal vector pCXLE, Oct3/4, Sox...Yamanaka 山中伸弥 Center for iPS Cell Research and Application, Kyoto University 京都大学iPS細胞研究所 ... Available RIKE... SKIP000219 ... Pulp 歯髄 Normal 454E2 454E2 HPS0077 HPS0077 ... 16 10-19 Female ... -- No Human iPS cel...2, Klf4, L-Myc, Lin28, p53 shRNA ... Yes SNL 76/7 (X-rays:5000R or MMC) 1.5-2.5x10^(6) cells/100mm dish Primate...N BRC 理化学研究所バイオリソースセンター http://www2.brc.riken.jp/lab/cell/detail.cgi?cell_no=HPS0077&type=1 ...

  10. Stemcell Information: SKIP001193 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001193 ... blood mononuclear cell 血中単核細胞 Diseased HPS0507 HPS0507 CiRA00160 Ci...line derived from a patient :Charcot-Marie-Tooth disease . ... シャルコー·マリー·トゥース病患者由来iPS細胞株。 human ES-like Researc... for iPS Cell Research and Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Center for iPS Cell Research an...d Application (CiRA), Kyoto University 京都大学iPS細胞研究所 Yamanaka Shinya 山中 伸弥 Availab...RA00160 シャルコー・マリー・トゥース病 G600 Charcot-Marie-Tooth disease 118210 ... -- -- Japanese 日本人 Yes No iPS cell

  11. Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival.

    Science.gov (United States)

    Sveen, Anita; Agesen, Trude H; Nesbakken, Arild; Rognum, Torleiv O; Lothe, Ragnhild A; Skotheim, Rolf I

    2011-05-27

    Colorectal cancer (CRC) is a heterogeneous disease that, on the molecular level, can be characterized by inherent genomic instabilities; chromosome instability and microsatellite instability. In the present study we analyze genome-wide disruption of pre-mRNA splicing, and propose transcriptome instability as a characteristic that is analogous to genomic instability on the transcriptome level. Exon microarray profiles from two independent series including a total of 160 CRCs were investigated for their relative amounts of exon usage differences. Each exon in each sample was assigned an alternative splicing score calculated by the FIRMA algorithm. Amounts of deviating exon usage per sample were derived from exons with extreme splicing scores. There was great heterogeneity within both series in terms of sample-wise amounts of deviating exon usage. This was strongly associated with the expression levels of approximately half of 280 splicing factors (54% and 48% of splicing factors were significantly correlated to deviating exon usage amounts in the two series). Samples with high or low amounts of deviating exon usage, associated with overall transcriptome instability, were almost completely separated into their respective groups by hierarchical clustering analysis of splicing factor expression levels in both sample series. Samples showing a preferential tendency towards deviating exon skipping or inclusion were associated with skewed transcriptome instability. There were significant associations between transcriptome instability and reduced patient survival in both sample series. In the test series, patients with skewed transcriptome instability showed the strongest prognostic association (P = 0.001), while a combination of the two characteristics showed the strongest association with poor survival in the validation series (P = 0.03). We have described transcriptome instability as a characteristic of CRC. This transcriptome instability has associations with splicing

  12. Health, behavioral, cognitive, and social correlates of breakfast skipping among women living in socioeconomically disadvantaged neighborhoods.

    Science.gov (United States)

    Smith, Kylie J; McNaughton, Sarah A; Cleland, Verity J; Crawford, David; Ball, Kylie

    2013-11-01

    Breakfast skipping is a potentially modifiable behavior that has negative effects on health and is socioeconomically patterned. This study aimed to examine the intrapersonal (health, behavioral, and cognitive) and social factors associated with breakfast skipping. Nonpregnant women (n = 4123) aged 18-45 y from socioeconomically disadvantaged neighborhoods throughout Victoria, Australia, completed a postal questionnaire. Sociodemographic characteristics, diet, physical activity, sedentary behaviors, and cognitive and social factors were assessed by self-report. Breakfast skipping was defined in 2 ways: 1) "rarely/never" eating breakfast (n = 498) and 2) eating breakfast ≤2 d/wk (includes those who rarely/never ate breakfast; n = 865). Poisson regression was used to calculate prevalence ratios and linear trends, adjusting for covariates. The P values for linear trends are reported below. Compared with breakfast consumers, women who reported rarely/never eating breakfast tended to have poorer self-rated health (P-trend breakfast skipping was defined as eating breakfast ≤2 d/wk, additional associations were found for having lower leisure-time physical activity (P-trend = 0.012) and less self-efficacy for eating a healthy diet (P-trend breakfast skipping among women living in socioeconomically disadvantaged areas. Acknowledging the cross-sectional design and need for causal confirmation, programs that aim to promote breakfast consumption in this population group should consider targeting family-related barriers to healthy eating and nutrition knowledge.

  13. Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells

    NARCIS (Netherlands)

    van Deutekom, J. C.; Bremmer-Bout, M.; Janson, A. A.; Ginjaar, I. B.; Baas, F.; den Dunnen, J. T.; van Ommen, G. J.

    2001-01-01

    Due to frame-shifting mutations in the DMD gene that cause dystrophin deficiency, Duchenne muscular dystrophy (DMD) patients suffer from lethal muscle degeneration. In contrast, mutations in the allelic Becker muscular dystrophy (BMD) do not disrupt the translational reading frame, resulting in a

  14. Clinical characterisation of Becker muscular dystrophy patients predicts favourable outcome in exon-skipping therapy

    NARCIS (Netherlands)

    van den Bergen, J. C.; Schade van Westrum, S. M.; Dekker, L.; van der Kooi, A. J.; de Visser, M.; Wokke, B. H. A.; Straathof, C. S.; Hulsker, M. A.; Aartsma-Rus, A.; Verschuuren, J. J.; Ginjaar, H. B.

    2014-01-01

    Objective Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose

  15. Antisense-mediated Exon Skipping Decreases Tau Protein Expression: A Potential Therapy For Tauopathies

    OpenAIRE

    Sud, Reeteka; Geller, Evan T.; Schellenberg, Gerard D.

    2014-01-01

    In Alzheimer's disease, progressive supranuclear palsy, and a number of other neurodegenerative diseases, the microtubule associated protein tau aggregates to form intracellular neurofibrillary tangles and glial tangles, abnormal structures that are part of disease pathogenesis. Disorders with aggregated tau are called tauopathies. Presently, there are no disease-modifying treatments for this disease class. Tau is encoded by the MAPT gene. We propose that reducing MAPT expression and thus the...

  16. Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance

    NARCIS (Netherlands)

    Lampe, A.K.; Zou, Y.; Sudano, D.; O'Brien, K.K.; Hicks, D.; Laval, S.H.; Charlton, R.; Jimenez-Mallebrera, C.; Zhang, R.Z.; Finkel, R.S.; Tennekoon, G.; Schreiber, G.; van der Knaap, M.S.; Marks, H.; Straub, V.; Flanigan, K.M.; Chu, M.L.; Muntoni, F.; Bushby, K.M.D.; Bonnemann, c.g.

    2008-01-01

    Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), two related conditions of differing severity. BM is a relatively mild dominantly inherited disorder characterized by proximal weakness and distal

  17. breakfast skipping and academic / social development of pupils in ...

    African Journals Online (AJOL)

    Abasiama Akpan

    . Hypothesis 2. There is no significant relationship between breakfast skipping and social development of the pupils. Table 3: Pearson Moment Product Correlation Co-efficient test of relationship between skipping of breakfast and social ...

  18. Skip segment Hirschsprung's disease: a systematic review.

    LENUS (Irish Health Repository)

    O'Donnell, Anne-Marie

    2012-02-01

    PURPOSE: Hirschsprung\\'s disease is characterised by the congenital absence of ganglion cells beginning in the distal rectum and extending proximally for varying distances. \\'Zonal aganglionosis\\' is a phenomenon involving a zone of aganglionosis occurring within normally innervated intestine. \\'Skip segment\\' Hirschsprung\\'s disease (SSHD) involves a \\'skip area\\' of normally ganglionated intestine, surrounded proximally and distally by aganglionosis. While Hirschsprung\\'s disease is believed to be the result of incomplete craniocaudal migration of neural crest-derived cells, the occurrence of SSHD has no clear embryological explanation. The aim of this study was to perform a systematic review of SSHD, reported in the literature between 1954 and 2009, in order to determine the clinical characteristics of this rare entity and its significance. METHODS: The first reported case of SSHD was published in 1954. A systematic review of SSHD cases in the literature, from 1954 to 2009, was carried out using the electronic database \\'Pubmed\\'. Detailed information was recorded regarding the age, gender, presenting symptoms and location of the skip segment in each patient. RESULTS: 24 cases of SSHD have been reported in the literature to date. 18\\/24 (75%) of these cases were males and 6\\/24 (25%) were females. Of these, 22\\/24 (92%) were cases of total colonic aganglionosis (TCA), and 2\\/24 (8%) were rectosigmoid Hirschsprung\\'s disease. Of the 22 TCA cases, 9 (41%) had a skip segment in the transverse colon, 6 (27%) in the ascending colon, 2 (9%) in the caecum and 5 (23%) had multiple skip segments. In both rectosigmoid Hirschsprung\\'s disease cases, the skip segment was in the sigmoid colon. Overall, the length of the skip segment was variable, with the entire transverse colon ganglionated in some cases. CONCLUSION: SSHD occurs predominantly in patients with TCA. The existence of a skip area of normally innervated colon in TCA may influence surgical

  19. Stemcell Information: SKIP000379 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000379 ... Diseased HPS0130 HPS0130 ... 孤発性筋萎縮性側索硬化症 G122 Amyotrophic lateral ...consent on use of it from the DEPOSITOR. Contact Us : このメールアドレスはスパムボットから保護されています。閲覧するにはJavaScriptを有効にする必要があります。 document.getElementById('cloak79ec44e467ab352da6e050229c8a6608').innerHTML = ''; var prefix = 'ma' + 'il' + 'to'; var path = 'hr' + 'ef' + '='; var addy79ec44e467ab352da6e050229c8a6608 = 'cellips' + '@'; addy79ec44e467ab352da6e050229c8a6608 = addy79ec44e467ab352da6e050229c8a6608 + 'brc' + '.' + 'riken' + '.' + 'jp'; var addy_text79ec44e467ab352da6e050229c8a6608 = 'cellips' + '@' + 'brc' + '.' + 'riken' + '.' + 'jp';document.getElementById('cloak79ec44e467ab352da6e050229c8a6608').innerHTML += ''+addy_text79ec44e467ab352da6e050229c8a6608+''; 疾患特異的iPS細胞株。孤発性筋萎縮性側索硬化

  20. Maternal and best friends' influences on meal-skipping behaviours.

    Science.gov (United States)

    Pearson, Natalie; Williams, Lauren; Crawford, David; Ball, Kylie

    2012-09-01

    Skipping meals is particularly common during adolescence and can have a detrimental effect on multiple aspects of adolescent health. Understanding the correlates of meal-skipping behaviours is important for the design of nutrition interventions. The present study examined maternal and best friends' influences on adolescent meal-skipping behaviours. Frequency of skipping breakfast, lunch and dinner was assessed using a Web-based survey completed by 3001 adolescent boys and girls from years 7 and 9 of secondary schools in Victoria, Australia. Perceived best friend and maternal meal skipping, modelling of healthy eating (eating healthy food, limiting junk food, eating fruit and vegetables) and weight watching were assessed. Best friend and maternal factors were differentially associated with meal-skipping behaviours. For example, boys and girls who perceived that their best friend often skipped meals were more likely to skip lunch (OR = 2·01, 95 % CI 1·33, 3·04 and OR = 1·93, 95 % CI 1·41, 2·65; P skipped meals were more likely to skip breakfast (OR = 1·48, 95 % CI 1·01, 2·15; P skipping behaviour. The involvement of mothers may be particularly important in such efforts. Encouraging a peer subculture that promotes regular consumption of meals and educates adolescents on the detrimental impact of meal-skipping behaviour on health may also offer a promising nutrition promotion strategy.

  1. The Relation between Breakfast Skipping and School Performance in Adolescents

    Science.gov (United States)

    Boschloo, Annemarie; Ouwehand, Carolijn; Dekker, Sanne; Lee, Nikki; de Groot, Renate; Krabbendam, Lydia; Jolles, Jelle

    2012-01-01

    Breakfast skipping is common in adolescents, but research on the effects of breakfast skipping on school performance is scarce. This current cross-sectional survey study of 605 adolescents aged 11-18 years investigated whether adolescents who habitually skip breakfast have lower end-of-term grades than adolescents who eat breakfast daily.…

  2. The relation between breakfast skipping and school performance in Adolescents

    NARCIS (Netherlands)

    Boschloo, A.M.; Ouwehand, C.; Dekker, S.J.; Lee, N.C.; de Groot, R.H.M.; Krabbendam, A.C.; Jolles, J.

    2012-01-01

    Breakfast skipping is common in adolescents, but research on the effects of breakfast skipping on school performance is scarce. This current cross-sectional survey study of 605 adolescents aged 11-18 years investigated whether adolescents who habitually skip breakfast have lower end-of-term grades

  3. Relationship between skipping breakfast and bone mineral density in young Japanese women.

    Science.gov (United States)

    Kuroda, Tatsuhiko; Onoe, Yoshiko; Yoshikata, Remi; Ohta, Hiroaki

    2013-01-01

    BACK GROUND AND AIMS: It is well known that insufficient nutrient intake leads to poor bone status. To find a simple evaluation method for prevention of nutrition intake disorder, a cross-sectional study with 275 healthy Japanese female students aged 19-25 was conducted. Anthropometric parameters, bone mineral density (BMD) at lumbar and total hip, bone metabolic markers and physical activity were measured in study participants and the frequency of skipping meals (breakfast, lunch, supper), and absolute values for nutrient intakes were assessed using a Diet History Questionnaire. The frequency of skipping breakfast significantly correlate to total energy intake (ρ= -0.276, pskipping breakfast (b= -0.018, p=0.048) were independent risk factors for lower total hip BMD by multiple regression analysis. The total hip BMD in participants who skipped breakfast three or more times was significantly lower than in those who did not skip breakfast (p=0.007). In conclusion, managing the frequency of skipping breakfast and reducing it to <3 times per week may be beneficial for the maintenance of bone health in younger women.

  4. Endoscopic Skipping of the Terminal Ileum in Pediatric Crohn Disease.

    Science.gov (United States)

    Mansuri, Ishrat; Fletcher, Joel G; Bruining, David H; Kolbe, Amy B; Fidler, Jeff L; Samuel, Sunil; Tung, Jeanne

    2017-06-01

    Pediatric small-bowel (SB) Crohn disease (CD) may be missed if the terminal ileum (TI) appears normal at endoscopy and SB imaging is not performed. We sought to estimate the prevalence and clinical characteristics of pediatric patients with CD and endoscopic skipping of the TI-that is, pediatric patients with active SB or upper gut inflammation and an endoscopically normal TI. This retrospective study included pediatric patients with CD who underwent both CT enterography (CTE) or MR enterography (MRE) and ileocolonoscopy within a 30-day period between July 2004 and April 2014. The physician global assessment was used as the reference standard for SB CD activity. Radiologists reviewed the CTE and MRE studies for inflammatory parameters; severity, length, and multifocality of SB inflammation; and the presence of penetrating complications. Of 170 patients who underwent ileal intubation, the TI was macroscopically normal or showed nonspecific inflammation in 73 patients (43%). Nearly half (36/73, 49%) of the patients with normal or nonspecific findings at ileocolonoscopy had radiologically active disease with a median length of SB involvement of 20 cm (range, 1 to > 100 cm). Seventeen (47%) of these patients had multifocal SB involvement and five (14%) had penetrating complications. Overall, endoscopic TI skipping was present in 43 (59%) patients with normal or nonspecific ileocolonoscopic findings: 20 with histologic inflammation (17 with positive imaging findings), 14 with inflammation at imaging only, and nine with proximal disease (upper gut, jejunum, or proximal ileum). There were no significant differences in the clinical parameters of the patients with and those without endoscopic TI skipping. Ileocolonoscopy may miss SB CD in pediatric patients that is due to isolated histologic, intramural, or proximal inflammation. Enterography is complementary to ileocolonoscopy in the evaluation of pediatric CD.

  5. Periodicity of DNA in exons

    Directory of Open Access Journals (Sweden)

    Kinghorn Brian

    2004-08-01

    Full Text Available Abstract Background The periodic pattern of DNA in exons is a known phenomenon. It was suggested that one of the initial causes of periodicity could be the universal (RNYnpattern (R = A or G, Y = C or U, N = any base of ancient RNA. Two major questions were addressed in this paper. Firstly, the cause of DNA periodicity, which was investigated by comparisons between real and simulated coding sequences. Secondly, quantification of DNA periodicity was made using an evolutionary algorithm, which was not previously used for such purposes. Results We have shown that simulated coding sequences, which were composed using codon usage frequencies only, demonstrate DNA periodicity very similar to the observed in real exons. It was also found that DNA periodicity disappears in the simulated sequences, when the frequencies of codons become equal. Frequencies of the nucleotides (and the dinucleotide AG at each location along phase 0 exons were calculated for C. elegans, D. melanogaster and H. sapiens. Two models were used to fit these data, with the key objective of describing periodicity. Both of the models showed that the best-fit curves closely matched the actual data points. The first dynamic period determination model consistently generated a value, which was very close to the period equal to 3 nucleotides. The second fixed period model, as expected, kept the period exactly equal to 3 and did not detract from its goodness of fit. Conclusions Conclusion can be drawn that DNA periodicity in exons is determined by codon usage frequencies. It is essential to differentiate between DNA periodicity itself, and the length of the period equal to 3. Periodicity itself is a result of certain combinations of codons with different frequencies typical for a species. The length of period equal to 3, instead, is caused by the triplet nature of genetic code. The models and evolutionary algorithm used for characterising DNA periodicity are proven to be an effective tool

  6. POEM, A 3-dimensional exon taxonomy and patterns in untranslated exons.

    Science.gov (United States)

    Knapp, Keith; Chonka, Ashley; Chen, Yi-Ping Phoebe

    2008-09-20

    The existence of exons and introns has been known for thirty years. Despite this knowledge, there is a lack of formal research into the categorization of exons. Exon taxonomies used by researchers tend to be selected ad hoc or based on an information poor de-facto standard. Exons have been shown to have specific properties and functions based on among other things their location and order. These factors should play a role in the naming to increase specificity about which exon type(s) are in question. POEM (Protein Oriented Exon Monikers) is a new taxonomy focused on protein proximal exons. It integrates three dimensions of information (Global Position, Regional Position and Region), thus its exon categories are based on known statistical exon features. POEM is applied to two congruent untranslated exon datasets resulting in the following statistical properties. Using the POEM taxonomy previous wide ranging estimates of initial 5' untranslated region exons are resolved. According to our datasets, 29-36% of genes have wholly untranslated first exons. Untranslated exon containing sequences are shown to have consistently up to 6 times more 5' untranslated exons than 3' untranslated exons. Finally, three exon patterns are determined which account for 70% of untranslated exon genes. We describe a thorough three-dimensional exon taxonomy called POEM, which is biologically and statistically relevant. No previous taxonomy provides such fine grained information and yet still includes all valid information dimensions. The use of POEM will improve the accuracy of genefinder comparisons and analysis by means of a common taxonomy. It will also facilitate unambiguous communication due to its fine granularity.

  7. Impact of breakfast skipping compared with dinner skipping on regulation of energy balance and metabolic risk.

    Science.gov (United States)

    Nas, Alessa; Mirza, Nora; Hägele, Franziska; Kahlhöfer, Julia; Keller, Judith; Rising, Russell; Kufer, Thomas A; Bosy-Westphal, Anja

    2017-06-01

    Background: Meal skipping has become an increasing trend of the modern lifestyle that may lead to obesity and type 2 diabetes.Objective: We investigated whether the timing of meal skipping impacts these risks by affecting circadian regulation of energy balance, glucose metabolism, and postprandial inflammatory responses.Design: In a randomized controlled crossover trial, 17 participants [body mass index (in kg/m(2)): 23.7 ± 4.6] underwent 3 isocaloric 24-h interventions (55%, 30%, and 15% carbohydrate, fat, and protein, respectively): a breakfast skipping day (BSD) and a dinner skipping day (DSD) separated by a conventional 3-meal-structure day (control). Energy and macronutrient balance was measured in a respiration chamber. Postprandial glucose, insulin, and inflammatory responses in leukocytes as well as 24-h glycemia and insulin secretion were analyzed.Results: When compared with the 3-meal control, 24-h energy expenditure was higher on both skipping days (BSD: +41 kcal/d; DSD: +91 kcal/d; both P energy expenditure. In contrast, higher postprandial insulin concentrations and increased fat oxidation with breakfast skipping suggest the development of metabolic inflexibility in response to prolonged fasting that may in the long term lead to low-grade inflammation and impaired glucose homeostasis. This trial was registered at clinicaltrials.gov as NCT02635139. © 2017 American Society for Nutrition.

  8. GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells.

    Science.gov (United States)

    van der Wal, Erik; Bergsma, Atze J; van Gestel, Tom J M; In 't Groen, Stijn L M; Zaehres, Holm; Araúzo-Bravo, Marcos J; Schöler, Hans R; van der Ploeg, Ans T; Pijnappel, W W M Pim

    2017-06-16

    Pompe disease is a metabolic myopathy caused by deficiency of the acid α-glucosidase (GAA) enzyme and results in progressive wasting of skeletal muscle cells. The c.-32-13T>G (IVS1) GAA variant promotes exon 2 skipping during pre-mRNA splicing and is the most common variant for the childhood/adult disease form. We previously identified antisense oligonucleotides (AONs) that promoted GAA exon 2 inclusion in patient-derived fibroblasts. It was unknown how these AONs would affect GAA splicing in skeletal muscle cells. To test this, we expanded induced pluripotent stem cell (iPSC)-derived myogenic progenitors and differentiated these to multinucleated myotubes. AONs restored splicing in myotubes to a similar extent as in fibroblasts, suggesting that they act by modulating the action of shared splicing regulators. AONs targeted the putative polypyrimidine tract of a cryptic splice acceptor site that was part of a pseudo exon in GAA intron 1. Blocking of the cryptic splice donor of the pseudo exon with AONs likewise promoted GAA exon 2 inclusion. The simultaneous blocking of the cryptic acceptor and cryptic donor sites restored the majority of canonical splicing and alleviated GAA enzyme deficiency. These results highlight the relevance of cryptic splicing in human disease and its potential as therapeutic target for splicing modulation using AONs. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  9. Correlates of meal skipping in young adults: a systematic review.

    Science.gov (United States)

    Pendergast, Felicity J; Livingstone, Katherine M; Worsley, Anthony; McNaughton, Sarah A

    2016-12-01

    Meal skipping rates may be highest during young adulthood, a period of transition and development. Although these dietary behaviours may increase future risk of chronic disease, limited research has investigated correlates of meal skipping in young adults. A systematic literature search was conducted to identify studies that investigated correlates of meal skipping behaviours in young adults (aged 18-30 years). EBSCO host, MEDLINE Complete, Global Health, Scopus, EMBASE, Web of Science and Informit platforms were searched for eligible articles. Correlates were defined as any factor that was either associated with meal skipping or was self-reported by the participant to have an influence on meal skipping. Randomised controlled trials, prospective cohort studies, case-control studies, nested case-control studies, cross-sectional studies, and longitudinal studies were eligible for inclusion. Three-hundred and thirty-one articles were identified, 141 full-text articles assessed for eligibility, resulting in 35 included studies. Multiple methodological and reporting weaknesses were apparent in the reviewed studies with 28 of the 35 studies scoring a negative rating in the risk of bias assessment. Meal skipping (any meal), defined as the skipping of any meal throughout the day, was reported in 12 studies with prevalence ranging between 5 and 83%. The remaining 25 studies identified specific meals and their skipping rates, with breakfast the most frequently skipped meal 14-88% compared to lunch 8-57% and dinner 4-57%. Lack of time was consistently reported as an important correlate of meal skipping, compared with correlates such as cost and weight control, while sex was the most commonly reported associated correlate. Breakfast skipping was more common among men while lunch or dinner skipping being more common among women. This review is the first to examine potential correlates of meal skipping in young adults. Future research would benefit from stronger design and

  10. Quiz Today: Should I Skip Class?

    Science.gov (United States)

    Zizler, Peter

    2013-01-01

    How does selective assessment, wherein one counts only the best "k" out of "n" quizzes set, impact grade inflation? Based on our analysis, a specific quantitative answer can be given to a student who plans to skip a quiz, depending, of course, on the student's quiz writing consistency or inconsistency.

  11. Stemcell Information: SKIP000250 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line derived from Pompe disease patient. Same patient as HPS0175 and HPS0176. ポンペ病患者由来iPS細胞... SKIP000250 ... Diseased HPS0176 HPS0176 ... ポンペ病 E740 Pompe disease 232300 ... -- -- ... No No iPS cell... ... Riken Bio Resource Center 理研BRC cellこのメールアドレスはスパムボットから保護されています。閲覧するにはJavaScriptを有効にする必要があります。 document.getElementById('cloake5a72404c200d2a05722631427cf329c').innerHTML = ''; var prefix = 'ma' + 'il' + 'to'; var path = 'hr' + 'ef' + '='; var addye5a72404c200d2a05722631427cf329c = 'ips' + '@'; addye5a72404c200d2a05722631427cf329c = addye5a72404c200d2a05722631427cf329c + 'brc' + '.' + 'riken' + '.' + 'jp'; var addy_texte5a72404c200d2a05722631427cf329c = 'ips' + '@' + 'brc' + '.' + 'riken' + '.' + 'jp';document.getElementById('cloake5a72404c200d2a05722631427cf329c').innerHTML += ''+addy_texte5a72404c200d2a05722631427cf329c+''; cellこのメールアドレスはスパムボットから保護されています。閲覧するにはJavaScriptを有効にする必要があります。 document.getElementById('cloak8a4cab045ad70ec892be63088f0dbfd4').innerHTML = ''; var prefix = 'ma' + 'il' + 'to'; var path = 'hr' + 'ef' + '='; var addy8a4cab045ad70ec892be63088f0dbfd4 = 'ips' + '@'; addy8a4cab045ad70ec892be63088f0dbfd4 = addy8a4cab045ad70ec892be63088f0dbfd4 + 'brc' + '.' + 'riken' + '.' + 'jp'; var addy_text8a4cab045ad70ec892be63088f0dbfd4 = 'ips' + '@' + 'brc' + '.' + 'riken' + '.' + 'jp';document.getElementById('cloak8a4cab045ad70ec892be63088f0dbfd4').innerHTML += ''+addy_text8a4cab045ad70ec892be63088f0dbfd4+''; Availab...le Riken Bio Resource Center 理研BRC http://www2.brc.riken.jp/lab/cell/detail.cgi?cell_no=HPS0176&type=1&lang=en ...

  12. Skip Regulates TGF-β1-Induced Extracellular Matrix Degrading Proteases Expression in Human PC-3 Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Victor Villar

    2013-01-01

    Full Text Available Purpose. To determine whether Ski-interacting protein (SKIP regulates TGF-β1-stimulated expression of urokinase-type plasminogen activator (uPA, matrix metalloproteinase-9 (MMP-9, and uPA Inhibitor (PAI-1 in the androgen-independent human prostate cancer cell model. Materials and Methods. PC-3 prostate cancer cell line was used. The role of SKIP was evaluated using synthetic small interference RNA (siRNA compounds. The expression of uPA, MMP-9, and PAI-1 was evaluated by zymography assays, RT-PCR, and promoter transactivation analysis. Results. In PC-3 cells TGF-β1 treatment stimulated uPA, PAI-1, and MMP-9 expressions. The knockdown of SKIP in PC-3 cells enhanced the basal level of uPA, and TGF-β1 treatment inhibited uPA production. Both PAI-1 and MMP-9 production levels were increased in response to TGF-β1. The ectopic expression of SKIP inhibited both TGF-β1-induced uPA and MMP-9 promoter transactivation, while PAI-1 promoter response to the factor was unaffected. Conclusions. SKIP regulates the expression of uPA, PAI-1, and MMP-9 stimulated by TGF-β1 in PC-3 cells. Thus, SKIP is implicated in the regulation of extracellular matrix degradation and can therefore be suggested as a novel therapeutic target in prostate cancer treatment.

  13. Exon prediction in eucaryotic genomes.

    Science.gov (United States)

    Vignal, L; d'Aubenton-Carafa, Y; Lisacek, F; Mephu Ngüifo, E; Rouzé, P; Quinqueton, J; Thermes, C

    1996-01-01

    Two independent computer systems, NetPlantGene and AMELIE, dedicated to the identification of splice sites in plant and human genomes, respectively, are introduced here. Both methods were designed in relation to experimental work; they rely on automatically generated rules involving the nucleotide content of sequences regardless of the coding properties of exons. The specificity of plant sequences as considered in NetPlantGene is shown to enhance the quality of detection as opposed to general methods such as GRAIL. A scanning model of the acceptor site recognition is being simulated by AMELIE leading to a relatively accurate selection process of sites.

  14. Investigation of ANGPTL3 expression, exon sequence and promotor ...

    African Journals Online (AJOL)

    like proteins, has been demonstrated to affect lipid metabolism by inhibiting the activity of lipoprotein lipase (LPL). Objective: To compare the ANGPTL3 mRNA and protein expression, exon mutation and promoter district CpG island methylation ...

  15. Exon-trapping mediated by the human retrotransposon SVA.

    Science.gov (United States)

    Hancks, Dustin C; Ewing, Adam D; Chen, Jesse E; Tokunaga, Katsushi; Kazazian, Haig H

    2009-11-01

    Although most human retrotransposons are inactive, both inactive and active retrotransposons drive genome evolution and may influence transcription through various mechanisms. In humans, three retrotransposon families are still active, but one of these, SVA, remains mysterious. Here we report the identification of a new subfamily of SVA, which apparently formed after an alternative splicing event where the first exon of the MAST2 gene spliced into an intronic SVA and subsequently retrotransposed. Additional examples of SVA retrotransposing upstream exons due to splicing into SVA were also identified in other primate genomes. After molecular and computational experiments, we found a number of functional 3' splice sites within many different transcribed SVAs across the human and chimpanzee genomes. Using a minigene splicing construct containing an SVA, we observed splicing in cell culture, along with SVA exonization events that introduced premature termination codons (PTCs). These data imply that an SVA residing within an intron in the same orientation as the gene may alter normal gene transcription either by gene-trapping or by introducing PTCs through exonization, possibly creating differences within and across species.

  16. ExonMiner: Web service for analysis of GeneChip Exon array data

    Directory of Open Access Journals (Sweden)

    Imoto Seiya

    2008-11-01

    Full Text Available Abstract Background Some splicing isoform-specific transcriptional regulations are related to disease. Therefore, detection of disease specific splice variations is the first step for finding disease specific transcriptional regulations. Affymetrix Human Exon 1.0 ST Array can measure exon-level expression profiles that are suitable to find differentially expressed exons in genome-wide scale. However, exon array produces massive datasets that are more than we can handle and analyze on personal computer. Results We have developed ExonMiner that is the first all-in-one web service for analysis of exon array data to detect transcripts that have significantly different splicing patterns in two cells, e.g. normal and cancer cells. ExonMiner can perform the following analyses: (1 data normalization, (2 statistical analysis based on two-way ANOVA, (3 finding transcripts with significantly different splice patterns, (4 efficient visualization based on heatmaps and barplots, and (5 meta-analysis to detect exon level biomarkers. We implemented ExonMiner on a supercomputer system in order to perform genome-wide analysis for more than 300,000 transcripts in exon array data, which has the potential to reveal the aberrant splice variations in cancer cells as exon level biomarkers. Conclusion ExonMiner is well suited for analysis of exon array data and does not require any installation of software except for internet browsers. What all users need to do is to access the ExonMiner URL http://ae.hgc.jp/exonminer. Users can analyze full dataset of exon array data within hours by high-level statistical analysis with sound theoretical basis that finds aberrant splice variants as biomarkers.

  17. Mechanistic Evaluation for Mixed-field Agglutination in the K562 Cell Study Model with Exon 3 Deletion of A1 Gene.

    Science.gov (United States)

    Chen, Ding-Ping; Tseng, Ching-Ping; Lin, Chi-Jui; Wang, Wei-Ting; Sun, Chien-Feng

    2015-01-01

    In the case of blood type B3 with typical mixed-field agglutination of RBCs in the presence of anti-B or anti-AB antibody, a number of genetic alternations have been reported. It is well known that the IVS3+5G→A mutation in the B gene destroys the consensus of the splice donor site leading to exon 3 skipping during mRNA splicing. The lack of exon 3 likely causes a short stem region, producing an unstable B3 protein, and is concomitant with a decrease in B3 protein expression. Whether the phenomenon also appears in the type A blood group is of question. In this study, we evaluate whether exon 3 deletion in the blood type A gene also results in mixed-field phenotype. Site-directed mutagenesis was used to generate cDNA encoding A1 gene with exon 3 deletion. The cDNA was stably expressed in K562 cells. The expression of A antigen was compared with expression in parental K562 cells that did not express A antigen and in the stable K562 cell line expressing A(1) cDNA by flow cytometry analyses. The expression of A antigen in A1 stable cells and parental K562 cells was set as 100% and 0%, respectively. The mean relative percentage of A antigen expression for the cells of A1 with exon 3 deletion was 59.9% of A1 stable cells. Consistent with the observations of B3, which is B gene with exon 3 deletion, mixed field agglutination was observed for the cells expressing A1 with exon 3 deletion. Exon 3 deletion results in mixed field phenotype in both type A and B RBCs. However, the degree of antigen expression change for exon 3 deletion in A gene was less severe when compared with the deletion occurred in B gene. © 2015 by the Association of Clinical Scientists, Inc.

  18. The deep intronic c.903+469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria.

    Science.gov (United States)

    Homolova, Katerina; Zavadakova, Petra; Doktor, Thomas Koed; Schroeder, Lisbeth Dahl; Kozich, Viktor; Andresen, Brage S

    2010-04-01

    Deep intronic mutations are often ignored as possible causes of human diseases. A deep intronic mutation in the MTRR gene, c.903+469T>C, is the most frequent mutation causing the cblE type of homocystinuria. It is well known to be associated with pre-mRNA mis-splicing, resulting in pseudoexon inclusion; however, the pathological mechanism remains unknown. We used minigenes to demonstrate that this mutation is the direct cause of MTRR pseudoexon inclusion, and that the pseudoexon is normally not recognized due to a suboptimal 5' splice site. Within the pseudoexon we identified an exonic splicing enhancer (ESE), which is activated by the mutation. Cotransfection and siRNA experiments showed that pseudoexon inclusion depends on the cellular amounts of SF2/ASF and in vitro RNA-binding assays showed dramatically increased SF2/ASF binding to the mutant MTRR ESE. The mutant MTRR ESE sequence is identical to an ESE of the alternatively spliced MST1R proto-oncogene, which suggests that this ESE could be frequently involved in splicing regulation. Our study conclusively demonstrates that an intronic single nucleotide change is sufficient to cause pseudoexon activation via creation of a functional ESE, which binds a specific splicing factor. We suggest that this mechanism may cause genetic disease much more frequently than previously reported. (c) 2010 Wiley-Liss, Inc.

  19. SparseLeap: Efficient Empty Space Skipping for Large-Scale Volume Rendering

    KAUST Repository

    Hadwiger, Markus

    2017-08-28

    Recent advances in data acquisition produce volume data of very high resolution and large size, such as terabyte-sized microscopy volumes. These data often contain many fine and intricate structures, which pose huge challenges for volume rendering, and make it particularly important to efficiently skip empty space. This paper addresses two major challenges: (1) The complexity of large volumes containing fine structures often leads to highly fragmented space subdivisions that make empty regions hard to skip efficiently. (2) The classification of space into empty and non-empty regions changes frequently, because the user or the evaluation of an interactive query activate a different set of objects, which makes it unfeasible to pre-compute a well-adapted space subdivision. We describe the novel SparseLeap method for efficient empty space skipping in very large volumes, even around fine structures. The main performance characteristic of SparseLeap is that it moves the major cost of empty space skipping out of the ray-casting stage. We achieve this via a hybrid strategy that balances the computational load between determining empty ray segments in a rasterization (object-order) stage, and sampling non-empty volume data in the ray-casting (image-order) stage. Before ray-casting, we exploit the fast hardware rasterization of GPUs to create a ray segment list for each pixel, which identifies non-empty regions along the ray. The ray-casting stage then leaps over empty space without hierarchy traversal. Ray segment lists are created by rasterizing a set of fine-grained, view-independent bounding boxes. Frame coherence is exploited by re-using the same bounding boxes unless the set of active objects changes. We show that SparseLeap scales better to large, sparse data than standard octree empty space skipping.

  20. SparseLeap: Efficient Empty Space Skipping for Large-Scale Volume Rendering.

    Science.gov (United States)

    Hadwiger, Markus; Al-Awami, Ali K; Beyer, Johanna; Agus, Marco; Pfister, Hanspeter

    2018-01-01

    Recent advances in data acquisition produce volume data of very high resolution and large size, such as terabyte-sized microscopy volumes. These data often contain many fine and intricate structures, which pose huge challenges for volume rendering, and make it particularly important to efficiently skip empty space. This paper addresses two major challenges: (1) The complexity of large volumes containing fine structures often leads to highly fragmented space subdivisions that make empty regions hard to skip efficiently. (2) The classification of space into empty and non-empty regions changes frequently, because the user or the evaluation of an interactive query activate a different set of objects, which makes it unfeasible to pre-compute a well-adapted space subdivision. We describe the novel SparseLeap method for efficient empty space skipping in very large volumes, even around fine structures. The main performance characteristic of SparseLeap is that it moves the major cost of empty space skipping out of the ray-casting stage. We achieve this via a hybrid strategy that balances the computational load between determining empty ray segments in a rasterization (object-order) stage, and sampling non-empty volume data in the ray-casting (image-order) stage. Before ray-casting, we exploit the fast hardware rasterization of GPUs to create a ray segment list for each pixel, which identifies non-empty regions along the ray. The ray-casting stage then leaps over empty space without hierarchy traversal. Ray segment lists are created by rasterizing a set of fine-grained, view-independent bounding boxes. Frame coherence is exploited by re-using the same bounding boxes unless the set of active objects changes. We show that SparseLeap scales better to large, sparse data than standard octree empty space skipping.

  1. Breakfast skipping and academic / social development of pupils in ...

    African Journals Online (AJOL)

    The researchers sought to find-out the effects of breakfast skipping on the academic and social development of the primary school child. A nine item researchers designed questionnaire titled “Assessment of the effects of skipping breakfast on the children by pupils was the basic instrument”. It was validated by experts in the ...

  2. 26 CFR 26.2653-1 - Taxation of multiple skips.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Taxation of multiple skips. 26.2653-1 Section 26.2653-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE...-1 Taxation of multiple skips. (a) General rule. If property is held in trust immediately after a GST...

  3. Skipped spawning in fishes: More common than you might think

    DEFF Research Database (Denmark)

    Rideout, Rick M.; Tomkiewicz, Jonna

    2011-01-01

    research on skipped spawning, covering a broad range of fishes with diverse life history strategies. Evidence for skipped spawning has been collected by use of traditional histological techniques as well as modern technological advances, such as satellite tags and the ability to track fish movements based...

  4. Exploring the reasons why school students eat or skip breakfast.

    Science.gov (United States)

    ALBashtawy, Mohammed

    2015-07-01

    Breakfast is considered to be the most important meal of the day. It provides the essential nutrients needed for the day's activities. To determine the prevalence of breakfast consumption and to assess the nutritional status of students aged 12-18 years. A school-based study carried out between September and October 2014 involved 1,303 school students from grades 7 to 12, aged 12 to 18 years, who completed a questionnaire on breakfast consumption. The chi-square test was used. An odds ratio and 95% confidence interval determined the predictive factors for skipping breakfast. The prevalence of breakfast consumption was 52.3%, statistically decreasing with age. Adjusted logistic regression analysis reflected a statistically high consumption among 12-15 year olds, those with highly educated mothers and those with low family income. For the target groups at risk, a community and school-based health education programme, conducted by school nurses and other healthcare providers, would be beneficial.

  5. Androgen Receptor Exon 1 Mutation Causes Androgen Insensitivity by Creating Phosphorylation Site and Inhibiting Melanoma Antigen-A11 Activation of NH2- and Carboxyl-terminal Interaction-dependent Transactivation*

    Science.gov (United States)

    Lagarde, William H.; Blackwelder, Amanda J.; Minges, John T.; Hnat, Andrew T.; French, Frank S.; Wilson, Elizabeth M.

    2012-01-01

    Naturally occurring germ line mutations in the X-linked human androgen receptor (AR) gene cause incomplete masculinization of the external genitalia by disrupting AR function in males with androgen insensitivity syndrome. Almost all AR missense mutations that cause androgen insensitivity syndrome are located in the highly structured DNA and ligand binding domains. In this report we investigate the functional defect associated with an AR exon 1 missense mutation, R405S, that caused partial androgen insensitivity. The 46,XX heterozygous maternal carrier had a wild-type Arg-405 CGC allele but transmitted an AGC mutant allele coding for Ser-405. At birth, the 46,XY proband had a bifid scrotum, hypospadias, and micropenis consistent with clinical stage 3 partial androgen insensitivity. Androgen-dependent transcriptional activity of AR-R405S expressed in CV1 cells was less than wild-type AR and refractory in androgen-dependent AR NH2- and carboxyl interaction transcription assays that depend on the coregulator effects of melanoma antigen-A11. This mutation created a Ser-405 phosphorylation site evident by the gel migration of an AR-R405S NH2-terminal fragment as a double band that converted to the wild-type single band after treatment with λ-phosphatase. Detrimental effects of the R405S mutation were related to the proximity of the AR WXXLF motif 433WHTLF437 required for melanoma antigen-A11 and p300 to stimulate transcriptional activity associated with the AR NH2- and carboxyl-terminal interaction. We conclude that the coregulator effects of melanoma antigen-A11 on the AR NH2- and carboxyl-terminal interaction amplify the androgen-dependent transcriptional response to p300 required for normal human male sex development in utero. PMID:22334658

  6. Androgen receptor exon 1 mutation causes androgen insensitivity by creating phosphorylation site and inhibiting melanoma antigen-A11 activation of NH2- and carboxyl-terminal interaction-dependent transactivation.

    Science.gov (United States)

    Lagarde, William H; Blackwelder, Amanda J; Minges, John T; Hnat, Andrew T; French, Frank S; Wilson, Elizabeth M

    2012-03-30

    Naturally occurring germ line mutations in the X-linked human androgen receptor (AR) gene cause incomplete masculinization of the external genitalia by disrupting AR function in males with androgen insensitivity syndrome. Almost all AR missense mutations that cause androgen insensitivity syndrome are located in the highly structured DNA and ligand binding domains. In this report we investigate the functional defect associated with an AR exon 1 missense mutation, R405S, that caused partial androgen insensitivity. The 46,XX heterozygous maternal carrier had a wild-type Arg-405 CGC allele but transmitted an AGC mutant allele coding for Ser-405. At birth, the 46,XY proband had a bifid scrotum, hypospadias, and micropenis consistent with clinical stage 3 partial androgen insensitivity. Androgen-dependent transcriptional activity of AR-R405S expressed in CV1 cells was less than wild-type AR and refractory in androgen-dependent AR NH(2)- and carboxyl interaction transcription assays that depend on the coregulator effects of melanoma antigen-A11. This mutation created a Ser-405 phosphorylation site evident by the gel migration of an AR-R405S NH(2)-terminal fragment as a double band that converted to the wild-type single band after treatment with λ-phosphatase. Detrimental effects of the R405S mutation were related to the proximity of the AR WXXLF motif (433)WHTLF(437) required for melanoma antigen-A11 and p300 to stimulate transcriptional activity associated with the AR NH(2)- and carboxyl-terminal interaction. We conclude that the coregulator effects of melanoma antigen-A11 on the AR NH(2)- and carboxyl-terminal interaction amplify the androgen-dependent transcriptional response to p300 required for normal human male sex development in utero.

  7. A novel point mutation within the EDA gene causes an exon dropping in mature RNA in Holstein Friesian cattle breed affected by X-linked anhidrotic ectodermal dysplasia

    Directory of Open Access Journals (Sweden)

    Pariset Lorraine

    2011-07-01

    Full Text Available Abstract Background X-linked anhidrotic ectodermal dysplasia is a disorder characterized by abnormal development of tissues and organs of ectodermal origin caused by mutations in the EDA gene. The bovine EDA gene encodes the ectodysplasin A, a membrane protein expressed in keratinocytes, hair follicles and sweat glands, which is involved in the interactions between cell and cell and/or cell and matrix. Four mutations causing ectodermal dysplasia in cattle have been described so far. Results We identified a new single nucleotide polymorphism (SNP at the 9th base of exon 8 in the EDA gene in two calves of Holstein Friesian cattle breed affected by ectodermal dysplasia. This SNP is located in the exonic splicing enhancer (ESEs recognized by SRp40 protein. As a consequence, the spliceosome machinery is no longer able to recognize the sequence as exonic and causes exon skipping. The mutation determines the deletion of the entire exon (131 bp in the RNA processing, causing a severe alteration of the protein structure and thus the disease. Conclusion We identified a mutation, never described before, that changes the regulation of alternative splicing in the EDA gene and causes ectodermal dysplasia in cattle. The analysis of the SNP allows the identification of carriers that can transmit the disease to the offspring. This mutation can thus be exploited for a rational and efficient selection of unequivocally healthy cows for breeding.

  8. Update History of This Database - SKIP Stemcell Database | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available List Contact us SKIP Stemcell Database Update History of This Database Date Update contents 2017/03/13 SKIP Stemcell Database... English archive site is opened. 2013/03/29 SKIP Stemcell Database ( https://www.skip.med.k...eio.ac.jp/SKIPSearch/top?lang=en ) is opened. About This Database Database Description Download License Update History of This Databa...se Site Policy | Contact Us Update History of This Database - SKIP Stemcell Database | LSDB Archive ...

  9. Exonic splicing enhancer-dependent selection of the bovine papillomavirus type 1 nucleotide 3225 3' splice site can be rescued in a cell lacking splicing factor ASF/SF2 through activation of the phosphatidylinositol 3-kinase/Akt pathway.

    Science.gov (United States)

    Liu, Xuefeng; Mayeda, Akila; Tao, Mingfang; Zheng, Zhi-Ming

    2003-02-01

    Bovine papillomavirus type 1 (BPV-1) late pre-mRNAs are spliced in keratinocytes in a differentiation-specific manner: the late leader 5' splice site alternatively splices to a proximal 3' splice site (at nucleotide 3225) to express L2 or to a distal 3' splice site (at nucleotide 3605) to express L1. Two exonic splicing enhancers, each containing two ASF/SF2 (alternative splicing factor/splicing factor 2) binding sites, are located between the two 3' splice sites and have been identified as regulating alternative 3' splice site usage. The present report demonstrates for the first time that ASF/SF2 is required under physiological conditions for the expression of BPV-1 late RNAs and for selection of the proximal 3' splice site for BPV-1 RNA splicing in DT40-ASF cells, a genetically engineered chicken B-cell line that expresses only human ASF/SF2 controlled by a tetracycline-repressible promoter. Depletion of ASF/SF2 from the cells by tetracycline greatly decreased viral RNA expression and RNA splicing at the proximal 3' splice site while increasing use of the distal 3' splice site in the remaining viral RNAs. Activation of cells lacking ASF/SF2 through anti-immunoglobulin M-B-cell receptor cross-linking rescued viral RNA expression and splicing at the proximal 3' splice site and enhanced Akt phosphorylation and expression of the phosphorylated serine/arginine-rich (SR) proteins SRp30s (especially SC35) and SRp40. Treatment with wortmannin, a specific phosphatidylinositol 3-kinase/Akt kinase inhibitor, completely blocked the activation-induced activities. ASF/SF2 thus plays an important role in viral RNA expression and splicing at the proximal 3' splice site, but activation-rescued viral RNA expression and splicing in ASF/SF2-depleted cells is mediated through the phosphatidylinositol 3-kinase/Akt pathway and is associated with the enhanced expression of other SR proteins.

  10. Skipping breakfast, alcohol consumption and physical inactivity as risk factors for overweight and obesity in adolescents: results of the E-MOVO project.

    Science.gov (United States)

    Croezen, S; Visscher, T L S; Ter Bogt, N C W; Veling, M L; Haveman-Nies, A

    2009-03-01

    To investigate the association between skipping breakfast, alcohol consumption and physical inactivity with overweight and obesity in adolescents. The design comprises cross-sectional electronic health survey (E-MOVO). Over 35 000 Dutch adolescents in grade 2 (13-14 years of age) and grade 4 (15-16 years of age) of secondary educational schools were recruited by seven community health services. Analyses were performed on 25 176 adolescents. Body mass index was calculated from self-reported body weight and height. Frequency of skipping breakfast per week, amount of alcoholic drinks consumed per occasion, and numbers of physical active days per week were considered as determinants for overweight and obesity. In grade 2, adjusted odds ratios for the association with overweight were 2.17 (95% CI: 1.66-2.85) for skipping breakfast, 1.86 (1.36-2.55) for alcohol consumption and 1.73 (1.19-2.51) for physical inactivity. Statistically significant associations with overweight were also found in grade 4. In grade 2, dose-response relations (P for trend breakfast skipping showed the strongest relation with overweight (OR 1.68, 95% CI 1.43-1.97 for grade 2, OR 1.32 95% CI 1.14-1.54 for grade 4) and obesity. Skipping breakfast, alcohol consumption and physical inactivity were associated with overweight in second and fourth grade adolescents. The associations were strongest for younger adolescents. The most important risk factor for overweight and obesity was skipping breakfast.

  11. Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy.

    Directory of Open Access Journals (Sweden)

    Johann Böhm

    2013-06-01

    Full Text Available Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM, a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM. However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD. Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.

  12. Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases.

    Science.gov (United States)

    Lasota, J; Wozniak, A; Sarlomo-Rikala, M; Rys, J; Kordek, R; Nassar, A; Sobin, L H; Miettinen, M

    2000-10-01

    Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases.

  13. Crystal Structure of the CLOCK Transactivation Domain Exon19 in Complex with a Repressor

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Zhiqiang; Su, Lijing; Pei, Jimin; Grishin, Nick V.; Zhang, Hong (UTSMC)

    2017-08-01

    In the canonical clock model, CLOCK:BMAL1-mediated transcriptional activation is feedback regulated by its repressors CRY and PER and, in association with other coregulators, ultimately generates oscillatory gene expression patterns. How CLOCK:BMAL1 interacts with coregulator(s) is not well understood. Here we report the crystal structures of the mouse CLOCK transactivating domain Exon19 in complex with CIPC, a potent circadian repressor that functions independently of CRY and PER. The Exon19:CIPC complex adopts a three-helical coiled-coil bundle conformation containing two Exon19 helices and one CIPC. Unique to Exon19:CIPC, three highly conserved polar residues, Asn341 of CIPC and Gln544 of the two Exon19 helices, are located at the mid-section of the coiled-coil bundle interior and form hydrogen bonds with each other. Combining results from protein database search, sequence analysis, and mutagenesis studies, we discovered for the first time that CLOCK Exon19:CIPC interaction is a conserved transcription regulatory mechanism among mammals, fish, flies, and other invertebrates.

  14. Crystal Structure of the CLOCK Transactivation Domain Exon19 in Complex with a Repressor.

    Science.gov (United States)

    Hou, Zhiqiang; Su, Lijing; Pei, Jimin; Grishin, Nick V; Zhang, Hong

    2017-08-01

    In the canonical clock model, CLOCK:BMAL1-mediated transcriptional activation is feedback regulated by its repressors CRY and PER and, in association with other coregulators, ultimately generates oscillatory gene expression patterns. How CLOCK:BMAL1 interacts with coregulator(s) is not well understood. Here we report the crystal structures of the mouse CLOCK transactivating domain Exon19 in complex with CIPC, a potent circadian repressor that functions independently of CRY and PER. The Exon19:CIPC complex adopts a three-helical coiled-coil bundle conformation containing two Exon19 helices and one CIPC. Unique to Exon19:CIPC, three highly conserved polar residues, Asn341 of CIPC and Gln544 of the two Exon19 helices, are located at the mid-section of the coiled-coil bundle interior and form hydrogen bonds with each other. Combining results from protein database search, sequence analysis, and mutagenesis studies, we discovered for the first time that CLOCK Exon19:CIPC interaction is a conserved transcription regulatory mechanism among mammals, fish, flies, and other invertebrates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy

    Science.gov (United States)

    Echigoya, Yusuke; Nakamura, Akinori; Nagata, Tetsuya; Urasawa, Nobuyuki; Trieu, Nhu; Panesar, Dharminder; Kuraoka, Mutsuki; Moulton, Hong M.; Saito, Takashi; Aoki, Yoshitsugu; Iversen, Patrick; Sazani, Peter; Kole, Ryszard; Maruyama, Rika; Partridge, Terry; Takeda, Shin’ichi; Yokota, Toshifumi

    2017-01-01

    Duchenne muscular dystrophy (DMD) is a lethal genetic disorder caused by an absence of the dystrophin protein in bodywide muscles, including the heart. Cardiomyopathy is a leading cause of death in DMD. Exon skipping via synthetic phosphorodiamidate morpholino oligomers (PMOs) represents one of the most promising therapeutic options, yet PMOs have shown very little efficacy in cardiac muscle. To increase therapeutic potency in cardiac muscle, we tested a next-generation morpholino: arginine-rich, cell-penetrating peptide-conjugated PMOs (PPMOs) in the canine X-linked muscular dystrophy in Japan (CXMDJ) dog model of DMD. A PPMO cocktail designed to skip dystrophin exons 6 and 8 was injected intramuscularly, intracoronarily, or intravenously into CXMDJ dogs. Intravenous injections with PPMOs restored dystrophin expression in the myocardium and cardiac Purkinje fibers, as well as skeletal muscles. Vacuole degeneration of cardiac Purkinje fibers, as seen in DMD patients, was ameliorated in PPMO-treated dogs. Although symptoms and functions in skeletal muscle were not ameliorated by i.v. treatment, electrocardiogram abnormalities (increased Q-amplitude and Q/R ratio) were improved in CXMDJ dogs after intracoronary or i.v. administration. No obvious evidence of toxicity was found in blood tests throughout the monitoring period of one or four systemic treatments with the PPMO cocktail (12 mg/kg/injection). The present study reports the rescue of dystrophin expression and recovery of the conduction system in the heart of dystrophic dogs by PPMO-mediated multiexon skipping. We demonstrate that rescued dystrophin expression in the Purkinje fibers leads to the improvement/prevention of cardiac conduction abnormalities in the dystrophic heart. PMID:28373570

  16. Exon - ASTRA | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available switchLanguage; BLAST Search Image Search Home About Archive Update History Data ...ontents Exons in variants Data file File name: astra_exon.zip File URL: ftp://ftp.biosciencedbc.jp/archive/a... About This Database Database Description Download License Update History of This Database Site Policy | Contact Us Exon - ASTRA | LSDB Archive ...

  17. Parallel Synthesis of Cell-Penetrating Peptide Conjugates of PMO Toward Exon Skipping Enhancement in Duchenne Muscular Dystrophy

    NARCIS (Netherlands)

    O'Donovan, Liz; Okamoto, Itaru; Arzumanov, Andrey A.; Williams, Donna L.; Deuss, Peter; Gait, Michael J.

    2015-01-01

    We describe two new methods of parallel chemical synthesis of libraries of peptide conjugates of phosphorodiamidate morpholino oligonucleotide (PMO) cargoes on a scale suitable for cell screening prior to in vivo analysis for therapeutic development. The methods represent an extension of the

  18. Factors associated with skipping breakfast among Inner Mongolia medical students in China

    National Research Council Canada - National Science Library

    Sun, Juan; Yi, He; Liu, Zhiyue; Wu, Yan; Bian, Jiang; Wu, Yanyan; Eshita, Yuki; Li, Gaimei; Zhang, Qing; Yang, Ying

    2013-01-01

    .... The aim of the present study was to determine the prevalence of skipping breakfast and factors associated with skipping breakfast among medical students in Inner Mongolia of China, and to assist...

  19. Mathematical modeling for optimizing skip-stop rail transit operation strategy using genetic algorithm.

    Science.gov (United States)

    2012-03-01

    "With skip-stop rail transit operation, transit agencies can reduce their operating costs and fleet size, : and passengers can experience reduced in-transit travel times without extra track and technological : improvement. However, since skip-stop op...

  20. Development of Multiexon Skipping Antisense Oligonucleotide Therapy for Duchenne Muscular Dystrophy

    Science.gov (United States)

    Yokota, Toshifumi; Wood, Matthew J. A.

    2013-01-01

    Duchenne muscular dystrophy (DMD) is an incurable, X-linked progressive muscle degenerative disorder that results from the absence of dystrophin protein and leads to premature death in affected individuals due to respiratory and/or cardiac failure typically by age of 30. Very recently the exciting prospect of an effective oligonucleotide therapy has emerged which restores dystrophin protein expression to affected tissues in DMD patients with highly promising data from a series of clinical trials. This therapeutic approach is highly mutation specific and thus is personalised. Therefore DMD has emerged as a model genetic disorder for understanding and overcoming of the challenges of developing personalised genetic medicines. One of the greatest weaknesses of the current oligonucleotide approach is that it is a mutation-specific therapy. To address this limitation, we have recently demonstrated that exons 45–55 skipping therapy has the potential to treat clusters of mutations that cause DMD, which could significantly reduce the number of compounds that would need to be developed in order to successfully treat all DMD patients. Here we discuss and review the latest preclinical work in this area as well as a variety of accompanying issues, including efficacy and potential toxicity of antisense oligonucleotides, prior to human clinical trials. PMID:23984357

  1. Development of Multiexon Skipping Antisense Oligonucleotide Therapy for Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Yoshitsugu Aoki

    2013-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is an incurable, X-linked progressive muscle degenerative disorder that results from the absence of dystrophin protein and leads to premature death in affected individuals due to respiratory and/or cardiac failure typically by age of 30. Very recently the exciting prospect of an effective oligonucleotide therapy has emerged which restores dystrophin protein expression to affected tissues in DMD patients with highly promising data from a series of clinical trials. This therapeutic approach is highly mutation specific and thus is personalised. Therefore DMD has emerged as a model genetic disorder for understanding and overcoming of the challenges of developing personalised genetic medicines. One of the greatest weaknesses of the current oligonucleotide approach is that it is a mutation-specific therapy. To address this limitation, we have recently demonstrated that exons 45–55 skipping therapy has the potential to treat clusters of mutations that cause DMD, which could significantly reduce the number of compounds that would need to be developed in order to successfully treat all DMD patients. Here we discuss and review the latest preclinical work in this area as well as a variety of accompanying issues, including efficacy and potential toxicity of antisense oligonucleotides, prior to human clinical trials.

  2. Association between polymorphisms of exon 12 and exon 24 of JHDM2A gene and male infertility

    Directory of Open Access Journals (Sweden)

    Zohreh Hojati

    2016-06-01

    Full Text Available Background: Some dynamic changes occurs during spermatogenesis such as histone removal and its replacement with transition nuclear protein and protamine. These proteins are required for packing and condensation of sperm chromatin. JHDM2A is a histone demethylase that directly binds to promoter regions of Tnp1 and Prm1 genes and controls their expression by removing H3K9 at their promoters. Objective: The association between polymorphisms of exon 12 and exon 24 in JHDM2A gene and male infertility were evaluated for the first time. Materials and Methods: In this experimental study, 400 infertile men (oligospermia and azoospermia and normal healthy fathers were evaluated (n=200. Single Strand Conformation Polymorphism (SSCP-PCR and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP methods were used for screening any polymorphisms that are exist in exon 12 and exon 24. Results: Exon 24 PCR products were analyzed by RFLP but no polymorphism was found in this exon at the restriction site of EcoRV enzyme. Our monitoring along the whole nucleotides of exon 12 and exon 24 were continued using SSCP method, but we found no change along these exons. Conclusion: Generally, this study evaluated the association between polymorphisms in exon 12 and exon 24 of JHDM2A gene and male infertility which suggests that polymorphisms of these exons may not be associated with the risk of male infertility.

  3. Breakfast Skipping, Extreme Commutes, and the Sex Composition at Birth.

    Science.gov (United States)

    Mazumder, Bhashkar; Seeskin, Zachary

    2015-01-01

    A growing body of literature has shown that environmental exposures in the period around conception can affect the sex ratio at birth through selective attrition that favors the survival of female conceptuses. Glucose availability is considered a key indicator of the fetal environment, and its absence as a result of meal skipping may inhibit male survival. We hypothesize that breakfast skipping during pregnancy may lead to a reduction in the fraction of male births. Using time use data from the United States we show that women with commute times of 90 minutes or longer are 20 percentage points more likely to skip breakfast. Using U.S. census data we show that women with commute times of 90 minutes or longer are 1.2 percentage points less likely to have a male child under the age of 2. Under some assumptions, this implies that routinely skipping breakfast around the time of conception leads to a 6 percentage point reduction in the probability of a male child. Skipping breakfast during pregnancy may therefore constitute a poor environment for fetal health more generally.

  4. Novel Rbfox2 isoforms associated with alternative exon usage in rat cortex and suprachiasmatic nucleus.

    Science.gov (United States)

    Partridge, L M M; Carter, D A

    2017-08-30

    Transcriptome diversity in adult neurons is partly mediated by RNA binding proteins (RBPs), including the RBFOX factors. RBFOX3/NeuN, a neuronal maturity marker, is strangely depleted in suprachiasmatic nucleus (SCN) neurons, and may be compensated by a change in Rbfox2 expression. In this study, we found no superficial changes in Rbfox2 expression in the SCN, but mRNA population analysis revealed a distinct SCN transcript profile that includes multiple novel Rbfox2 isoforms. Of eleven isoforms in SCN and cerebral cortex that exhibit exon variation across two protein domains, we found a 3-fold higher abundance of a novel ('-12-40') C-terminal domain (CTD)-variant in the SCN. This isoform embraces an alternative reading frame that imparts a 50% change in CTD protein sequence, and functional impairment of exon 7 exclusion activity in a RBFOX2-target, the L-type calcium channel gene, Cacna1c. We have also demonstrated functional correlates in SCN gene transcripts; inclusion of Cacna1c exon 7, and also exclusion of both NMDA receptor gene Grin1 exon 4, and Enah exon 12, all consistent with a change in SCN RBFOX activity. The demonstrated regional diversity of Rbfox2 in adult brain highlights the functional adaptability of this RBP, enabling neuronal specialization, and potentially responding to disease-related neuronal dysfunction.

  5. Social inequalities in young children's meal skipping behaviors: The Generation R Study

    NARCIS (Netherlands)

    A.I. Wijtzes (Anne); W. Jansen (Wilma); V.W.V. Jaddoe (Vincent); O.H. Franco (Oscar); A. Hofman (Albert); F.J. van Lenthe (Frank); H. Raat (Hein)

    2015-01-01

    textabstractBackground: Regular meal consumption is considered an important aspect of a healthy diet. While ample evidence shows social inequalities in breakfast skipping among adolescents, little is known about social inequalities in breakfast skipping and skipping of other meals among young

  6. 7 CFR 42.123 - Flow diagram for skip lot sampling and inspection.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Flow diagram for skip lot sampling and inspection. 42... STANDARD CONTAINER REGULATIONS STANDARDS FOR CONDITION OF FOOD CONTAINERS Skip Lot Sampling and Inspection Procedures § 42.123 Flow diagram for skip lot sampling and inspection. EC02SE91.000 Notes: 1. Only normal...

  7. Modulation of mdm2 pre-mRNA splicing by 9-aminoacridine-PNA (peptide nucleic acid conjugates targeting intron-exon junctions

    Directory of Open Access Journals (Sweden)

    Nielsen Peter E

    2010-06-01

    Full Text Available Abstract Background Modulation of pre-mRNA splicing by antisense molecules is a promising mechanism of action for gene therapeutic drugs. In this study, we have examined the potential of peptide nucleic acid (PNA 9-aminoacridine conjugates to modulate the pre-mRNA splicing of the mdm2 human cancer gene in JAR cells. Methods We screened 10 different 15 mer PNAs targeting intron2 at both the 5' - and the 3'-splice site for their effects on the splicing of mdm2 using RT-PCR analysis. We also tested a PNA (2512 targeting the 3'-splice site of intron3 with a complementarity of 4 bases to intron3 and 11 bases to exon4 for its splicing modulation effect. This PNA2512 was further tested for the effects on the mdm2 protein level as well as for inhibition of cell growth in combination with the DNA damaging agent camptothecin (CPT. Results We show that several of these PNAs effectively inhibit the splicing thereby producing a larger mRNA still containing intron2, while skipping of exon3 was not observed by any of these PNAs. The most effective PNA (PNA2406 targeting the 3'-splice site of intron2 had a complementarity of 4 bases to intron2 and 11 bases to exon3. PNA (2512 targeting the 3'-splice site of intron3 induced both splicing inhibition (intron3 skipping and skipping of exon4. Furthermore, treatment of JAR cells with this PNA resulted in a reduction in the level of MDM2 protein and a concomitant increase in the level of tumor suppressor p53. In addition, a combination of this PNA with CPT inhibited cell growth more than CPT alone. Conclusion We have identified several PNAs targeting the 5'- or 3'-splice sites in intron2 or the 3'-splice site of intron3 of mdm2 pre-mRNA which can inhibit splicing. Antisense targeting of splice junctions of mdm2 pre-mRNA may be a powerful method to evaluate the cellular function of MDM2 splice variants as well as a promising approach for discovery of mdm2 targeted anticancer drugs.

  8. Optimized Exon-Exon Junction Library and its Application on Rodents' Brain Transcriptome Analysis

    Directory of Open Access Journals (Sweden)

    Tong-Hai Dou

    2017-05-01

    Full Text Available ABSTRACT Background: Alternative splicing (AS, which plays an important role in gene expression and functional regulation, has been analyzed on genome-scale by various bioinformatic approaches based on RNA-seq data. Compared with the huge number of studies on mouse, the AS researches approaching the rat, whose genome is intermedia between mouse and human, were still limited. To enrich the knowledge on AS events in rodents' brain, we perfomed a comprehensive analysis on four transcriptome libraries (mouse cerebrum, mouse cerebellum, rat cerebrum, and rat cerebellum, recruiting high-throughput sequencing technology. An optimized exon-exon junction library approach was introduced to adapt the longer RNA-seq reads and to improve mapping efficiency. Results: In total, 7,106 mouse genes and 2,734 rat genes were differentially expressed between cerebrum and cerebellum, while 7,125 mouse genes and 1,795 rat genes exhibited varieties on transcript variant level. Only half of the differentially expressed exon-exon junctions could be reflected at gene expression level. Functional cluster analysis showed that 32 pathways in mouse and 9 pathways in rat were significantly enriched, and 6 of them were in both. Interestingly, some differentially expressed transcript variants did not show difference on gene expression level, such as PLCβ1 and Kcnma1. Conclusion: Our work provided a case study of a novel exon-exon junction strategy to analyze the expression of genes and isoforms, helping us understand which transcript contributes to the overall expression and further functional change.

  9. Exon Shuffling and Origin of Scorpion Venom Biodiversity

    Directory of Open Access Journals (Sweden)

    Xueli Wang

    2016-12-01

    Full Text Available Scorpion venom is a complex combinatorial library of peptides and proteins with multiple biological functions. A combination of transcriptomic and proteomic techniques has revealed its enormous molecular diversity, as identified by the presence of a large number of ion channel-targeted neurotoxins with different folds, membrane-active antimicrobial peptides, proteases, and protease inhibitors. Although the biodiversity of scorpion venom has long been known, how it arises remains unsolved. In this work, we analyzed the exon-intron structures of an array of scorpion venom protein-encoding genes and unexpectedly found that nearly all of these genes possess a phase-1 intron (one intron located between the first and second nucleotides of a codon near the cleavage site of a signal sequence despite their mature peptides remarkably differ. This observation matches a theory of exon shuffling in the origin of new genes and suggests that recruitment of different folds into scorpion venom might be achieved via shuffling between body protein-coding genes and ancestral venom gland-specific genes that presumably contributed tissue-specific regulatory elements and secretory signal sequences.

  10. Impact of Breakfast Skipping and Breakfast Choice on the Nutrient Intake and Body Mass Index of Australian Children

    OpenAIRE

    Flavia Fayet-Moore; Jean Kim; Nilani Sritharan; Peter Petocz

    2016-01-01

    Recent data on breakfast consumption among Australian children are limited. This study examined the impact of breakfast skipping and breakfast type (cereal or non-cereal) on nutrient intakes, likelihood of meeting nutrient targets and anthropometric measures. A secondary analysis of two 24-h recall data from the 2007 Australian National Children’s Nutrition and Physical Activity Survey was conducted (2–16 years; n = 4487) to identify (a) breakfast skippers and (b) breakfast consumers, with br...

  11. Fuzzy-adaptive-thresholding-based exon prediction.

    Science.gov (United States)

    Agrawal, Ankit; Mittal, Ankush; Jain, Rahul; Takkar, Raghav

    2010-01-01

    Thresholding is always critical and decisive in many bioinformatics problems. In this paper, we propose and apply a fuzzy-logic-based adaptive thresholding approach to a well-known solution for the exon prediction problem, which uses a threshold on the frequency component at f = 1/3 in the nucleotide sequence. The proposed approach allows the thresholds to vary along the data set based on the local statistical properties. Experiments and results on the nucleotide data of Saccharomyces cerevisiae (Bakers yeast) illustrate the advantage of our approach. A user-friendly GUI in MATLAB is freely available for academic use at www.cs.iastate.edu/˜ankitag/FATBEP.html.

  12. Skipping Syntactically Illegal "the" Previews: The Role of Predictability

    Science.gov (United States)

    Abbott, Matthew J.; Angele, Bernhard; Ahn, Y. Danbi; Rayner, Keith

    2015-01-01

    Readers tend to skip words, particularly when they are short, frequent, or predictable. Angele and Rayner (2013) recently reported that readers are often unable to detect syntactic anomalies in parafoveal vision. In the present study, we manipulated target word predictability to assess whether contextual constraint modulates…

  13. Association between breakfast skipping and adiposity status among ...

    African Journals Online (AJOL)

    Association between breakfast skipping and adiposity status among civil servants in the Tamale metropolis. V Mogre, JA Atibilla, BNA Kandoh. Abstract. Breakfast meal contributes at least 25% of the daily requirements of an individual making it crucial for healthy growth and development. The aim of this study was to assess ...

  14. Frame Filtering and Skipping for Point Cloud Data Video Transmission

    Directory of Open Access Journals (Sweden)

    Carlos Moreno

    2017-01-01

    Full Text Available Sensors for collecting 3D spatial data from the real world are becoming more important. They are a prime research area topic and have applications in consumer markets, such as medical, entertainment, and robotics. However, a primary concern with collecting this data is the vast amount of information being generated, and thus, needing to be processed before being transmitted. To address the issue, we propose the use of filtering methods and frame skipping. To collect the 3D spatial data, called point clouds, we used the Microsoft Kinect sensor. In addition, we utilized the Point Cloud Library to process and filter the data being generated by the Kinect. Two different computers were used: a client which collects, filters, and transmits the point clouds; and a server that receives and visualizes the point clouds. The client is also checking for similarity in consecutive frames, skipping those that reach a similarity threshold. In order to compare the filtering methods and test the effectiveness of the frame skipping technique, quality of service (QoS metrics such as frame rate and percentage of filter were introduced. These metrics indicate how well a certain combination of filtering method and frame skipping accomplishes the goal of transmitting point clouds from one location to another. We found that the pass through filter in conjunction with frame skipping provides the best relative QoS. However, results also show that there is still too much data for a satisfactory QoS. For a real-time system to provide reasonable end-to-end quality, dynamic compression and progressive transmission need to be utilized.

  15. Skipping breakfast is detrimental for primary school children: cross-sectional analysis of determinants for targeted prevention.

    Science.gov (United States)

    Kesztyüs, Dorothea; Traub, Meike; Lauer, Romy; Kesztyüs, Tibor; Steinacker, Jürgen Michael

    2017-03-14

    Skipping breakfast was found to be associated with abdominal obesity in primary school children. The aim of this research was to examine factors associated with skipping breakfast in primary school children in order to develop targeted preventive measures. Baseline data assessment (2010) of a cluster-randomized controlled trial for the evaluation of a school-based health promotion program in primary school children in the state of Baden-Württemberg, Germany. Anthropometric measures of 1,943 primary school children aged 7.1 ± 0.6 years (51.2% boys) were conducted according to ISAK-standards (International Standard for Anthropometric Assessment) by trained staff. Further information on the health and living conditions of the children and their parents were assessed in parental questionnaires. Generalized linear mixed regression analysis was calculated to define correlates for skipping breakfast in terms of odds ratios (OR) and 95% confidence intervals (CI). According to the final regression models, significant correlates of skipping breakfast can be divided into modifiable behavioral components (high consumption of soft drinks (OR 2.49, 95% CI 1.81; 3.43), screen media (OR 2.48, 95% CI 1.77; 3.46) and high levels of physical activity (OR 0.64, 95% CI 0.44; 0.93)) on the one hand, and more or less static socio-economic factors (migration background (OR 2.81, 95% CI 2.02; 3.91), single parenting (OR 2.13, 95% CI 1.34; 3.40), and high family education level (OR 0.42, 95% CI 0.28; 0.64)) on the other hand, and finally individual factors (female gender (OR 1.43, 95% CI 1.03; 1.99) and having a percentage of body fat at or above the 95th percentile (OR 1.47, 95% CI 1.00; 2.17)). Targeted prevention should aim at health-related behaviors accompanying the habit of skipping breakfast. Focusing on vulnerable groups, characterized by not so easily modifiable socio-economic as well as individual factors, may improve results. Interventions should synergistically promote

  16. Skipping breakfast is detrimental for primary school children: cross-sectional analysis of determinants for targeted prevention

    Directory of Open Access Journals (Sweden)

    Dorothea Kesztyüs

    2017-03-01

    Full Text Available Abstract Background Skipping breakfast was found to be associated with abdominal obesity in primary school children. The aim of this research was to examine factors associated with skipping breakfast in primary school children in order to develop targeted preventive measures. Methods Baseline data assessment (2010 of a cluster-randomized controlled trial for the evaluation of a school-based health promotion program in primary school children in the state of Baden-Württemberg, Germany. Anthropometric measures of 1,943 primary school children aged 7.1 ± 0.6 years (51.2% boys were conducted according to ISAK-standards (International Standard for Anthropometric Assessment by trained staff. Further information on the health and living conditions of the children and their parents were assessed in parental questionnaires. Generalized linear mixed regression analysis was calculated to define correlates for skipping breakfast in terms of odds ratios (OR and 95% confidence intervals (CI. Results According to the final regression models, significant correlates of skipping breakfast can be divided into modifiable behavioral components (high consumption of soft drinks (OR 2.49, 95% CI 1.81; 3.43, screen media (OR 2.48, 95% CI 1.77; 3.46 and high levels of physical activity (OR 0.64, 95% CI 0.44; 0.93 on the one hand, and more or less static socio-economic factors (migration background (OR 2.81, 95% CI 2.02; 3.91, single parenting (OR 2.13, 95% CI 1.34; 3.40, and high family education level (OR 0.42, 95% CI 0.28; 0.64 on the other hand, and finally individual factors (female gender (OR 1.43, 95% CI 1.03; 1.99 and having a percentage of body fat at or above the 95th percentile (OR 1.47, 95% CI 1.00; 2.17. Conclusion Targeted prevention should aim at health-related behaviors accompanying the habit of skipping breakfast. Focusing on vulnerable groups, characterized by not so easily modifiable socio-economic as well as individual factors, may improve

  17. Concurrent mutation in exons 1 and 2 of the K-ras oncogene in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Fiorella Guadagni

    2012-01-01

    Full Text Available The K-ras gene is frequently mutated in colorectal cancer and has been associated with tumor initiation and progression; approximately 90% of the activating mutations are found in codons 12 and 13 of exon 1 and just under 5% in codon 61 located in exon 2. These mutations determine single aminoacidic substitutions in the GTPase pocket leading to a block of the GTP hydrolytic activity of the K-ras p21 protein, and therefore to its constitutive activation. Point mutations in sites of the K-ras gene, other than codons 12, 13 and 61, and other types of genetic alterations, may occur in a minority of cases, such as in the less frequent cases of double mutations in the K-ras gene. However, all mutations in this gene, even those which occur in non-canonical sites or double mutations, are relevant oncogenic alterations in colorectal cancer and may underlie K-ras pathway hyperactivation. In the present study, we report the case of a patient with colorectal cancer presenting a concurrent point mutation in exons 1 and 2 of the K-ras gene, a GGT to TGT substitution (Glycine to Cysteine at codon 12, and a GAC to AAC substitution (Aspartic Acid to Asparagine at codon 57. In addition, we found in the same patient’s sample a silent polymorphism at codon 11 (Ala11Ala of exon 1. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 729–733

  18. De novo disruption of promoter and exon 1 of STAR gene reveals essential role for gonadal development.

    Science.gov (United States)

    Piya, Anil; Kaur, Jasmeet; Rice, Alan M; Bose, Himangshu S

    2017-01-01

    Cholesterol transport into the mitochondria is required for synthesis of the first steroid, pregnenolone. Cholesterol is transported by the steroidogenic acute regulatory protein (STAR), which acts at the outer mitochondrial membrane prior to its import. Mutations in the STAR protein result in lipoid congenital adrenal hyperplasia (CAH). Although the STAR protein consists of seven exons, biochemical analysis in nonsteroidogenic COS-1 cells showed that the first two were not essential for pregnenolone synthesis. Here, we present a patient with ambiguous genitalia, salt-lossing crisis within two weeks after birth and low cortisol levels. Sequence analysis of the STAR, including the exon-intron boundaries, showed the complete deletion of exon 1 as well as more than 50 nucleotides upstream of STAR promoter. Mitochondrial protein import with the translated protein through synthesis cassette of the mutant STAR lacking exon 1 showed protein translation, but it is less likely to have synthesized without a promoter in our patient. Thus, a full-length STAR gene is necessary for physiological mitochondrial cholesterol transport in vivo. STAR exon 1 deletion caused lipoid CAH.Exon 1 substitution does not affect biochemical activity.StAR promoter is responsible for gonadal development.

  19. Acetylcholinesterase (AChE) gene modification in transgenic animals: functional consequences of selected exon and regulatory region deletion.

    Science.gov (United States)

    Camp, Shelley; Zhang, Limin; Marquez, Michael; de la Torre, Brian; Long, Jeffery M; Bucht, Goran; Taylor, Palmer

    2005-12-15

    . delaTorre, P. Taylor, Knockout mice with deletions of alternatively spliced exons of Acetylcholinesterase, in: N.C. Inestrosa, E.O. Campus (Eds.), VII International Meeting on Cholinesterases, Pucon-Chile Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects. P. Universidad Catholica de Chile-FONDAP Biomedicina, 2004, pp. 43-48; R.Y.Y. Chan, C. Boudreau-Larivière, L.A. Angus, F. Mankal, B.J. Jasmin, An intronic enhancer containing an N-box motif is required for synapse- and tissue-specific expression of the acetylcholinesterase gene in skeletal muscle fibers. Proc. Natl. Acad. Sci. USA 96 (1999) 4627-4632], is also presented. The intronic region was floxed and then deleted by mating with Ella-cre transgenic mice. The deletion of this region produced a dramatic phenotype; a mouse with near normal AChE expression in brain and other CNS tissues, but no AChE expression in muscle. Phenotype and AChE tissue activities are compared with the total AChE knockout mouse [W. Xie, J.A. Chatonnet, P.J. Wilder, A. Rizzino, R.D. McComb, P. Taylor, S.H. Hinrichs, O. Lockridge, Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. J. Pharmacol. Exp. Ther. 293 (3) (2000) 896-902].

  20. Skipping of meals has a significant impact on dietary intake and nutritional status of old (65+ y) nursing home residents.

    Science.gov (United States)

    Beck, A M; Ovesen, L

    2004-01-01

    In spite of a high prevalence of undernutrition among old nursing home residents, studies have generally reported a mean intake of energy sufficient to cover the mean estimated energy requirement. This discrepancy could be due to skipping of meals and hence periods of insufficient energy intake too intermittent to be identified, when mean results are presented. To examine the significance of skipping of (part of) meals on dietary intake and nutritional status of old (65+y) nursing home residents. Participants were 132 nursing home residents (84 (82-85) y). They were characterised according to activity of daily living-functions (ADL-functions), cognitive performance, intake of energy and protein (4-days dietary record), skipping of meals, energy and protein balance, and nutritional status (body mass index (BMI)). The participants had an energy intake, which was significantly higher than the estimated energy requirement (p nutritional assessment in order to discover the cause to this problem and target individuals who could be helped by nutritional intervention.

  1. Widespread evolutionary conservation of alternatively spliced exons in caenorhabditis

    DEFF Research Database (Denmark)

    Irimia, Manuel; Rukov, Jakob L; Penny, David

    2007-01-01

    Alternative splicing (AS) contributes to increased transcriptome and proteome diversity in various eukaryotic lineages. Previous studies showed low levels of conservation of alternatively spliced (cassette) exons within mammals and within dipterans. We report a strikingly different pattern...... in Caenorhabditis nematodes-more than 92% of cassette exons from Caenorhabditis elegans are conserved in Caenorhabditis briggsae and/or Caenorhabditis remanei. High levels of conservation extend to minor-form exons (present in a minority of transcripts) and are particularly pronounced for exons showing complex...... patterns of splicing. The functionality of the vast majority of cassette exons is underscored by various other features. We suggest that differences in conservation between lineages reflect differences in levels of functionality and further suggest that these differences are due to differences in intron...

  2. Impact of breakfast skipping on the health status of the population

    Directory of Open Access Journals (Sweden)

    Raksha Goyal

    2014-01-01

    Full Text Available Background: Obesity has become a worldwide epidemic and its prevalence continues to increase at a rapid rate in various populations and across all age-group. The effect of meal skipping, both behaviorally and physiologically, may have an impact on the outcome of weight-loss efforts. Aims and Objectives: Therefore, the aim of this study was to examine the prevalence of breakfast skipping and obesity in subjects. Materials and Methods: A retrospective analysis of the patients visited to a metabolic clinic of the city was done. Results: One hundred and eighty-six eligible subjects were included for the study. A questionnaire was used for data collection which included information regarding dietary factors and exercise schedule/physical activity. A 24-hour dietary recall method was used to assess the amount of food consumed. Anthropometric measurements were taken. Results: Overweight is generally higherin females than males. The prevalence of overweight was higher among those who consumed more than recommended calories than those who were taking recommended or fewer calories per day. The average intake of fat and protein by the study subjects was quite different than the recommended intake of these food items. There was positive association between fat (oil intake and overweight status and a negative association between protein intake and overweight status which was statistically significant. Conclusion: The higher prevalence of overweight and obesity in the present study could be because of imbalance in the diet and faulty food habits prevalent in the region.

  3. Skipping breakfast adversely affects menstrual disorders in young college students.

    Science.gov (United States)

    Fujiwara, Tomoko; Sato, Natsuyo; Awaji, Hiroyo; Sakamoto, Hiroko; Nakata, Rieko

    2009-01-01

    In the present study we conducted a questionnaire survey to examine the relationship between dietary habits and menstrual disorders in young women. Subjects were recruited from 315 college students and were classified as: Group I, eating breakfast; Group II, skipping breakfast; Group III, not eating fast foods; Group IV, eating fast foods; Group V, not eating processed foods; and Group VI, eating processed foods. The intensity of dysmenorrhea was scored using three grades. All participants were further divided into groups based on having regular or irregular menstruation, having premenstrual symptoms or not, and self-perception of good or poor general health. General health was poor in Groups II and VI, and dysmenorrhea scores were high in Groups II, IV and VI. The incidence of irregular menses was also high in Group II. However, there was no apparent relation between premenstrual symptoms and dietary habits. These findings suggest that skipping breakfast adversely affects menstrual disorders in young college students.

  4. Social Inequalities in Young Children's Meal Skipping Behaviors: The Generation R Study.

    Science.gov (United States)

    Wijtzes, Anne I; Jansen, Wilma; Jaddoe, Vincent W V; Franco, Oscar H; Hofman, Albert; van Lenthe, Frank J; Raat, Hein

    2015-01-01

    Regular meal consumption is considered an important aspect of a healthy diet. While ample evidence shows social inequalities in breakfast skipping among adolescents, little is known about social inequalities in breakfast skipping and skipping of other meals among young school-aged children. Such information is crucial in targeting interventions aimed to promote a healthy diet in children. We examined data from 4704 ethnically diverse children participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Information on family socioeconomic position (SEP), ethnic background, and meal skipping behaviors was assessed by parent-reported questionnaire when the child was 6 years old. Multiple logistic regression analyses were performed to assess the associations of family SEP (educational level, household income, employment status, family composition) and ethnic background with meal skipping behaviors, using high SEP children and native Dutch children as reference groups. Meal skipping prevalence ranged from 3% (dinner) to 11% (lunch). The prevalence of meal skipping was higher among low SEP children and ethnic minority children. Maternal educational level was independently associated with breakfast skipping ([low maternal educational level] OR: 2.21; 95% CI: 1.24,3.94). Paternal educational level was independently associated with lunch skipping ([low paternal educational level] OR: 1.53; 95% CI: 1.06,2.20) and dinner skipping ([mid-high paternal educational level] OR: 0.39; 95% CI: 0.20,0.76). Household income was independently associated with breakfast skipping ([low income] OR: 2.43, 95% CI: 1.40,4.22) and dinner skipping ([low income] OR: 2.44; 95% CI: 1.22,4.91). In general, ethnic minority children were more likely to skip breakfast, lunch, and dinner compared with native Dutch children. Adjustment for family SEP attenuated the associations of ethnic minority background with meal skipping behaviors considerably

  5. Social Inequalities in Young Children's Meal Skipping Behaviors: The Generation R Study.

    Directory of Open Access Journals (Sweden)

    Anne I Wijtzes

    Full Text Available Regular meal consumption is considered an important aspect of a healthy diet. While ample evidence shows social inequalities in breakfast skipping among adolescents, little is known about social inequalities in breakfast skipping and skipping of other meals among young school-aged children. Such information is crucial in targeting interventions aimed to promote a healthy diet in children.We examined data from 4704 ethnically diverse children participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Information on family socioeconomic position (SEP, ethnic background, and meal skipping behaviors was assessed by parent-reported questionnaire when the child was 6 years old. Multiple logistic regression analyses were performed to assess the associations of family SEP (educational level, household income, employment status, family composition and ethnic background with meal skipping behaviors, using high SEP children and native Dutch children as reference groups.Meal skipping prevalence ranged from 3% (dinner to 11% (lunch. The prevalence of meal skipping was higher among low SEP children and ethnic minority children. Maternal educational level was independently associated with breakfast skipping ([low maternal educational level] OR: 2.21; 95% CI: 1.24,3.94. Paternal educational level was independently associated with lunch skipping ([low paternal educational level] OR: 1.53; 95% CI: 1.06,2.20 and dinner skipping ([mid-high paternal educational level] OR: 0.39; 95% CI: 0.20,0.76. Household income was independently associated with breakfast skipping ([low income] OR: 2.43, 95% CI: 1.40,4.22 and dinner skipping ([low income] OR: 2.44; 95% CI: 1.22,4.91. In general, ethnic minority children were more likely to skip breakfast, lunch, and dinner compared with native Dutch children. Adjustment for family SEP attenuated the associations of ethnic minority background with meal skipping behaviors

  6. Kinematic characteristics of motor patterns in rope skipping

    Directory of Open Access Journals (Sweden)

    Luiz Henrique da Silva

    2009-09-01

    Full Text Available Rope skipping seems to be an easy task to be performed. However, careful analysis of this motor skill shows how complex the execution of this task is. The objective of this study was to examine kinematic variables of jump patterns as a function of skipping frequency. Eight male university students performed a sequence of 30 rope jumps using two jump patterns (alternating support of the feet and simultaneous support of the feet at three skipping frequencies (1.5, 1.7,1.9 Hz. Frequencies were determined with a digital metronome and the rope was turned by the student himself. Rope jumping performance was recorded with two digital cameras for 3Danalysis. Passive markers were attached to the rope and to the ankle, knee and hip joints forcollection of the following dependent variables: continuous relative phase, time interval betweenthe loss of contact of the feet with the ground and cross of the rope under the feet of the volunteer,jump height, and rope height. ANOVA showed that for the pattern with alternating support ofthe feet the jump is executed at a lower height. In addition, analysis of the time interval revealeda delay in the withdrawal of the feet for crossing the rope in the case of the jump pattern with simultaneous support of the feet.

  7. SKIP SEQUENCING: A DECISION PROBLEM IN QUESTIONNAIRE DESIGN.

    Science.gov (United States)

    Manski, Charles F; Molinari, Francesca

    2008-03-01

    This paper studies questionnaire design as a formal decision problem, focusing on one element of the design process: skip sequencing. We propose that a survey planner use an explicit loss function to quantify the trade-off between cost and informativeness of the survey and aim to make a design choice that minimizes loss. We pose a choice between three options: ask all respondents about an item of interest, use skip sequencing, thereby asking the item only of respondents who give a certain answer to an opening question, or do not ask the item at all. The first option is most informative but also most costly. The use of skip sequencing reduces respondent burden and the cost of interviewing, but may spread data quality problems across survey items, thereby reducing informativeness. The last option has no cost but is completely uninformative about the item of interest. We show how the planner may choose among these three options in the presence of two inferential problems, item nonresponse and response error.

  8. High resolution analysis of the human transcriptome: detection of extensive alternative splicing independent of transcriptional activity

    Directory of Open Access Journals (Sweden)

    Rouet Fabien

    2009-10-01

    Full Text Available Abstract Background Commercially available microarrays have been used in many settings to generate expression profiles for a variety of applications, including target selection for disease detection, classification, profiling for pharmacogenomic response to therapeutics, and potential disease staging. However, many commercially available microarray platforms fail to capture transcript diversity produced by alternative splicing, a major mechanism for driving proteomic diversity through transcript heterogeneity. Results The human Genome-Wide SpliceArray™ (GWSA, a novel microarray platform, utilizes an existing probe design concept to monitor such transcript diversity on a genome scale. The human GWSA allows the detection of alternatively spliced events within the human genome through the use of exon body and exon junction probes to provide a direct measure of each transcript, through simple calculations derived from expression data. This report focuses on the performance and validation of the array when measured against standards recently published by the Microarray Quality Control (MAQC Project. The array was shown to be highly quantitative, and displayed greater than 85% correlation with the HG-U133 Plus 2.0 array at the gene level while providing more extensive coverage of each gene. Almost 60% of splice events among genes demonstrating differential expression of greater than 3 fold also contained extensive splicing alterations. Importantly, almost 10% of splice events within the gene set displaying constant overall expression values had evidence of transcript diversity. Two examples illustrate the types of events identified: LIM domain 7 showed no differential expression at the gene level, but demonstrated deregulation of an exon skip event, while erythrocyte membrane protein band 4.1 -like 3 was differentially expressed and also displayed deregulation of a skipped exon isoform. Conclusion Significant changes were detected independent of

  9. Breakfast skipping and body mass index among adolescents in Greece: whether an association exists depends on how breakfast skipping is defined.

    Science.gov (United States)

    Dialektakou, Kiranni D; Vranas, Peter B M

    2008-09-01

    Many studies have found an association between breakfast skipping and either body mass index (BMI; calculated as kg/m(2)) or overweight/obesity among adolescents, but several studies have found no association. This cross-sectional study investigated the hypothesis that this discrepancy is partly due to three differences in methodology. First, some studies have examined BMI, but other studies have examined overweight/obesity. Second, some studies have controlled for potential confounders, but other studies have not. Third, different studies have used different definitions of breakfast skipping. This study examined both the relationship between breakfast skipping and BMI and the relationship between breakfast skipping and overweight/obesity, compared unadjusted results with results adjusted for potential confounders, and compared results for 24 definitions of breakfast skipping. The sample consisted of 811 students at high schools in Piraeus, Greece, who completed a questionnaire and had their height and weight measured. The results supported this hypothesis. First, fewer breakfast-skipping variables were associated with BMI than with overweight/obesity. Second, fewer associations were found when controlling than when not controlling for potential confounders. Third, fewer associations were found for variables corresponding to some definitions of breakfast skipping than for variables corresponding to other definitions.

  10. JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis

    Science.gov (United States)

    Scott, Linda M.; Tong, Wei; Levine, Ross L.; Scott, Mike A.; Beer, Philip A.; Stratton, Michael R.; Futreal, P. Andrew; Erber, Wendy N.; McMullin, Mary Frances; Harrison, Claire N.; Warren, Alan J.; Gilliland, D. Gary; Lodish, Harvey F.; Green, Anthony R.

    2010-01-01

    BACKGROUND The V617F mutation, which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase (JAK) 2 gene (JAK2), is often present in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear. METHODS We searched for new mutations in members of the JAK and signal transducer and activator of transcription (STAT) gene families in patients with V617F-negative polycythemia vera or idiopathic erythrocytosis. The mutations were characterized biochemically and in a murine model of bone marrow transplantation. RESULTS We identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. Those with a JAK2 exon 12 mutation presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum erythropoietin levels. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin. All such erythroid colonies were heterozygous for the mutation, whereas colonies homozygous for the mutation occur in most patients with V617F-positive polycythemia vera. BaF3 cells expressing the murine erythropoietin receptor and also carrying exon 12 mutations could proliferate without added interleukin-3. They also exhibited increased phosphorylation of JAK2 and extracellular regulated kinase 1 and 2, as compared with cells transduced by wild-type JAK2 or V617F JAK2. Three of the exon 12 mutations included a substitution of leucine for lysine at position 539 of JAK2. This mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation. CONCLUSIONS JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis

  11. The exon-level biomarker SLC39A14 has organ-confined cancer-specificity in colorectal cancer.

    Science.gov (United States)

    Sveen, Anita; Bakken, Anne Cathrine; Ågesen, Trude H; Lind, Guro E; Nesbakken, Arild; Nordgård, Oddmund; Brackmann, Stephan; Rognum, Torleiv O; Lothe, Ragnhild A; Skotheim, Rolf I

    2012-09-15

    An alternative transcript variant of SLC39A14, caused by pre-mRNA splicing, was recently suggested as a biomarker for colorectal cancer (CRC). In our study, we have validated the cancer-specific splicing pattern of the mutually exclusive exons 4A and 4B in altogether 244 colorectal tissue samples. Exon-specific quantitative RT-PCR analyses across 136 Stage I-IV CRC samples and 44 normal colonic mucosa samples showed complete cancer-specificity, as well as 94% sensitivity of SLC39A14-exon4B relative to SLC39A14-exon4A expression. However, across 20 samples from a range of healthy tissues, 18 expressed the CRC variant. This was true also for ten benign lymph nodes, demonstrating that the cancer-specificity is mainly confined to the colon and rectum. Hence, clinical use of SLC39A14-exon4B as a detection marker for CRC other than in samples taken from the bowel wall is diminished. Prognostic value by detection of metastasis to lymph nodes is also abated, elucidating an important pitfall to biomarker discovery. However, analyses of ten nondysplastic biopsies from patients with active inflammatory bowel disease showed negative results in seven samples and only weakly positive results in three samples, suggesting value of SLC39A14-exon4B as a marker to distinguish CRC from other pathologic conditions of the colon. In conclusion, the SLC39A14-exon4B transcript variant is a CRC biomarker with high sensitivity and organ-confined specificity. Further use of the transcript and its encoded protein isoform should be explored in an organ-confined context. Copyright © 2011 UICC.

  12. Exclusion of alternative exon 33 of CaV1.2 calcium channels in heart is proarrhythmogenic.

    Science.gov (United States)

    Li, Guang; Wang, Juejin; Liao, Ping; Bartels, Peter; Zhang, Hengyu; Yu, Dejie; Liang, Mui Cheng; Poh, Kian Keong; Yu, Chye Yun; Jiang, Fengli; Yong, Tan Fong; Wong, Yuk Peng; Hu, Zhenyu; Huang, Hua; Zhang, Guangqin; Galupo, Mary Joyce; Bian, Jin-Song; Ponniah, Sathivel; Trasti, Scott Lee; See, Kelvin; Foo, Roger; Hoppe, Uta C; Herzig, Stefan; Soong, Tuck Wah

    2017-05-23

    Alternative splicing changes the CaV1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed CaV1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the CaV1.2 calcium channel in heart function. Exclusion of exon 33 in CaV1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of CaV1.2Δ33 channels was observed in rat myocardial infarcted hearts. However, how a change in CaV1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33(-/-)-null mice. These mice contained CaV1.2Δ33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33(-/-) mice from β-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing CaV1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in CaV1.2 channels may play in the pathogenesis of human heart failure remains unclear.

  13. Measuring Physical Activity Intensity

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  14. Measuring Physical Activity Intensity

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  15. Origin of introns by 'intronization' of exonic sequences

    DEFF Research Database (Denmark)

    Irimia, Manuel; Rukov, Jakob Lewin; Penny, David

    2008-01-01

    The mechanisms of spliceosomal intron creation have proved elusive. Here we describe a new mechanism: the recruitment of internal exonic sequences ('intronization') in Caenorhabditis species. The numbers of intronization events and introns gained by other mechanisms are similar, suggesting...

  16. Human glucose phosphate isomerase: Exon mapping and gene structure

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Weiming; Lee, Pauline; Beutler, E. [Scripps Research Inst., La Jolla, CA (United States)

    1995-10-10

    The structure of the gene for human glucose phosphate isomerase (GPI) has been determined. Three GPI clones were isolated from a human genomic library by using a full-length GPI cDNA probe and were characterized. Oligonucleotides based on the known cDNA sequence were used as primers in amplification and sequence analyses. This led to the identification of the exon-intron junctions. By this approach, 18 exons and 17 introns have been identified. The exons range in size from 44 to 431 nucleotides. The intronic sequences surrounding the exons provide useful information for the identification of mutations that give rise to human GPI deficiency associated with chronic hemolytic anemia. 13 refs., 4 figs., 1 tab.

  17. The effect of skips on the grain yield of the adjacent hills in trials with maize hybrids under different conditions

    NARCIS (Netherlands)

    Hindi, L.H.A.

    1962-01-01

    Experiments were carried out with maize during 1959-61 to find the effect of skips (gaps) on adjoining hills and some factors influencing this effect. The effect of skips was influenced by the size and shape of skips, the type of stand, nitrogen fertilizer, the maize hybrids and the

  18. Deep Temporal Models using Identity Skip-Connections for Speech Emotion Recognition

    NARCIS (Netherlands)

    Kim, Jaebok; Englebienne, Gwenn; Truong, Khiet P.; Evers, Vanessa

    2017-01-01

    Deep architectures using identity skip-connections have demonstrated groundbreaking performance in the field of image classification. Recently, empirical studies suggested that identity skip-connections enable ensemble-like behaviour of shallow networks, and that depth is not a solo ingredient for

  19. ABERRANT SPLICING OF A BRAIN-ENRICHED ALTERNATIVE EXON ELIMINATES TUMOR SUPPRESSOR FUNCTION AND PROMOTES ONCOGENE FUNCTION DURING BRAIN TUMORIGENESIS

    Science.gov (United States)

    Bredel, Markus; Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; Elverfeldt, Dominik v.; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.

    2014-01-01

    BACKGROUND: Tissue-specific alternative splicing is known to be critical to emergence of tissue identity during development, yet its role in malignant transformation is undefined. Tissue-specific splicing involves evolutionary-conserved, alternative exons, which represent only a minority of total alternative exons. Many, however, have functional features that influence activity in signaling pathways to profound biological effect. Given that tissue-specific splicing has a determinative role in brain development and the enrichment of genes containing tissue-specific exons for proteins with roles in signaling and development, it is thus plausible that changes in such exons could rewire normal neurogenesis towards malignant transformation. METHODS: We used integrated molecular genetic and cell biology analyses, computational biology, animal modeling, and clinical patient profiles to characterize the effect of aberrant splicing of a brain-enriched alternative exon in the membrane-binding tumor suppressor Annexin A7 (ANXA7) on oncogene regulation and brain tumorigenesis. RESULTS: We show that aberrant splicing of a tissue-specific cassette exon in ANXA7 diminishes endosomal targeting and consequent termination of the signal of the EGFR oncoprotein during brain tumorigenesis. Splicing of this exon is mediated by the ribonucleoprotein Polypyrimidine Tract-Binding Protein 1 (PTBP1), which is normally repressed during brain development but, we find, is excessively expressed in glioblastomas through either gene amplification or loss of a neuron-specific microRNA, miR-124. Silencing of PTBP1 attenuates both malignancy and angiogenesis in a stem cell-derived glioblastoma animal model characterized by a high native propensity to generate tumor endothelium or vascular pericytes to support tumor growth. We show that EGFR amplification and PTBP1 overexpression portend a similarly poor clinical outcome, further highlighting the importance of PTBP1-mediated activation of EGFR

  20. Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome.

    Science.gov (United States)

    Seifert, Wenke; Meinecke, Peter; Krüger, Gabriele; Rossier, Eva; Heinritz, Wolfram; Wüsthof, Achim; Horn, Denise

    2014-11-30

    Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS. Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment. Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP. Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected.