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Sample records for deleted wolframin wfs1

  1. Energy metabolism and thyroid function of mice with deleted wolframin (Wfs1) gene.

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    Noormets, K; Kõks, S; Ivask, M; Aunapuu, M; Arend, A; Vasar, E; Tillmann, V

    2014-05-01

    There is no data about the energy metabolism of patients with Wolfram syndrome caused by mutations in the wolframin (Wfs1) gene. The aim of this study was to investigate the role of Wfs1 in energy metabolism and thyroid function in Wfs1 deficient mice (Wfs1KO). 16 male (8 Wfs1KO, 8 wild type (wt)) and 16 female (8 Wfs1KO, 8wt) mice aged 11-13 weeks were studied alone in a specific metabolic cage for 48 h. Body weight, food, water and O2 consumption, motor activity, CO2 and heat production of mice were recorded. At the age of 14-20 weeks, plasma levels of thyroxine (T4), TSH and leptin were measured and histology of thyroid tissues examined. Mean CO2 and heat production was not different between the groups. Mean O2 consumption was higher in the Wfs1KO females compared to the Wfs1KO males (3 410.0±127.0 vs. 2 806.0±82.4 ml/kg/h; pWfs1 has a role in energy metabolism when the disease progresses further. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  2. Sex differences in the development of diabetes in mice with deleted wolframin (Wfs1) gene.

    Science.gov (United States)

    Noormets, K; Kõks, S; Muldmaa, M; Mauring, L; Vasar, E; Tillmann, V

    2011-05-01

    Wolfram syndrome, caused by mutations in the wolframin (Wfs1) gene, is characterised by juvenile-onset diabetes mellitus, progressive optic atrophy, diabetes insipidus and deafness. Diabetes tend to start earlier in boys. This study investigated sex differences in longitudinal changes in blood glucose concentration (BGC) in wolframin-deficient mice (Wfs1KO) and compared their plasma proinsulin and insulin levels with those of wild-type (wt) mice. Non-fasting BGC was measured weekly in 42 (21 males) mice from both groups at nine weeks of age. An intraperitoneal glucose tolerance test (IPGTT) was conducted at the 30 (th) week and plasma insulin, c-peptide and proinsulin levels were measured at the 32 (nd) week. At the 32 (nd) week, Wfs1KO males had increased BGC compared to wt males (9.40±0.60 mmol/l vs. 7.91±0.20 mmol/l; p<0.05). The opposite tendency was seen in females. Both male and female Wfs1KO mice had impaired glucose tolerance on IPGTT. Wfs1KO males had significantly lower mean plasma insulin levels than wt males (57.78±1.80 ng/ml vs. 69.42±3.06 ng/ml; p<0.01) and Wfs1KO females (70.30±4.42 ng/ml; p<0.05). Wfs1KO males had a higher proinsulin/insulin ratio than wt males (0.09±0.02 vs. 0.05±0.01; p=0.05) and Wfs1KO females (0.04±0.01; p<0.05). Plasma c-peptide levels in males were lower in Wfs1KO males (mean 55.3±14.0 pg/ml vs. 112.7±21.9 pg/ml; p<0.05). Male Wfs1KO mice had a greater risk of developing diabetes than female Wfs1KO mice. Low plasma insulin concentration with an increased proinsulin/insulin ratio in Wfs1KO males indicates possible disturbances in converting proinsulin to insulin which in long-term may lead to insulin deficiency. Further investigation is needed to clarify the mechanism for the sex differences in the development of diabetes in Wolfram syndrome. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  3. Male mice with deleted Wolframin (Wfs1) gene have reduced fertility

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    Noormets, Klari; K?ks, Sulev; Kavak, Ants; Arend, Andres; Aunapuu, Marina; Keldrimaa, Aivi; Vasar, Eero; Tillmann, Vallo

    2009-01-01

    Abstract Background Wolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes. Methods Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) ...

  4. Male mice with deleted Wolframin (Wfs1) gene have reduced fertility.

    Science.gov (United States)

    Noormets, Klari; Kõks, Sulev; Kavak, Ants; Arend, Andres; Aunapuu, Marina; Keldrimaa, Aivi; Vasar, Eero; Tillmann, Vallo

    2009-08-10

    Wolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes. Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured. The pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p Wfs1 gene influences sperm morphology needs to be clarified in further studies.

  5. Male mice with deleted Wolframin (Wfs1 gene have reduced fertility

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    Aunapuu Marina

    2009-08-01

    Full Text Available Abstract Background Wolfram Syndrome (WS is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO male mice have reduced fertility and, if so, to examine possible causes. Methods Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured. Results The pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p Conclusion The impaired fertility of Wfs1KO male mice is most likely due to changes in sperm morphology and reduced number of spermatogenic cells. The exact mechanism through which the Wfs1 gene influences sperm morphology needs to be clarified in further studies.

  6. Expression of the diabetes risk gene wolframin (WFS1) in the human retina

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    Schmidt-Kastner, Rainald; Kreczmanski, Pawel; Preising, Markus; Diederen, Roselie; Schmitz, Christoph; Reis, Danielle; Blanks, Janet; Dorey, C. Kathleen

    2009-01-01

    Wolfram syndrome 1 (WFS1, OMIM 222300), a rare genetic disorder characterized by optic nerve atrophy, deafness, diabetes insipidus and diabetes mellitus, is caused by mutations of WFS1, encoding WFS1/wolframin. Non-syndromic WFS1 variants are associated with the risk of diabetes mellitus due to altered function of wolframin in pancreatic islet cells, expanding the importance of wolframin. This study extends a previous report for the monkey retina, using immunohistochemistry to localize wolfra...

  7. WFS1/wolframin mutations, Wolfram syndrome, and associated diseases.

    Science.gov (United States)

    Khanim, F; Kirk, J; Latif, F; Barrett, T G

    2001-05-01

    Wolfram syndrome (WS) is the inherited association of juvenile-onset insulin-dependant diabetes mellitus and progressive bilateral optic atrophy. A nuclear gene, WFS1/wolframin, was identified that segregated with disease status and demonstrated an autosomal recessive mode of inheritance. Mutation analysis of the WFS1 gene in WS patients has identified mutations in 90% of patients. Most were compound heterozygotes with private mutations distributed throughout the gene with no obvious hotspots. The private nature of the mutations in WS patients and the low frequencies make it difficult to determine the biological or clinical relevance of these mutations. Mutation screening in patients with psychiatric disorders or diabetes mellitus has also been performed to test the hypothesis that heterozygous carriers of WFS1 gene mutations are at an increased risk following the observation that WS first-degree relatives have a higher frequency of these disorders. Most studies showed no association, however two missense mutations were identified that demonstrated significant association with psychiatric disorders and diabetes mellitus. Population association studies and functional studies of these variants will need to be performed to confirm these preliminary results. The elucidation of functions and functional pathways for the WFS1 gene product and variants will shed light on the effect of such disparate mutations on gene function and their role in the resulting clinical phenotype in WS and associated disorders. Copyright 2001 Wiley-Liss, Inc.

  8. Expression of the diabetes risk gene wolframin (WFS1) in the human retina.

    Science.gov (United States)

    Schmidt-Kastner, Rainald; Kreczmanski, Pawel; Preising, Markus; Diederen, Roselie; Schmitz, Christoph; Reis, Danielle; Blanks, Janet; Dorey, C Kathleen

    2009-10-01

    Wolfram syndrome 1 (WFS1, OMIM 222300), a rare genetic disorder characterized by optic nerve atrophy, deafness, diabetes insipidus and diabetes mellitus, is caused by mutations of WFS1, encoding WFS1/wolframin. Non-syndromic WFS1 variants are associated with the risk of diabetes mellitus due to altered function of wolframin in pancreatic islet cells, expanding the importance of wolframin. This study extends a previous report for the monkey retina, using immunohistochemistry to localize wolframin on cryostat and paraffin sections of human retina. In addition, the human retinal pigment epithelial (RPE) cell line termed ARPE-19 and retinas from both pigmented and albino mice were studied to assess wolframin localization. In the human retina, wolframin was expressed in retinal ganglion cells, optic axons and the proximal optic nerve. Wolframin expression in the human retinal pigment epithelium (RPE) was confirmed with intense cytoplasmic labeling in ARPE-19 cells. Strong labeling of the RPE was also found in the albino mouse retina. Cryostat sections of the mouse retina showed a more extended pattern of wolframin labeling, including the inner nuclear layer (INL) and photoreceptor inner segments, confirming the recent report of Kawano et al. [Kawano, J., Tanizawa, Y., Shinoda, K., 2008. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J. Comp. Neurol. 510, 1-23]. Absence of these cells in the human specimens despite the use of human-specific antibodies to wolframin may be related to delayed fixation. Loss of wolframin function in RGCs and the unmyelinated portion of retinal axons could explain optic nerve atrophy in Wolfram Syndrome 1.

  9. A single base-pair deletion in the WFS1 gene causes Wolfram syndrome.

    Science.gov (United States)

    Pitt, Katherine; James, Chela; Kochar, Inderpal S; Kapoor, Akshay; Jain, Shilpi; Hussain, Khalid; Bennett, Kate

    2011-01-01

    Wolfram syndrome is a progressive neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness). The majority of cases are caused by mutations in the WFS1 gene. WFS1 is located at 4p16.1 and encodes wolframin, a transmembrane endoplasmic reticulum (ER) protein involved in the negative regulation of ER stress signalling. To date, over 120 WFS1 mutations have been described. In this study, we report a consanguineous family with three siblings affected by Wolfram syndrome. A homozygous single base pair deletion (c.877delC, L293fsX303) was found in the WFS1 gene in all three affected siblings.

  10. Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product.

    Science.gov (United States)

    Hofmann, Sabine; Philbrook, Christine; Gerbitz, Klaus-Dieter; Bauer, Matthias F

    2003-08-15

    Mutations of the WFS1 gene are responsible for Wolfram syndrome, a rare, recessive disorder characterized by early-onset, non-autoimmune diabetes mellitus, optic atrophy and further neurological and endocrinological abnormalities. The WFS1 gene encodes wolframin, a putative multispanning membrane glycoprotein of the endoplasmic reticulum. The function of wolframin is completely unknown. In order to characterize wolframin, we have generated polyclonal antibodies against both hydrophilic termini of the protein. Wolframin was found to be ubiquitously expressed with highest levels in brain, pancreas, heart and insulinoma beta-cell lines. Analysis of the structural features provides experimental evidence that wolframin contains nine transmembrane segments and is embedded in the membrane in an N(cyt)/C(lum) topology. Wolframin assembles into higher molecular weight complexes of approximately 400 kDa in the membrane. Pulse-chase experiments demonstrate that during maturation wolframin is N-glycosylated but lacks proteolytical processing. Moreover, N-glycosylation appears to be essential for the biogenesis and stability of wolframin. Here we investigate, for the first time, the molecular mechanisms that cause loss-of-function of wolframin in affected individuals. In patients harboring nonsense mutations complete absence of the mutated wolframin is caused by instability and rapid decay of WFS1 nonsense transcripts. In a patient carrying a compound heterozygous missense mutation, R629W, we found markedly reduced steady-state levels of wolframin. Pulse-chase experiments of mutant wolframin expressed in COS-7 cells indicated that the R629W mutation leads to instability and strongly reduced half-life of wolframin. Thus, the Wolfram syndrome in patients investigated here is caused by reduced protein dosage rather than dysfunction of the mutant wolframin.

  11. Expression pattern of wolframin, the WFS1 (Wolfram syndrome-1 gene) product, in common marmoset (Callithrix jacchus) cochlea.

    Science.gov (United States)

    Suzuki, Noriomi; Hosoya, Makoto; Oishi, Naoki; Okano, Hideyuki; Fujioka, Masato; Ogawa, Kaoru

    2016-08-03

    Wolfram syndrome is an autosomal recessive disorder of the neuroendocrine system, known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome, and considered an endoplasmic reticulum disease. Patients show mutations in WFS1, which encodes the 890 amino acid protein wolframin. Although Wfs1 knockout mice develop diabetes, their hearing level is completely normal. In this study, we examined the expression of wolframin in the cochlea of a nonhuman primate common marmoset (Callithrix jacchus) to elucidate the discrepancy in the phenotype between species and the pathophysiology of Wolfram syndrome-associated deafness. The marmoset cochlea showed wolframin immunoreactivity not only in the spiral ligament type I fibrocytes, spiral ganglion neurons, outer hair cells, and supporting cells, but in the stria vascularis basal cells, where wolframin expression was not observed in the previous mouse study. Considering the absence of the deafness phenotype in Wfs1 knockout mice, the expression of wolframin in the basal cells of primates may play an essential role in the maintenance of hearing. Elucidating the function of wolframin protein in the basal cells of primates would be essential for understanding the pathogenesis of hearing loss in patients with Wolfram syndrome, which may lead to the discovery of new therapeutics.

  12. Identification and characterization of wolframin, the product of the wolfram syndrome gene (WFS1), as a novel calmodulin-binding protein.

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    Yurimoto, Saki; Hatano, Naoya; Tsuchiya, Mitsumasa; Kato, Kiyohito; Fujimoto, Tomohito; Masaki, Tsutomu; Kobayashi, Ryoji; Tokumitsu, Hiroshi

    2009-05-12

    To search for calmodulin (CaM) targets, we performed affinity chromatography purification of a rat brain extract using CaM fused with GST as the affinity ligand. Proteomic analysis was then carried out to identify CaM-binding proteins. In addition to identifying 36 known CaM-binding proteins, including CaM kinases, calcineurin, nNOS, the IP(3) receptor, and Ca(2+)-ATPase, we identified an ER transmembrane protein, wolframin [the product of the Wolfram syndrome gene (WFS1)] as interacting. A CaM overlay and an immunoprecipitation assay revealed that wolframin is capable of binding the Ca(2+)/CaM complex in vitro and in transfected cells. Surface plasmon resonance analysis and zero-length cross-linking showed that the N-terminal cytoplasmic domain (residues 2-285) of wolframin binds to an equimolar unit of CaM in a Ca(2+)-dependent manner with a K(D) for CaM of 0.15 muM. Various truncation and deletion mutants showed that the Ca(2+)/CaM binding region in wolframin is located from Glu90 to Trp186. Furthermore, we demonstrated that three mutations (Ala127Thr, Ala134Thr, and Arg178Pro) associated with Wolfram syndrome completely abolished CaM binding of wolframin. This observation may indicate that CaM binding is important for wolframin function and that impairment of this interaction by mutation contributes to the pathology seen in Wolfram syndrome.

  13. No association of mutations and mRNA expression of WFS1/wolframin with bipolar disorder in humans.

    Science.gov (United States)

    Kato, Tadafumi; Iwamoto, Kazuya; Washizuka, Shinsuke; Mori, Kanako; Tajima, Osamu; Akiyama, Tsuyoshi; Nanko, Shinichiro; Kunugi, Hiroshi; Kato, Nobumasa

    2003-02-20

    Association of WFS1 (wolframin) and bipolar disorder has been suggested by psychiatric manifestations in patients or non-symptomatic carriers of Wolfram disease and linkage of bipolar disorder with 4p16, the locus of WFS1. Five studies of WFS1 in bipolar disorder did not support this association, although possible association of several missense mutations has not been excluded yet. In this study, four such mutations were genotyped in 184 patients with bipolar disorder and 207 controls. None had the A559T and A602V mutations, and no association of G576S and H611R with bipolar disorder was found. We also quantified the expression levels of WFS1 mRNA in the postmortem brains of patients with bipolar disorder, depression, schizophrenia, and controls. There was no significant difference of the expression levels. These results did not support the pathophysiological significance of WFS1 in bipolar disorder. Copyright 2002 Elsevier Science Ireland Ltd.

  14. Polymorphisms in wolframin (WFS1) gene are possibly related to increased risk for mood disorders.

    Science.gov (United States)

    Koido, Kati; Kõks, Sulev; Nikopensius, Tiit; Maron, Eduard; Altmäe, Signe; Heinaste, Evelin; Vabrit, Kristel; Tammekivi, Veronika; Hallast, Pille; Kurg, Ants; Shlik, Jakov; Vasar, Veiko; Metspalu, Andres; Vasar, Eero

    2005-06-01

    Wolfram syndrome gene (WFS1) has been suggested to have a role in the susceptibility for mood disorders. A 26-fold increased risk for psychiatric disorders in WFS1 mutation carriers has been suggested. In this study we tested the hypothesis that the WFS1 gene is related to the risk for mood disorders. We analysed 28 single-nucleotide polymorphisms (SNPs) of the WFS1 gene in 224 unrelated patients with major depressive disorder and bipolar disorder and in 160 healthy control subjects. Patients were further stratified according to their comorbidity with anxiety disorders. We applied arrayed primer extension (APEX)-based genotyping technology followed by association and haplotype analysis. Five SNPs in the WFS1 gene were associated with major depressive disorder, and three SNPs with bipolar disorder. Haplotype analysis revealed a common GTA haplotype, formed by SNPs 684C/G, 1185C/T and 1832G/A, conferring risk for affective disorders. Specifically, for major depression the GTA haplotype has an OR of 1.59 (p = 0.01) and for bipolar disorder an OR of 1.89 (p = 0.03). These results support the hypothesis that the WFS1 gene is involved in the genetic predisposition for mood disorders.

  15. Missense variations of the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg456His mutation to type 1 diabetes as a nonautoimmune genetic basis.

    Science.gov (United States)

    Awata, T; Inoue, K; Kurihara, S; Ohkubo, T; Inoue, I; Abe, T; Takino, H; Kanazawa, Y; Katayama, S

    2000-02-16

    Recently, a novel gene for a putative transmembrane protein (WFS1/wolframin) was found to be mutated in patients with Wolfram syndrome or DI-DM-OA-D (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome. It is suggested that the WFS1 protein is important in the survival of islet beta-cells. We studied the WFS1 gene in a Japanese population to assess its possible role in common type 1 diabetes. Mutation screening revealed four missense mutations; R456H, G576S, H611R, and I720V. By genetic association studies of 185 type 1 diabetes patients and 380 control subjects, we found that R456H was significantly increased in the type 1 diabetes group compared to the control group (P = 0.0005); H611R and I720V were also significantly increased with weaker significance. Furthermore, in patients with the R456H mutation, type 1 diabetes-resistant HLA-DRB1 alleles (DRB1*0406, 1501, and 1502) were significantly increased compared to mutation-negative patients while susceptible DRB1*0901 was significantly decreased. Frequencies of autoimmunity characteristics (ICA or GAD-Ab positiveness and combination of autoimmune thyroid disease) were decreased in the R456H-positive patients compared to the R456H-negative patients. These data suggest that the WFS1 gene may have a role in the development of common type 1 diabetes as a nonautoimmune genetic basis. Copyright 2000 Academic Press.

  16. Expansion of the clinical ocular spectrum of Wolfram Syndrome in a family carrying a novel WFS1 gene deletion.

    Science.gov (United States)

    Chacón-Camacho, Oscar; Arce-Gonzalez, Rocio; Granillo-Alvarez, Mariella; Flores-Limas, Sanjuanita; Ramírez, Magdalena; Zenteno, Juan C

    2013-12-01

    To present the results of the clinical and molecular analyses of a familial case of Wolfram Syndrome (WFS) associated with a novel ocular anomaly. Full ophthalmologic examination was performed in two WFS siblings. Visante OCT imaging was used for assessing anterior segment anomalies. Genetic analysis included PCR amplification and exon-by-exon nucleotide sequencing of the WFS1 gene. Ocular anomalies in both affected siblings included congenital cataract, glaucoma, and optic atrophy. Interestingly, microspherophakia, a feature that has not been previously associated with WFS, was observed in both siblings. Genetic analysis disclosed a novel c.1525_1539 homozygous deletion in exon 8 of WFS1 in DNA from both affected patients. The recognition of microspherophakia in two siblings carrying a novel WFS1 mutation expands the clinical and molecular spectrum of Wolfram syndrome.

  17. Evidence for linkage on chromosome 4p16.1 in Type 1 diabetes Danish families and complete mutation scanning of the WFS1 (Wolframin) gene.

    Science.gov (United States)

    Larsen, Z M; Johannesen, J; Kristiansen, O P; Nerup, J; Pociot, F

    2004-03-01

    To investigate whether the WFS1 gene, the gene for Wolfram syndrome, is a susceptibility gene for more common forms of diabetes in the Danish population. One hundred and fifty-two Danish Type 1 diabetes mellitus sib-pair families were genotyped for two microsatellite markers situated within 5 cM of the WFS1 gene and analysed for linkage and association using the sib-TDT. The entire coding region, the 5'UTR and 3'UTR of the WFS1 gene, were screened for mutations by direct sequencing in 29 selected Type 1 diabetes patients. Four of the identified mutations were tested for linkage and association in 255 Danish Type 1 diabetes families (including 103 simplex families). Evidence for linkage to Type 1 diabetes was found as the second most frequent allele of the marker D4S394 were transmitted 137 times (T = 61%) and not transmitted 88 times to affected offspring (Puc = 0.0011). Twelve mutations were found in the coding region and three mutations in the 3'UTR. No evidence for linkage and association to Type 1 diabetes was found testing four of the identified amino acid substitutions. Evidence of linkage to Type 1 diabetes was observed in the Danish family collection. However, no evidence of linkage and association was observed for any of the analysed polymorphisms, suggesting that other variations must be responsible for the observed evidence of linkage in the region.

  18. Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf-Hirschhorn syndrome.

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    Flipsen-ten Berg, Klara; van Hasselt, Peter M; Eleveld, Marc J; van der Wijst, Suzanne E; Hol, Frans A; de Vroede, Monique A M; Beemer, Frits A; Hochstenbach, P F Ron; Poot, Martin

    2007-11-01

    The Wolf-Hirschhorn syndrome (WHS (MIM 194190)), which is characterized by growth delay, mental retardation, epilepsy, facial dysmorphisms, and midline fusion defects, shows extensive phenotypic variability. Several of the proposed mutational and epigenetic mechanisms in this and other chromosomal deletion syndromes fail to explain the observed phenotypic variability. To explain the complex phenotype of a patient with WHS and features reminiscent of Wolfram syndrome (WFS (MIM 222300)), we performed extensive clinical evaluation and classical and molecular cytogenetic (GTG banding, FISH and array-CGH) and WFS1 gene mutation analyses. We detected an 8.3 Mb terminal deletion and an adjacent 2.6 Mb inverted duplication in the short arm of chromosome 4, which encompasses a gene associated with WFS (WFS1). In addition, a nonsense mutation in exon 8 of the WFS1 gene was found on the structurally normal chromosome 4. The combination of the 4p deletion with the WFS1 point mutation explains the complex phenotype presented by our patient. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletions represents an additional explanation for the phenotypic variability observed in chromosomal deletion disorders.

  19. Deletion of the Wolfram syndrome-related gene Wfs1 results in increased sensitivity to ethanol in female mice.

    Science.gov (United States)

    Raud, Sirli; Reimets, Riin; Loomets, Maarja; Sütt, Silva; Altpere, Alina; Visnapuu, Tanel; Innos, Jürgen; Luuk, Hendrik; Plaas, Mario; Volke, Vallo; Vasar, Eero

    2015-08-01

    Wolfram syndrome, induced by mutation in WFS1 gene, increases risk of developing mood disorders in humans. In mice, Wfs1 deficiency cause higher anxiety-like behaviour and increased response to anxiolytic-like effect of diazepam, a GABAA receptor agonist. As GABAergic system is also target for ethanol, we analysed its anxiolytic-like and sedative properties in Wfs1-deficient mice using elevated plus-maze test and tests measuring locomotor activity and coordination, respectively. Additionally loss of righting reflex test was conducted to study sedative/hypnotic properties of ethanol, ketamine and pentobarbital. To evaluate pharmacokinetics of ethanol in mice enzymatic colour test was used. Finally, gene expression of alpha subunits of GABAA receptors following ethanol treatment was studied by real-time-PCR. Compared to wild-types, Wfs1-deficient mice were more sensitive to ethanol-induced anxiolytic-like effect, but less responsive to impairment of motor coordination. Ethanol and pentobarbital, but not ketamine, caused longer duration of hypnosis in Wfs1-deficient mice. The expression of Gabra2 subunit at 30 minutes after ethanol injection was significantly increased in the frontal cortex of Wfs1-deficient mice as compared to respective vehicle-treated mice. For the temporal lobe, similar change in Gabra2 mRNA occurred at 60 minutes after ethanol treatment in Wfs1-deficient mice. No changes were detected in Gabra1 and Gabra3 mRNA following ethanol treatment. Taken together, increased anxiolytic-like effect of ethanol in Wfs1-deficient mice is probably related to altered Gabra2 gene expression. Increased anti-anxiety effect of GABAA receptor agonists in the present work and earlier studies (Luuk et al., 2009) further suggests importance of Wfs1 gene in the regulation of emotional behaviour. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Prohormone convertase 2 activity is increased in the hippocampus of Wfs1 knockout mice

    OpenAIRE

    Tein, Karin; Kasvandik, Sergo; Kõks, Sulev; Vasar, Eero; Terasmaa, Anton

    2015-01-01

    BackgroundMutations in WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder, characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness (DIDMOAD). The WFS1 gene product wolframin is located in the endoplasmic reticulum. Mice lacking this gene exhibit disturbances in the processing and secretion of peptides, such as vasopressin and insulin. In the brain, high levels of the wolframin protein have been observed in the hippocampus, amygdala ...

  1. Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin.

    Science.gov (United States)

    Hofmann, Sabine; Bauer, Matthias F

    2006-07-10

    Wolfram syndrome is caused by mutations in WFS1 encoding wolframin, a polytopic membrane protein of the endoplasmic reticulum. Here, we investigated the molecular pathomechanisms of four missense and two truncating mutations in WFS1. Expression in COS-7 cells as well as direct analysis of patient cells revealed that WFS1 mutations lead to drastically reduced steady-state levels of wolframin. All mutations resulted in highly unstable proteins which were delivered to proteasomal degradation. No wolframin aggregates were found in patient cells suggesting that Wolfram syndrome is not a disease of protein aggregation. Rather, WFS1 mutations cause loss-of-function by cellular depletion of wolframin.

  2. Identification of a novel WFS1 homozygous nonsense mutation in Jordanian children with Wolfram syndrome.

    Science.gov (United States)

    Bodoor, Khaldon; Batiha, Osama; Abu-Awad, Ayman; Al-Sarihin, Khaldon; Ziad, Haya; Jarun, Yousef; Abu-Sheikha, Aya; Abu Jalboush, Sara; Alibrahim, Khoulod S

    2016-09-01

    Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder characterized by the presentation of early onset type I diabetes mellitus and optic atrophy with later onset diabetes insipidus and deafness. WFS1 gene was identified on chromosome 4p16.1 as the gene responsible for WS disease given that most of the WS patients were found to carry mutations in this gene. This study was carried out to investigate the molecular spectrum of WFS1 gene in Jordanian families. Molecular and clinical characterization was performed on five WS patients from two unrelated Jordanian families. Our data indicated that WS patients of the first family harbored two deletion mutations (V415del and F247fs) located in exon 8 and exon 7 respectively, with a compound heterozygous pattern of inheritance; while in the second family, we identified a novel nonsense mutation (W185X) located in exon 5 in the N-terminal cytoplasmic domain with a homozygous pattern of inheritance. This mutation can be considered as loss of function mutation since the resulting truncated protein lost both the transmembrane domain and the C-terminal domain. Additionally, the W185X mutation lies within the CaM binding domain in wolframin protein which is thought to have a role in the regulation of wolframin function in response to calcium levels.

  3. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment.

    Science.gov (United States)

    Rendtorff, Nanna D; Lodahl, Marianne; Boulahbel, Houda; Johansen, Ida R; Pandya, Arti; Welch, Katherine O; Norris, Virginia W; Arnos, Kathleen S; Bitner-Glindzicz, Maria; Emery, Sarah B; Mets, Marilyn B; Fagerheim, Toril; Eriksson, Kristina; Hansen, Lars; Bruhn, Helene; Möller, Claes; Lindholm, Sture; Ensgaard, Stefan; Lesperance, Marci M; Tranebjaerg, Lisbeth

    2011-06-01

    Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome. Copyright © 2011 Wiley-Liss, Inc.

  4. A novel nonsense mutation in the WFS1 gene causes the Wolfram syndrome.

    Science.gov (United States)

    Noorian, Shahab; Savad, Shahram; Mohammadi, Davood Shah

    2016-05-01

    Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder, which is mostly caused by mutations in the WFS1 gene. The WFS1 gene product, which is called wolframin, is thought to regulate the function of endoplasmic reticulum. The endoplasmic reticulum has a critical role in protein folding and material transportation within the cell or to the surface of the cell. Identification of new mutations in WFS1 gene will unravel the molecular pathology of WS. The aim of this case report study is to describe a novel mutation in exon 4 of the WFS1 gene (c.330C>A) in a 9-year-old boy with WS.

  5. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease

    NARCIS (Netherlands)

    Cryns, K; Sivakumaran, TA; Van den Ouweland, JMW; Pennings, RJE; Cremers, CWRJ; Flothmann, K; Young, TL; Smith, RJH; Lesperance, MM; Van Camp, G

    2003-01-01

    WFS1 is a novel gene and encodes an 890 amino-acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition,

  6. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease.

    NARCIS (Netherlands)

    Cryns, K.; Sivakumaran, T.A.; Ouweland, J.M.W. van den; Pennings, R.J.E.; Cremers, C.W.R.J.; Flothmann, K.; Young, T.L.; Smith, R.J.H.; Lesperance, M.M.; Camp, G. van

    2003-01-01

    WFS1 is a novel gene and encodes an 890 amino-acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition,

  7. Association Study of the Effect of WFS1 Polymorphisms on Risk of Type 2 Diabetes in Japanese Population

    OpenAIRE

    Mita,Masaki; Miyake,Kazuaki; Zenibayashi,Masako; Hirota,Yushi; Teranishi,Tetsuya; Kouyama,Kunichi; Sakaguchi,Kazuhiko; Kasuga,Masato

    2008-01-01

    Mutations of WFS1 gene cause Wolfram syndrome, which is a rare autosomalrecessive disorder characterized by juvenile diabetes mellitus, optic atrophy, deafnessand diabetes insipidus. The product encoded by WFS1 gene, wolframin, could beinvolved in ER stress response causing β-cell loss through impaired cell cycleprogression and increased apoptosis. Recently, polymorphisms in the WFS1 gene werestrongly associated with type 2 diabetes in Caucasians. The aim of the present studywas to examine wh...

  8. Prohormone convertase 2 activity is increased in the hippocampus of Wfs1 knockout mice.

    Science.gov (United States)

    Tein, Karin; Kasvandik, Sergo; Kõks, Sulev; Vasar, Eero; Terasmaa, Anton

    2015-01-01

    Mutations in WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder, characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, and deafness. The WFS1 gene product wolframin is located in the endoplasmic reticulum. Mice lacking this gene exhibit disturbances in the processing and secretion of peptides, such as vasopressin and insulin. In the brain, high levels of the wolframin protein have been observed in the hippocampus, amygdala, and limbic structures. The aim of this study was to investigate the effect of Wfs1 knockout (KO) on peptide processing in mouse hippocampus. A peptidomic approach was used to characterize individual peptides in the hippocampus of wild-type and Wfs1 KO mice. We identified 126 peptides in hippocampal extracts and the levels of 10 peptides differed between Wfs1 KO and wild-type mice at P Wfs1 KO mice compared to wild-type mice. Processing (cleavage) of little-LEN from the Pcsk1n gene product proSAAS involves prohormone convertase 2 (PC2). Thus, PC2 activity was measured in extracts prepared from the hippocampus of Wfs1 KO mice. The activity of PC2 in Wfs1 mutant mice was significantly higher (149.9 ± 2.3%, p Wfs1-KO mice, which is caused by increased activity of PC2. Increased activity of PC2 in Wfs1 KO mice is not caused by alteration in the levels of PC2 protein. Our results suggest a functional link between Wfs1 and PC2. Thus, the detailed molecular mechanism of the role of Wfs1 in the regulation of PC2 activity needs further investigation.

  9. Autoimmune Disease in a DFNA6/14/38 Family carrying a Novel Missense Mutation in WFS1

    OpenAIRE

    Hildebrand, Michael S.; Sorensen, Jessica L.; Jensen, Maren; Kimberling, William J.; Smith, Richard J.H.

    2008-01-01

    Most familial cases of autosomal dominant low frequency sensorineural hearing loss (LFSNHL) are attributable to mutations in the Wolframin syndrome 1 (WFS1) gene at the DFNA6/14/38 locus. WFS1 mutations at this locus were first described in 2001 in six families segregating LFSNHL that was non-progressive below 2000 Hz; the causative mutations all clustered in the C-terminal domain of the wolframin protein. Mutations in WFS1 also cause Wolfram syndrome (WS), an autosomal recessive neurodegener...

  10. Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1.

    NARCIS (Netherlands)

    Hogewind, B.F.T.; Pennings, R.J.E.; Hol, F.A.; Kunst, H.P.M.; Hoefsloot, E.H.; Cruysberg, J.R.M.; Cremers, C.W.R.J.

    2010-01-01

    PURPOSE: To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series. METHODS: Seven members of a Dutch family underwent ophthalmological, otological, and

  11. Autoimmune disease in a DFNA6/14/38 family carrying a novel missense mutation in WFS1.

    Science.gov (United States)

    Hildebrand, Michael S; Sorensen, Jessica L; Jensen, Maren; Kimberling, William J; Smith, Richard J H

    2008-09-01

    Most familial cases of autosomal dominant low frequency sensorineural hearing loss (LFSNHL) are attributable to mutations in the wolframin syndrome 1 (WFS1) gene at the DFNA6/14/38 locus. WFS1 mutations at this locus were first described in 2001 in six families segregating LFSNHL that was non-progressive below 2,000 Hz; the causative mutations all clustered in the C-terminal domain of the wolframin protein. Mutations in WFS1 also cause Wolfram syndrome (WS), an autosomal recessive neurodegenerative disorder defined by diabetes mellitus, optic atrophy and often deafness, while numerous single nucleotide polymorphisms (SNPs) in WFS1 have been associated with increased risk for diabetes mellitus, psychiatric illnesses and Parkinson disease. This study was conducted in an American family segregating autosomal dominant LFSNHL. Two hearing impaired family members also had autoimmune diseases-Graves disease (GD) and Crohn disease (CD). Based on the low frequency audioprofile, mutation screening of WFS1 was completed and a novel missense mutation (c.2576G --> A) that results in an arginine-to-glutamine substitution (p.R859Q) was identified in the C-terminal domain of the wolframin protein where most LFSNHL-causing mutations cluster. The family member with GD also carried polymorphisms in WFS1 that have been associated with other autoimmune diseases. (c) 2008 Wiley-Liss, Inc.

  12. Prohormone convertase 2 activity is increased in the hippocampus of Wfs1 knockout mice

    Directory of Open Access Journals (Sweden)

    Karin eTein

    2015-08-01

    Full Text Available BackgroundMutations in WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder, characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness (DIDMOAD. The WFS1 gene product wolframin is located in the endoplasmic reticulum. Mice lacking this gene exhibit disturbances in the processing and secretion of peptides, such as vasopressin and insulin. In the brain, high levels of the wolframin protein have been observed in the hippocampus, amygdala and limbic structures. The aim of this study was to investigate the effect of Wfs1 knockout on peptide processing in mouse hippocampus. A peptidomic approach was used to characterize individual peptides in the hippocampus of wild-type and Wfs1 knockout mice. ResultsWe identified 126 peptides in hippocampal extracts and the levels of 10 peptides differed between Wfs1 KO and wild-type mice at P<0.05. The peptide with the largest alteration was little-LEN, which level was 25 times higher in the hippocampus of Wfs1 KO mice compared to wild-type mice. Processing (cleavage of little-LEN from the Pcsk1n gene product proSAAS involves prohormone convertase 2 (PC2. Thus, PC2 activity was measured in extracts prepared from the hippocampus of Wfs1 knockout mice. The activity of PC2 in Wfs1 mutant mice was significantly higher (149.9±2.3%, p<0.0001, n=8 than in wild-type mice (100.0±7.0%, n=8. However, Western blot analysis showed that protein levels of 7B2, proPC2 and PC2 were same in both groups, and so were gene expression levels.ConclusionsProcessing of proSAAS is altered in the hippocampus of Wfs1-KO mice, which is caused by increased activity of PC2. Increased activity of PC2 in Wfs1 knockout mice is not caused by alteration in the levels of PC2 protein. Our results suggest a functional link between Wfs1 and PC2. Thus, the detailed molecular mechanism of the role of Wfs1 in the regulation of PC2 activity needs further investigation.

  13. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system.

    Science.gov (United States)

    Kawano, June; Tanizawa, Yukio; Shinoda, Koh

    2008-09-01

    Wolfram syndrome (OMIM 222300) is a neurodegenerative disorder defined by insulin-dependent diabetes mellitus and progressive optic atrophy. This syndrome has been attributed to mutations in the WFS1 gene, which codes for a putative multi-spanning membrane glycoprotein of the endoplasmic reticulum. The function of WFS1 (wolframin), the distribution of this protein in the mammalian visual system, and the pathogenesis of optic atrophy in Wolfram syndrome are unclear. In this study we made a detailed analysis of the distribution of Wfs1 mRNA and protein in the normal mouse visual system by using in situ hybridization and immunohistochemistry. The mRNA and protein were observed in the retina, optic nerve, and brain. In the retina, Wfs1 expression was strong in amacrine and Müller cells, and moderate in photoreceptors and horizontal cells. In addition, it was detectable in bipolar and retinal ganglion cells. Interestingly, moderate Wfs1 expression was seen in the optic nerve, particularly in astrocytes, while little Wfs1 was expressed in the optic chiasm or optic tract. In the brain, moderate Wfs1 expression was observed in the zonal, superficial gray, and intermediate gray layers of the superior colliculus, in the dorsomedial part of the suprachiasmatic nucleus, and in layer II of the primary and secondary visual cortices. Thus, Wfs1 mRNA and protein were widely distributed in the normal mouse visual system. This evidence may provide clues as to the physiological role of Wfs1 protein in the biology of vision, and help to explain the selective vulnerability of the optic nerve to WFS1 loss-of-function. (c) 2008 Wiley-Liss, Inc.

  14. Localization and distribution of wolframin in human tissues.

    Science.gov (United States)

    De Falco, Maria; Manente, Lucrezia; Lucariello, Angela; Baldi, Gianluca; Fiore, Paola; Laforgia, Vincenza; Baldi, Alfonso; Iannaccone, Alessandro; De Luca, Antonio

    2012-01-01

    Wolframin is a transmembrane glycoprotein of 890 aminoacids, encoded by WFS1 gene. WFS1 mutations are responsible for Wolfram syndrome, an autosomal recessive disorder. In the present paper, we first characterized the polyclonal wolframin antibody by dot blot. Secondly, we verified antibody specificity by western blotting using different human cell lines. Thirdly, we studied wolframin localization in human foetal (14-35 weeks) and adult tissues by immunohistochemistry. Wolframin expression was distributed in many organs, with different tissue and cell localization and expression levels. In foetal systems, wolframin expression was faint at 14-16 weeks and increased when development proceeded. In adult human tissues a variable positive staining was observed in both simple and stratified epithelia. A moderate wolframin expression was observed in liver and in the endocrine portion of the pancreas. In conclusion, our data suggest that this protein may have important roles in a number of different tissues, including many that are not known to be affected by WFS1-linked diseases. The immunopositivity in adult human tissues suggests that it may function maintaining physiological cellular homeostasis.

  15. Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans.

    Science.gov (United States)

    Berry, Vanita; Gregory-Evans, Cheryl; Emmett, Warren; Waseem, Naushin; Raby, Jacob; Prescott, DeQuincy; Moore, Anthony T; Bhattacharya, Shomi S

    2013-12-01

    Congenital cataracts are an important cause of bilateral visual impairment in infants. Through genome-wide linkage analysis in a four-generation family of Irish descent, the disease-associated gene causing autosomal-dominant congenital nuclear cataract was mapped to chromosome 4p16.1. The maximum logarithm of odds (LOD) score was 2.62 at a recombination fraction θ=0, obtained for marker D4S432 physically close to the Wolfram gene (WFS1). By sequencing the coding regions and intron-exon boundaries of WFS1, we identified a DNA substitution (c.1385A-to-G) in exon 8, causing a missense mutation at codon 462 (E462G) of the Wolframin protein. This is the first report of a mutation in this gene causing an isolated nuclear congenital cataract. These findings suggest that the membrane trafficking protein Wolframin may be important for supporting the developing lens.

  16. Initiation and developmental dynamics of Wfs1 expression in the context of neural differentiation and ER stress in mouse forebrain.

    Science.gov (United States)

    Tekko, Triin; Lilleväli, Kersti; Luuk, Hendrik; Sütt, Silva; Truu, Laura; Örd, Tiit; Möls, Märt; Vasar, Eero

    2014-06-01

    Wolframin (Wfs1) is a membrane glycoprotein that resides in the endoplasmic reticulum (ER) and regulates cellular Ca(2+) homeostasis. In pancreas Wfs1 attenuates unfolded protein response (UPR) and protects cells from apoptosis. Loss of Wfs1 function results in Wolfram syndrome (OMIM 222300) characterized by early-onset diabetes mellitus, progressive optic atrophy, diabetes insipidus, deafness, and psychiatric disorders. Similarly, Wfs1-/- mice exhibit diabetes and increased basal anxiety. In the adult central nervous system Wfs1 is prominent in central extended amygdala, striatum and hippocampus, brain structures largely involved in behavioral adaptation of the organism. Here, we describe the initiation pattern of Wfs1 expression in mouse forebrain using mRNA in situ hybridization and compare it with Synaptophysin (Syp1), a gene encoding synaptic vesicle protein widely used as neuronal differentiation marker. We show that the expression of Wfs1 starts during late embryonic development in the dorsal striatum and amygdala, then expands broadly at birth, possessing several transitory regions during maturation. Syp1 expression precedes Wfs1 and it is remarkably upregulated during the period of Wfs1 expression initiation and maturation, suggesting relationship between neural activation and Wfs1 expression. Using in situ hybridization and quantitative real-time PCR we show that UPR-related genes (Grp78, Grp94, and Chop) display dynamic expression in the perinatal brain when Wfs1 is initiated and their expression pattern is not altered in the brain lacking functional Wfs1. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

  17. Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1

    OpenAIRE

    Hogewind, Barend F.T.; Pennings, Ronald J.E.; Hol, Frans A.; Kunst, Henricus P.M.; Hoefsloot, Elisabeth H.; Cruysberg, Johannes R.M.; Cremers, Cor W.R.J.

    2010-01-01

    PURPOSE: To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series. METHODS: Seven members of a Dutch family underwent ophthalmological, otological, and genetical examinations in one institution. Fasting serum glucose was assessed in the affected family members. RESULTS: All affected individuals showed loss of neuroretinal rim of the optic nerve at fundosc...

  18. Identification of four novel mutations of the WFS1 gene in Iranian Wolfram syndrome pedigrees.

    Science.gov (United States)

    Ghahraman, Martha; Abbaszadegan, Mohammad Reza; Vakili, Rahim; Hosseini, Sousan; Fardi Golyan, Fatemeh; Ghaemi, Nosrat; Forghanifard, Mohammad Mahdi

    2016-12-01

    Wolfram syndrome is a rare neurodegenerative disorder with an autosomal recessive pattern of inheritance characterized by various clinical manifestations. The related gene, WFS1, encodes a transmembrane glycoprotein, named wolframin. Genetic analyses demonstrated that mutations in this gene are associated with WS type 1. Our aim in this study was to sequence WFS1 coding region in Iranian Wolfram syndrome pedigrees. Genomic DNA was extracted from peripheral blood of 12 WS patients and their healthy parents. Exons 2-8 and the exon-intron junctions of WFS1 were sequenced. DNA sequences were compared to the reference using Sequencher software. Molecular analysis of WFS1 revealed six different mutations. Four novel and two previously reported mutations were identified. One novel mutation, c.1379_1381del, is predicted to produce an aberrant protein. A second novel mutation, c.1384G > T, encodes a truncated protein. Novel mutation, c.1097-1107dup (11 bp), causes a frameshift which results in a premature stop codon. We screened for the novel missense mutation, c.1010C > T, in 100 control alleles. This mutation was not found in any of the healthy controls. Our study increased the spectrum of WFS1 mutations and supported the role of WFS1 in susceptibility to WS. We hope that these findings open new horizons to future molecular investigations which may help to prevent and treat this devastating disease.

  19. A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

    OpenAIRE

    Chistiakov, Dimitry A; Khodyrev, Dmitry S.; Smetanina, Svetlana A.; Bel'chikova, Larisa N.; Suplotova, Lyudmila A.; Nosikov, Valery V.

    2010-01-01

    BACKGROUND: Rare variants of the WFS1 gene encoding wolframin cause Wolfram syndrome, a monogenic disease associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. In contrast, common variants of WFS1 showed association with type 2 diabetes (T2D) in numerous Caucasian populations. AIM: In this study, we tested whether the markers rs752854, rs10010131, and rs734312, located in the WFS1 gene, are related to the development of T2D in a Russian population. METHODS: The p...

  20. A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings

    OpenAIRE

    Bramhall, Naomi F; Kallman, Jeremy C; Verrall, Aimee M; Street, Valerie A

    2008-01-01

    Abstract Background Low frequency sensorineural hearing loss (LFSNHL) is an uncommon clinical finding. Mutations within three different identified genes (DIAPH1, MYO7A, and WFS1) are known to cause LFSNHL. The majority of hereditary LFSNHL is associated with heterozygous mutations in the WFS1 gene (wolframin protein). The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and Ecoch...

  1. Rapidly progressive renal disease as part of Wolfram syndrome in a large inbred Turkish family due to a novel WFS1 mutation (p.Leu511Pro)

    DEFF Research Database (Denmark)

    Yuca, Sevil Ari; Rendtorff, Nanna Dahl; Boulahbel, Houda

    2012-01-01

    Wolfram syndrome, also named "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an inherited association of juvenile-onset diabetes mellitus and optic atrophy as key diagnostic criteria. Renal tract abnormalities and neurodegenerative disorder may occur in the third...... and fourth decade. The wolframin gene, WFS1, associated with this syndrome, is located on chromosome 4p16.1. Many mutations have been described since the identification of WFS1 as the cause of Wolfram syndrome. We identified a new homozygous WFS1 mutation (c.1532T>C; p.Leu511Pro) causing Wolfram syndrome...

  2. Association of the WFS1 gene with disease progression in children with new onset T1D. Results from the Hvidoere study group on childhood diabetes

    DEFF Research Database (Denmark)

    Nielsen, L.B.; Andersen, M.L.M.; Svensson, Jannete

    2010-01-01

    Objective: The wolframin gene, WFS1, encodes a glucoprotein involved in the calcium homeostasis of the endoplasmatic reticulum; WFS1 is critical for the function and survival of the pancreatic beta-cells. Genetic variation within the WFS1 gene is known to be associated with T2D and for rare...... variants the Wolfram syndrome. The aim of this study was to investigate the impact of a common genetic variant (rs10010131) of the WFS1 gene on disease progression in a group of children newly diagnosed with T1D. Methods: The study is a multicenter longitudinal investigation with 18 participating...... with proinsulin (est.: 1.55, P = 0.005) the first 12 month after disease onset compared to the AA genotype carriers. Conclusions: A common variant of the WFS1 gene is highly associated with better residual beta-cell function and corresponding better metabolic control during disease progression in new onset T1D...

  3. A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings.

    Science.gov (United States)

    Bramhall, Naomi F; Kallman, Jeremy C; Verrall, Aimee M; Street, Valerie A

    2008-06-02

    Low frequency sensorineural hearing loss (LFSNHL) is an uncommon clinical finding. Mutations within three different identified genes (DIAPH1, MYO7A, and WFS1) are known to cause LFSNHL. The majority of hereditary LFSNHL is associated with heterozygous mutations in the WFS1 gene (wolframin protein). The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and EcochG testing to further characterize the family's audiovestibular phenotype. The clinical phenotype of the American family was characterized by audiologic testing, vestibular evoked myogenic potentials (VEMP), and electrocochleography (EcochG) evaluation. Genetic characterization was performed by microsatellite analysis and direct sequencing of WFS1 for mutation detection. Sequence analysis of the WFS1 gene revealed a novel heterozygous mutation at c.2054G>C predicting a p.R685P amino acid substitution in wolframin. The c.2054G>C mutation segregates faithfully with hearing loss in the family and is absent in 230 control chromosomes. The p.R685 residue is located within the hydrophilic C-terminus of wolframin and is conserved across species. The VEMP and EcochG findings were normal in individuals segregating the WFS1 c.2054G>C mutation. We discovered a novel heterozygous missense mutation in exon 8 of WFS1 predicting a p.R685P amino acid substitution that is likely to underlie the LFSNHL phenotype in the American family. For the first time, we describe VEMP and EcochG findings for individuals segregating a heterozygous WFS1 mutation.

  4. A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings

    Directory of Open Access Journals (Sweden)

    Verrall Aimee M

    2008-06-01

    Full Text Available Abstract Background Low frequency sensorineural hearing loss (LFSNHL is an uncommon clinical finding. Mutations within three different identified genes (DIAPH1, MYO7A, and WFS1 are known to cause LFSNHL. The majority of hereditary LFSNHL is associated with heterozygous mutations in the WFS1 gene (wolframin protein. The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and EcochG testing to further characterize the family's audiovestibular phenotype. Methods The clinical phenotype of the American family was characterized by audiologic testing, vestibular evoked myogenic potentials (VEMP, and electrocochleography (EcochG evaluation. Genetic characterization was performed by microsatellite analysis and direct sequencing of WFS1 for mutation detection. Results Sequence analysis of the WFS1 gene revealed a novel heterozygous mutation at c.2054G>C predicting a p.R685P amino acid substitution in wolframin. The c.2054G>C mutation segregates faithfully with hearing loss in the family and is absent in 230 control chromosomes. The p.R685 residue is located within the hydrophilic C-terminus of wolframin and is conserved across species. The VEMP and EcochG findings were normal in individuals segregating the WFS1 c.2054G>C mutation. Conclusion We discovered a novel heterozygous missense mutation in exon 8 of WFS1 predicting a p.R685P amino acid substitution that is likely to underlie the LFSNHL phenotype in the American family. For the first time, we describe VEMP and EcochG findings for individuals segregating a heterozygous WFS1 mutation.

  5. The wolframin His611Arg polymorphism influences medication overuse headache.

    Science.gov (United States)

    Di Lorenzo, C; Sances, G; Di Lorenzo, G; Rengo, C; Ghiotto, N; Guaschino, E; Perrotta, A; Santorelli, F M; Grieco, G S; Troisi, A; Siracusano, A; Pierelli, F; Nappi, G; Casali, C

    2007-09-13

    Homozygosis for wolframin (WFS1) mutations determines Wolfram syndrome (WS), and common polymorphisms of WFS1 are associated with psychiatric illnesses and dependence behaviour. To test the influence of WFS1 polymorphisms on medication overuse headache (MOH), a chronic headache condition related to symptomatic drugs overuse, we analyzed 82 MOH patients for the WFS1 His611Arg polymorphism, and performed a comparison between clinical features of Arg/Arg (R/R) and non-R/R individuals. Individuals harbouring the R/R genotype showed significantly higher monthly drug consumption (t=-3.504; p=0.00075) and more severe depressive symptoms on the BDI questionnaire (t=-3.048; p=0.003) than non-R/R. WFS1 polymorphism emerged as the only significant predictor of drug consumption, at the multivariate regression analysis (F=12.277; d.f.=1,80; p=0.00075, adjusted R2=0.122). These results implicate WFS1 in the clinical picture of MOH, may be through an influence on need for drugs as in other conditions of abuse behaviour.

  6. Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration.

    Science.gov (United States)

    Plaas, Mario; Seppa, Kadri; Reimets, Riin; Jagomäe, Toomas; Toots, Maarja; Koppel, Tuuliki; Vallisoo, Tuuli; Nigul, Mait; Heinla, Indrek; Meier, Riho; Kaasik, Allen; Piirsoo, Andres; Hickey, Miriam A; Terasmaa, Anton; Vasar, Eero

    2017-08-31

    Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5-KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1-ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS.

  7. WFS1 variants in Finnish patients with diabetes mellitus, sensorineural hearing impairment or optic atrophy, and in suicide victims.

    Science.gov (United States)

    Kytövuori, Laura; Seppänen, Allan; Martikainen, Mika H; Moilanen, Jukka S; Kamppari, Seija; Särkioja, Terttu; Remes, Anne M; Räsänen, Pirkko; Rönnemaa, Tapani; Majamaa, Kari

    2013-08-01

    Mutations in the wolframin gene, WFS1, cause Wolfram syndrome, a rare recessive neurodegenerative disorder. The clinical features include early-onset bilateral optic atrophy (OA), diabetes mellitus (DM), diabetes insipidus, hearing impairment, urinary tract abnormalities and psychiatric illness, and, furthermore, WFS1 variants appear to be associated with non-syndromic DM and hearing impairment. Variation of WFS1 was investigated in Finnish subjects consisting 182 patients with DM, 117 patients with sensorineural hearing impairment (SNHI) and 44 patients with OA, and in 95 suicide victims. Twenty-two variants were found in the coding region of WFS1, including three novel nonsynonymous variants. The frequency of the p.[His456] allele was significantly higher in the patients with SNHI (11.5%; corrected P=0.00008), DM (6.6%; corrected P=0.036) or OA (9.1%; corrected P=0.043) than that in the 285 controls (3.3%). The frequency of the p.[His611] allele was 55.8% in the patients with DM being higher than that in the controls (47%; corrected P=0.039). The frequencies of p.[His456] and p.[His611] were similarly increased in an independent group of patients with DM (N=299). The results support previous findings that genetic variation of WFS1 contributes to the risk of DM and SNHI.

  8. Association study of the effect of WFS1 polymorphisms on risk of type 2 diabetes in Japanese population.

    Science.gov (United States)

    Mita, Masaki; Miyake, Kazuaki; Zenibayashi, Masako; Hirota, Yushi; Teranishi, Tetsuya; Kouyama, Kunichi; Sakaguchi, Kazuhiko; Kasuga, Masato

    2008-10-30

    Mutations of WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder characterized by juvenile diabetes mellitus, optic atrophy, deafness and diabetes insipidus. The product encoded by WFS1 gene, wolframin, could be involved in ER stress response causing beta-cell loss through impaired cell cycle progression and increased apoptosis. Recently, polymorphisms in the WFS1 gene were strongly associated with type 2 diabetes in Caucasians. The aim of the present study was to examine whether the variants of WFS1 are associated with risk of type 2 diabetes in Japanese individuals. Four single nucleotide polymorphisms, rs6446482, rs12511742, rs1801208 (R456H) and rs734312 (H611R) were genotyped in a total of 536 diabetic patients and 398 nondiabetic control subjects. Among the four variants, rs12511742 showed a marginal association with susceptibility to type 2 diabetes (odds ratio = 1.32, 95% confidence interval = 1.02-1.71, P = 0.033). Carriers of the risk allele at rs12511742 exhibited lower pancreas beta-cell function (P = 0.017). However, this association disappeared after adjustment for sex, age and BMI (Adjusted P = 0.24). Although we found no evidence for a substantial effect of WFS1 polymorphisms on risk of type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population, this gene is still a good candidate for a type 2 diabetes susceptibility gene, potentially, through impaired insulin secretion.

  9. Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus

    Science.gov (United States)

    Elek, Zsuzsanna; Németh, Nóra; Nagy, Géza; Németh, Helga; Somogyi, Anikó; Hosszufalusi, Nóra; Sasvári-Székely, Mária; Rónai, Zsolt

    2015-01-01

    The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ 2-test in combination with correction for multiple testing. For functional analysis, the entire 3’ UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3’ UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function. PMID:26426397

  10. Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus.

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    Zsuzsanna Elek

    Full Text Available The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ2-test in combination with correction for multiple testing. For functional analysis, the entire 3' UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.

  11. Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus.

    Science.gov (United States)

    Elek, Zsuzsanna; Németh, Nóra; Nagy, Géza; Németh, Helga; Somogyi, Anikó; Hosszufalusi, Nóra; Sasvári-Székely, Mária; Rónai, Zsolt

    2015-01-01

    The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ2-test in combination with correction for multiple testing. For functional analysis, the entire 3' UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.

  12. Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1.

    Science.gov (United States)

    Hogewind, Barend F T; Pennings, Ronald J E; Hol, Frans A; Kunst, Henricus P M; Hoefsloot, Elisabeth H; Cruysberg, Johannes R M; Cremers, Cor W R J

    2010-01-12

    To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series. Seven members of a Dutch family underwent ophthalmological, otological, and genetical examinations in one institution. Fasting serum glucose was assessed in the affected family members. All affected individuals showed loss of neuroretinal rim of the optic nerve at fundoscopy with enlarged blind spots at perimetry. They showed a red-green color vision defect at color vision tests and deviations at visually evoked response tests. The audiograms of the affected individuals showed hearing loss and were relatively flat. The unaffected individuals showed no visual deviations or hearing impairment. The affected family members had no glucose intolerance. Leber hereditary optic neuropathy (LHON) mitochondrial mutations and mutations in the Optic atrophy-1 gene (OPA1) were excluded. In the affected individuals, a novel missense mutation c.2508G>C (p.Lys836Asn) in exon 8 of WFS1 was identified. This study describes the phenotype of a family with autosomal dominant optic neuropathy and hearing impairment associated with a novel missense mutation in WFS1.

  13. Relation of exploratory behaviour to plasma corticosterone and Wfs1 gene expression in Wistar rats.

    Science.gov (United States)

    Sütt, S; Raud, S; Abramov, U; Innos, J; Luuk, H; Plaas, M; Kõks, S; Zilmer, K; Mahlapuu, R; Zilmer, M; Vasar, E

    2010-06-01

    Male Wistar rats exhibit significant variations in exploratory behaviour in the elevated plus-maze (EPM) model of anxiety. We have now investigated the relation between exploratory behaviour and levels of corticosterone and systemic oxidative stress. Also, the expression levels of endocannabinoid-related and wolframin (Wfs1) genes were measured in the forebrain structures. The rats were divided into high, intermediate and low exploratory activity groups. Exposure to EPM significantly elevated the serum levels of corticosterone in all rats, but especially in the high exploratory group. Oxidative stress indices and expression of endocannabinoid-related genes were not significantly affected by exposure to EPM. Wfs1 mRNA level was highly dependent on exploratory behaviour of animals. In low exploratory activity rats, Wfs1 gene expression was reduced in the temporal lobe, whereas in high exploratory activity group it was reduced in the mesolimbic area and hippocampus. Altogether, present study indicates that in high exploratory activity rats, the activation of brain areas related to novelty seeking is apparent, whereas in low exploratory activity group the brain structures linked to anxiety are activated.

  14. Metabolomics of the Wolfram Syndrome 1 Gene (Wfs1) Deficient Mice.

    Science.gov (United States)

    Porosk, Rando; Terasmaa, Anton; Mahlapuu, Riina; Soomets, Ursel; Kilk, Kalle

    2017-12-01

    Wolfram syndrome 1 is a rare autosomal recessive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Mutations in the WFS1 gene encoding the wolframin glycoprotein can lead to endoplasmic reticulum stress and unfolded protein responses in cells, but the pathophysiology at whole organism level is poorly understood. In this study, several organs (heart, liver, kidneys, and pancreas) and bodily fluids (trunk blood and urine) of 2- and 6-month old Wfs1 knockout (KO), heterozygote (HZ), and wild-type (WT) mice were analyzed by untargeted and targeted metabolomics using liquid chromatography-mass spectrometry. The key findings were significant perturbations in the metabolism of pancreas and heart before the onset of related clinical signs such as glycosuria that precedes hyperglycemia and thus implies a kidney dysfunction before the onset of classical diabetic nephropathy. The glucose use and gluconeogenesis in KO mice are intensified in early stages, but later the energetic needs are mainly covered by lipolysis. Furthermore, in young mice liver and trunk blood hypouricemia, which in time turns to hyperuricemia, was detected. In summary, we show that the metabolism in Wfs1-deficient mice markedly differs from the metabolism of WT mice in many aspects and discuss the future biological and clinical relevance of these observations.

  15. Modulation of wolframin expression in human placenta during pregnancy: comparison among physiological and pathological states.

    Science.gov (United States)

    Lucariello, Angela; Perna, Angelica; Sellitto, Carmine; Baldi, Alfonso; Iannaccone, Alessandro; Cobellis, Luigi; De Luca, Antonio; De Falco, Maria

    2014-01-01

    The WFS1 gene, encoding a transmembrane glycoprotein of the endoplasmic reticulum called wolframin, is mutated in Wolfram syndrome, an autosomal recessive disorder defined by the association of diabetes mellitus, optic atrophy, and further organ abnormalities. Disruption of the WFS1 gene in mice causes progressive β-cell loss in the pancreas and impaired stimulus-secretion coupling in insulin secretion. However, little is known about the physiological functions of this protein. We investigated the immunohistochemical expression of wolframin in human placenta throughout pregnancy in normal women and diabetic pregnant women. In normal placenta, there was a modulation of wolframin throughout pregnancy with a strong level of expression during the first trimester and a moderate level in the third trimester of gestation. In diabetic women, wolframin expression was strongly reduced in the third trimester of gestation. The pattern of expression of wolframin in normal placenta suggests that this protein may be required to sustain normal rates of cytotrophoblast cell proliferation during the first trimester of gestation. The decrease in wolframin expression in diabetic placenta suggests that this protein may participate in maintaining the physiologic glucose homeostasis in this organ.

  16. Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations.

    Science.gov (United States)

    Franks, P W; Rolandsson, O; Debenham, S L; Fawcett, K A; Payne, F; Dina, C; Froguel, P; Mohlke, K L; Willer, C; Olsson, T; Wareham, N J; Hallmans, G; Barroso, I; Sandhu, M S

    2008-03-01

    Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish case-control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from Sweden, Finland and France, to obtain updated summary effect estimates. Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case-control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR) 0.85, 95% CI 0.75-0.96, p=0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI 0.82-0.93, p=4.5 x 10(-5)). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95% CI 0.86-0.92; p=4.9 x 10(-11)). In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and the risk of type 2 diabetes.

  17. Rapidly progressive renal disease as part of Wolfram syndrome in a large inbred Turkish family due to a novel WFS1 mutation (p.Leu511Pro).

    Science.gov (United States)

    Yuca, Sevil Ari; Rendtorff, Nanna Dahl; Boulahbel, Houda; Lodahl, Marianne; Tranebjærg, Lisbeth; Cesur, Yasar; Dogan, Murat; Yilmaz, Cahide; Akgun, Cihangir; Acikgoz, Mehmet

    2012-01-01

    Wolfram syndrome, also named "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an inherited association of juvenile-onset diabetes mellitus and optic atrophy as key diagnostic criteria. Renal tract abnormalities and neurodegenerative disorder may occur in the third and fourth decade. The wolframin gene, WFS1, associated with this syndrome, is located on chromosome 4p16.1. Many mutations have been described since the identification of WFS1 as the cause of Wolfram syndrome. We identified a new homozygous WFS1 mutation (c.1532T>C; p.Leu511Pro) causing Wolfram syndrome in a large inbred Turkish family. The patients showed early onset of IDDM, diabetes insipidus, optic atrophy, sensorineural hearing impairment and very rapid progression to renal failure before age 12 in three females. Ectopic expression of the wolframin mutant in HEK cells results in greatly reduced levels of protein expression compared to wild-type wolframin, strongly supporting that this mutation is disease-causing. The mutation showed perfect segregation with disease in the family, characterized by early and severe clinical manifestations. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  18. WFS1 and non-syndromic low-frequency sensorineural hearing loss: a novel mutation in a Portuguese case.

    Science.gov (United States)

    Gonçalves, A C; Matos, T D; Simões-Teixeira, H R; Pimenta Machado, M; Simão, M; Dias, O P; Andrea, M; Fialho, G; Caria, H

    2014-04-01

    Low-frequency sensorineural hearing loss (LFSNHL) is an unusual type of HL in which frequencies at 2,000 Hz and below are predominantly affected. Most of the families with LFSNHL carry missense mutations in WFS1 gene, coding for wolframin. A Portuguese patient aged 49, reporting HL since her third decade of life, and also referring tinnitus, was shown to display bilateral moderate LFSNHL after audiological evaluation. Molecular analysis led to the identification of a novel mutation, c.511G>A (p.Asp171Asn), found in heterozygosity in the exon 5 of the WFS1 gene, and changing the aspartic acid at position 171 to an asparagine, in the extracellular N-terminus domain of the wolframin protein. This novel mutation wasn't present either in 200 control chromosomes analyzed or in the hearing proband's half-brother, and it had not been reported in 1000 Genomes, Exome Variant Server, HGMD or dbSNP databases. No mutations were found in GJB2 and GJB6 genes. Multi-alignment of 27 wolframin sequences from mammalian species, against the human wolframin sequence in ConSurf, indicated a conservation score corresponding to 7 in a 1-9 color scale where 9 is conserved and 1 is variable. In addition, the mutation p.Asp171Asn was predicted to be damaging and possibly damaging by SIFT and Polyphen-2, respectively. The auditory phenotype of this patient could thus be due to the novel mutation p.Asp171Asn. Further functional characterization might enable to elucidate in which way the change in the residue 171, as other changes introduced by LFSNHL-associated mutations previously described, leads to this type of HL. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. RNA-sequencing of WFS1-deficient pancreatic islets.

    Science.gov (United States)

    Ivask, Marilin; Hugill, Alison; Kõks, Sulev

    2016-04-01

    Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in theWFS1gene.WFS1encodes an endoplasmic reticulum resident transmembrane protein. TheWfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of this study was to describe the insulin secretion and transcriptome of pancreatic islets inWFS1-deficient mice.WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KOpancreatic islets secreted less insulin after incubation in 2 and 10 mmol/L glucose and with tolbutamide solution compared toWTand Wfs1HZislets, but not after stimulation with 20 mmol/L glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KOhad an increased level of proinsulin. After incubation in 2 mmol/L glucose solution the proinsulin/insulin ratio in Wfs1KOwas significantly higher than that ofWTand Wfs1HZRNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated inWFS1-deficient mice. Functional annotation ofRNAsequencing results showed thatWFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  20. Identification of two novel missense WFS1 mutations, H696Y and R703H, in patients with non-syndromic low-frequency sensorineural hearing loss.

    Science.gov (United States)

    Sun, Yi; Cheng, Jing; Lu, Yanping; Li, Jianzhong; Lu, Yu; Jin, Zhanguo; Dai, Pu; Wang, Rongguang; Yuan, Huijun

    2011-02-01

    Non-syndromic low-frequency sensorineural hearing loss (LFSNHL) is an unusual type of hearing loss in which frequencies ≤2000 Hz predominantly are affected. To date, different mutations in two genes, DIAPH1 and WFS1, have been found to be associated with LFSNHL. Here, we report a five-generation Chinese family with postlingual and progressive LFSNHL. We mapped the disease locus to a 2.5 Mb region on chromosome 4p16 between markers SNP_A-2167174 and D4S431, overlapping with the DFNA6/14/38 locus. Sequencing of candidate gene revealed a heterozygous c.2086C>T substitution in exon 8 of WFS1, leading to p.H696Y substitution at the C-terminus of Wolframin (WFS1). In addition, we performed mutational screening of WFS1 in 37 sporadic patients, 7-50 years of age, with LFSNHL. We detected a heterozygous c.2108G>A substitution in exon 8 of WFS1, leading to p.R703H substitution in a patient. The H696 and R703 in WFS1 are highly conserved across species, including human, orangutan, rat, mouse, and frog (Xenopus). Sequence analysis demonstrated the absence of c.2086C>T or c.2108G>A substitutions in the WFS1 genes among 200 unrelated control subjects of Chinese background, supporting the hypothesis that they represent causative mutations, and not rare polymorphisms. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype correlation for LFSNHL. Copyright © 2011. Published by Elsevier Ltd.

  1. Expressional and functional studies of Wolframin, the gene function deficient in Wolfram syndrome, in mice and patient cells.

    Science.gov (United States)

    Philbrook, Christine; Fritz, Eberhard; Weiher, Hans

    2005-01-01

    Wolfram Syndrome is an autosomal recessive degenerative disorder of the neuroendocrine system. Diabetes mellitus is its lead symptom. Patients show mutations in the wolframin (WFS1) gene coding for a hydrophobic transmembrane protein of 890 amino acids. This protein was preliminarily localised in the endoplasmatic reticulum (ER) in cells of mice and rats. Mice lacking the WFS1 gene display degeneration of pancreatic beta-cells following induction of ER stress. We here used antibodies against substructures of the wolframin protein in order to analyse its expression and localisation. Expression was detected in both pancreatic beta-cells and the limbic system of mice. Using the rat insulinoma cell line RIN 5AH and fractionated mouse brain tissue, we confirmed wolframin localisation to the endoplasmic reticulum. Expression profiling on patient's primary fibroblasts revealed down-regulation of the diabetes associated plasma membrane glycoprotein (PC-1) gene, and up-regulation of fibulin-3, a gene connected to senescence. However, cell proliferation was indistinguishable from non-mutated cells. In contrast to data obtained on murine pancreatic islets, we found no increased apoptosis following induction of ER stress but rather by staurosporine treatment in the absence of WFS1 function. This indicates a new role of WFS1 deficiency in programmed cell death.

  2. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome.

    Science.gov (United States)

    Morikawa, Shuntaro; Tajima, Toshihiro; Nakamura, Akie; Ishizu, Katsura; Ariga, Tadashi

    2017-12-01

    Wolfram syndrome (WS) is a disorder characterized by the association of insulin-dependent diabetes mellitus (DM), diabetes insipidus, deafness, and optic nerve atrophy. WS is caused by WFS1 mutations encoding WFS1 protein expressed in endoplasmic reticulum (ER). During ER protein synthesis, misfolded and unfolded proteins accumulate, known as "ER stress". This is attenuated by the unfolded protein response (UPR), which recovers and maintains ER functions. Because WFS1 is a UPR component, mutant WFS1 might cause unresolvable ER stress conditions and cell apoptosis, the major causes underlying WS symptoms. We encountered an 11-month-old Japanese female WS patient with insulin-dependent DM, congenital cataract and severe bilateral hearing loss. Analyze the WFS1 and functional consequence of the patient WFS1 in vitro. The patient WFS1 contained a heterozygous 4 amino acid in-frame deletion (p.N325_I328del). Her mutant WFS1 increased GRP78 and ATF6α promoter activities in the absence of thapsigargin, indicating constitutive ER stress and nuclear factor of activated T-cell reporter activity, reflecting elevated cytosolic Ca 2+ signals. Mutant transfection into cells reduced mRNA expression levels of sarcoplasmic/endoplasmic reticulum Ca 2+ transport ATPase 2b (SERCA2b) compared with wild type. Because SERCA2b is required for ER and cytoplasmic Ca 2+ homeostasis, decreased SERCA2b expression might affect ER Ca 2+ efflux, causing cell apoptosis. A novel heterozygous mutation of WFS1 induced constitutive ER stress through ATF6α activation and ER Ca 2+ efflux, resulting in cell apoptosis. These results provide new insights into the roles of WFS1 in UPR and mechanism of monogenic DM. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Variants inWFS1and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity.

    Science.gov (United States)

    Wheeler, Heather E; Gamazon, Eric R; Frisina, Robert D; Perez-Cervantes, Carlos; El Charif, Omar; Mapes, Brandon; Fossa, Sophie D; Feldman, Darren R; Hamilton, Robert J; Vaughn, David J; Beard, Clair J; Fung, Chunkit; Kollmannsberger, Christian; Kim, Jeri; Mushiroda, Taisei; Kubo, Michiaki; Ardeshir-Rouhani-Fard, Shirin; Einhorn, Lawrence H; Cox, Nancy J; Dolan, M Eileen; Travis, Lois B

    2017-07-01

    Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO). Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding. Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO ( P = 1.4 × 10 -8 ). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele ( P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort ( n = 18,620 patients, Bonferroni adjusted P WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. Clin Cancer Res; 23(13); 3325-33. ©2016 AACR . ©2016 American Association for Cancer Research.

  4. A WFS1 haplotype consisting of the minor alleles of rs752854, rs10010131, and rs734312 shows a protective role against type 2 diabetes in Russian patients.

    Science.gov (United States)

    Chistiakov, Dimitry A; Khodyrev, Dmitry S; Smetanina, Svetlana A; Bel'chikova, Larisa N; Suplotova, Lyudmila A; Nosikov, Valery V

    2010-01-01

    Rare variants of the WFS1 gene encoding wolframin cause Wolfram syndrome, a monogenic disease associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. In contrast, common variants of WFS1 showed association with type 2 diabetes (T2D) in numerous Caucasian populations. In this study, we tested whether the markers rs752854, rs10010131, and rs734312, located in the WFS1 gene, are related to the development of T2D in a Russian population. The polymorphic markers were genotyped in Russian diabetic (n = 1,112) and non-diabetic (n = 1,097) patients using a Taqman allele discrimination assay. The correlation between the carriage of disease-associated WFS1 variants and the patients' clinical and metabolic characteristics was studied using ANOVA and ANCOVA. Adjustment for confounding variables such as gender, age, body mass index, obesity, HbA1c, and hypertension was made. Haplotype GAG, consisting of the minor alleles of rs752854, rs10010131, and rs734312, respectively, showed association with decreased risk of T2D (OR = 0.44, 95% CI = 0.32-0.61, p = 4.3 x 10(-7)). Compared to other WFS1 variants, non-diabetic individuals homozygous for GAG/CAG had significantly increased fasting insulin (p(adjusted) = 0.047) and homeostasis model assessment of β-cell function (HOMA-β) index (p(adjusted) = 0.006). Diabetic patients homozygous for GAG/GAG showed significantly elevated levels of 2-h insulin (p(adjusted) = 0.029) and HOMA-β = 0.011. Disease-associated variants of WFS1 contribute to the pathogenesis of T2D through impaired insulin response to glucose stimulation and altered β-cell function.

  5. Replication of the association between variants in the WFS1 gene and risk of type 2 diabetes in European populations

    Science.gov (United States)

    Franks, P.W.; Rolandsson, O.; Debenham, S.L.; Fawcett, K.A.; Payne, F.; Dina, C.; Froguel, P.; Mohlke, K.L.; Willer, C.; Olsson, T.; Wareham, N.J.; Hallmans, G.; Barroso, I; Sandhu, M.S.

    2009-01-01

    Aims/hypothesis: Mutations at the Wolframin encoding gene, WFS1, cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. In the present study, we sought to replicate those associations in a northern Swedish case-control study for type 2 diabetes. We also meta-analyzed published and previously unpublished data from Sweden, Finland and France to obtain updated summary effect estimates. Methods: Four WFS1 SNPs (rs10010131, rs6446482, rs752854, rs734312 [R611H]) were genotyped in a type 2 diabetes case-control study (N=1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex, and body mass index. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 cases and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. Results: In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk (OR=0.85; 95% CI=0.75-0.96; p=0.010). Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131, or its proxy variants, showed evidence for statistical association (OR=0.87; 95% CI=0.82-0.93; p=4.5×10−5). In an updated meta-analysis of all 11 studies, comprising 14,139 cases and 16,109 controls, strong evidence for statistical association was also observed (OR=0.89; 95% CI=0.86-0.92; p=4.9×10−11). Conclusion: In this study of WFS1 gene variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and risk of type 2 diabetes. PMID:18040659

  6. [Wolfram syndrome: clinical features, molecular genetics of WFS1 gene].

    Science.gov (United States)

    Tanabe, Katsuya; Matsunaga, Kimie; Hatanaka, Masayuki; Akiyama, Masaru; Tanizawa, Yukio

    2015-02-01

    Wolfram syndrome(WFS: OMIM 222300) is a rare recessive neuro-endocrine degenerative disorder, known as DIDMOAD(Diabetes Insipidus, early-onset Diabetes Mellitus, Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene(WFS1). The WFS1 protein is an endoplasmic reticulum(ER) embedded protein, which functions in ER calcium homeostasis and unfolded protein responses. Dysregulation of these cellular processes results in the development of ER stress, leading to apoptosis. In addition, abundantly present WFS1 protein in insulin secretory granules plays a role in the intra-granular acidification. However, the phenotypic pleiomorphism and molecular complexity of this disease limit the understanding of WFS. Here we review clinical features, molecular mechanisms and mutations of WFS1 gene that relate to this syndrome.

  7. WFS1 mutations in hearing-impaired children.

    Science.gov (United States)

    Häkli, Sanna; Kytövuori, Laura; Luotonen, Mirja; Sorri, Martti; Majamaa, Kari

    2014-07-01

    Mutations in the WFS1 gene can cause Wolfram syndrome or nonsyndromic hearing impairment (HI). The objective of this study was to ascertain the presence of mutations in WFS1 among children with HI from unknown causes. We screened 105 Finnish children with HI for mutations in exon 8 in WFS1. Children were born in a defined area in Northern Finland and they had sensorineural, mild to profound, syndromic, or nonsyndromic HI. They were negative for GJB2 mutations and for the m.1555A> G and m.3243A> G mutations in mitochondrial DNA. We found three rare variants and the novel p.Gly831Ser variant in WFS1. Segregation analysis suggested that the novel variant had arisen de novo. The p.Gly831Ser variant may be a new member to the group of heterozygous WFS1 mutations that lead to HI, while the pathogenicity of the rare variant p.Gly674Arg remained unclear. The other two rare variants, p.Glu385Lys and p.Glu776Val, did not segregate with HI in the families. WFS1 gene mutations are a rare cause of HI among Finnish children with HI.

  8. Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family.

    Science.gov (United States)

    Niu, Zhijie; Feng, Yong; Hu, Zhengmao; Li, Jiada; Sun, Jie; Chen, Hongsheng; He, Chufeng; Wang, Xueping; Jiang, Lu; Liu, Yalan; Cai, Xinzhang; Wang, Lili; Cai, Yuxiang; Liu, Xuezhong; Mei, Lingyun

    2017-09-01

    Autosomal dominant non-syndromic low-frequency sensorineural hearing loss (LFSNHL) DFNA6/14/38 is an uncommon type of hearing loss that classically affects low frequencies of 2000 Hz and below, demonstrating an ascending configuration. The current study aimed to investigate the cause of LFSNHL in a five-generation Chinese family. The phenotype of the Chinese family was characterized using audiologic testing and pedigree analysis. The combined approach of array screening and whole-exome sequencing was used to identify the disease-causing gene in this family. This pedigree, in which the affected subjects presented isolated low-frequency sensorineural hearing impairment with childhood onset, was associated with autosomal dominant inheritance of the c.2591A > G mutation in exon 8 of the Wolframin syndrome 1 (WFS1) gene which was not present in 286 unrelated controls with matched ancestry and is highly conserved across species. In addition, several mutations affecting the Glu864 residue have been previously identified in different populations, suggesting that this site is likely to be a mutational hot spot. We identified a novel substitution, Glu864Gly, of WFS1 as the causative variant for this pedigree. Our data extend the mutation spectrum of the WFS1 gene in Chinese individuals and may contribute to establishing a better genotype-phenotype correlation for LFSNHL. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Congenital central diabetes insipidus and optic atrophy in a Wolfram newborn: is there a role for WFS1 gene in neurodevelopment?

    Science.gov (United States)

    Ghirardello, Stefano; Dusi, Elisa; Castiglione, Bianca; Fumagalli, Monica; Mosca, Fabio

    2014-09-26

    Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus (DM), optic atrophy (OA), central diabetes insipidus (CDI) and deafness (D). The phenotype of the disease has been associated with several mutations in the WFS1 gene, a nuclear gene localized on chromosome 4. Since the discovery of the association between WFS1 gene and Wolfram syndrome, more than 150 mutations have been identified in WS patients. We previously described the first case of perinatal onset of Wolfram syndrome newborn carrying a segmental uniparental heterodysomy affecting the short arm of chromosome 4 responsible for a significant reduction in wolframin expression. Here we review and discuss the pathophysiological mechanisms that we believe responsible for the perinatal onset of Wolfram syndrome as these data strongly suggest a role for WFS1 gene in foetal and neonatal neurodevelopment. We described a male patient of 30 weeks' gestation with intrauterine growth restriction and poly-hydramnios. During the first days of life, the patient showed a 19% weight loss associated with polyuria and hypernatremia. The presence of persistent hypernatremia (serum sodium 150 mEq/L), high plasma osmolarity (322 mOsm/L) and low urine osmolarity (190 mOsm/l) with a Uosm/Posm ratio Wolfram syndrome should be considered in the differential diagnosis of the rare cases of congenital central diabetes insipidus developed in the neonatal period.

  10. Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress.

    Science.gov (United States)

    Zatyka, Malgorzata; Ricketts, Christopher; da Silva Xavier, Gabriela; Minton, Jayne; Fenton, Sarah; Hofmann-Thiel, Sabine; Rutter, Guy A; Barrett, Timothy G

    2008-01-15

    Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein, Wolframin. Although its precise functions are unknown, Wolframin deficiency increases ER stress, impairs cell cycle progression and affects calcium homeostasis. To gain further insight into its function and identify molecular partners, we used the WFS1-C-terminal domain as bait in a yeast two-hybrid screen with a human brain cDNA library. Na+/K+ ATPase beta1 subunit was identified as an interacting clone. We mapped the interaction to the WFS1 C-terminal and transmembrane domains, but not the N-terminal domain. Our mapping data suggest that the interaction most likely occurs in the ER. We confirmed the interaction by co-immunoprecipitation in mammalian cells and with endogenous proteins in JEG3 placental cells, neuroblastoma SKNAS and pancreatic MIN6 beta cells. Na+/K+ ATPase beta1 subunit expression was reduced in plasma membrane fractions of human WFS1 mutant fibroblasts and WFS1 knockdown MIN6 pancreatic beta-cells compared with wild-type cells; Na+/K+ ATPase alpha1 subunit expression was also reduced in WFS-depleted MIN6 beta cells. Induction of ER stress in wild-type cells only partly accounted for the reduced Na+/K+ ATPase beta1 subunit expression observed. We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation; loss of this interaction may contribute to the pathology seen in Wolfram syndrome via reductions in sodium pump alpha1 and beta1 subunit expression in pancreatic beta-cells.

  11. Ultrafast haplotyping of putative microRNA-binding sites in the WFS1 gene by multiplex polymerase chain reaction and capillary gel electrophoresis.

    Science.gov (United States)

    Kerékgyártó, Márta; Németh, Nóra; Kerekes, Tamás; Rónai, Zsolt; Guttman, András

    2013-04-19

    The transmembrane protein wolframin (WSF1) plays a crucial role in cell integrity in pancreatic beta cells and maintaining ER homeostasis. Genetic variations in the WFS1 gene have been described to be associated with Wolfram syndrome or type 2 diabetes mellitus. In this paper we report on an efficient double-tube allele-specific amplification method in conjunction with ultrafast capillary gel electrophoresis for direct haplotyping analysis of the SNPs in two important miRNA-binding sites (rs1046322 and rs9457) in the WFS1 gene. An automated single-channel capillary gel electrophoresis system was utilized in the method that provided dsDNA fragment analysis in less than 240 s. The light-emitting diode induced fluorescence (LEDIF) detection system enabled excellent sensitivity for automated haplotyping of a large number of clinical samples. The detection limit was 0.002 ng/μL using field amplified injection from water diluted samples. The dynamic quantitation range was 0.08-10.00 ng/μL (R(2)=0.9997) in buffer diluted samples. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Whole exome sequencing identifies a pathogenic mutation in WFS1 in two large Chinese families with autosomal dominant all-frequency hearing loss and prenatal counseling.

    Science.gov (United States)

    Cheng, Hongbo; Zhang, Qin; Wang, Wenbin; Meng, Qingxia; Wang, Fuxin; Liu, Minjuan; Mao, Jun; Shi, Yichao; Wang, Wei; Li, Hong

    2018-03-01

    To identify the pathogenic mutation and provide prenatal counseling and diagnosis in two large Chinese families with autosomal dominant all-frequency hearing loss. Whole exome sequencing technology was used to identify the pathogenic mutation of the two families. In addition, 298 patients with sporadic hearing loss and 400 normal controls were studied to verify the mutation/polymorphism nature of the identified variant. Prenatal diagnosis was carried out. A rare missense mutation c.2389G > A (p.D572N) in the Wolframin syndrome 1 (WFS1) gene was identified. It was reported in only one previous Chinese study, and never in other populations/ethnicities. The mutation was also found in one patient with sporadic hearing loss (1/298, 0.3%). A healthy baby was born after prenatal diagnosis. Our findings strongly suggest that the c.2389G > A mutation in WFS1 is associated with all-frequency hearing loss, rather than low- or high-frequency loss. So far, the mutation is only reported in Chinese. Prenatal diagnosis and prenatal counseling is available for these two Chinese families. Copyright © 2018. Published by Elsevier B.V.

  13. Sex-related hearing impairment in Wolfram syndrome patients identified by inactivating WFS1 mutations

    NARCIS (Netherlands)

    Pennings, RJE; Huygen, PLM; van den Ouweland, JMW; Cryns, K; Dikkeschei, LD; Van Camp, G; Cremers, CWRJ

    2004-01-01

    This study examined the audiovestibular profile of 11 Wolfram syndrome patients (4 males, 7 females) from 7 families, with identified WFS1 mutations, and the audiometric profile of 17 related heterozygous carriers of WFS1 mutations. Patients with Wolfram syndrome showed a downsloping audiogram and

  14. Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein

    International Nuclear Information System (INIS)

    Yamaguchi, Suguru; Ishihara, Hisamitsu; Tamura, Akira; Yamada, Takahiro; Takahashi, Rui; Takei, Daisuke; Katagiri, Hideki; Oka, Yoshitomo

    2004-01-01

    Mutations of the WFS1 gene are responsible for two hereditary diseases, Wolfram syndrome and low frequency sensorineural hearing loss. The WFS1 protein is a glycoprotein located in the endoplasmic reticulum (ER) membrane but its function is poorly understood. Herein we show WFS1 mRNA and protein levels in pancreatic islets to be increased with ER-stress inducers, thapsigargin and dithiothreitol. Another ER-stress inducer, the N-glycosylation inhibitor tunicamycin, also raised WFS1 mRNA but not protein levels. Site-directed mutagenesis showed both Asn-663 and Asn-748 to be N-glycosylated in mouse WFS1 protein. The glycosylation-defective WFS1 protein, in which Asn-663 and Asn-748 had been substituted with aspartate, exhibited an increased protein turnover rate. Consistent with this, the WFS1 protein was more rapidly degraded in the presence of tunicamycin. These data indicate that ER-stress and N-glycosylation play important roles in WFS1 expression and stability, and also suggest regulatory roles for this protein in ER-stress induced cell death

  15. Sex-related hearing impairment in Wolfram syndrome patients identified by inactivating WFS1 mutations.

    NARCIS (Netherlands)

    Pennings, R.J.E.; Huygen, P.L.M.; Ouweland, J.M.W. van den; Cryns, K.; Dikkeschei, L.D.; Camp, G. van; Cremers, C.W.R.J.

    2004-01-01

    This study examined the audiovestibular profile of 11 Wolfram syndrome patients (4 males, 7 females) from 7 families, with identified WFS1 mutations, and the audiometric profile of 17 related heterozygous carriers of WFS1 mutations. Patients with Wolfram syndrome showed a downsloping audiogram and

  16. Impairment of visual function and retinal ER stress activation in Wfs1-deficient mice.

    Directory of Open Access Journals (Sweden)

    Delphine Bonnet Wersinger

    Full Text Available Wolfram syndrome is an early onset genetic disease (1/180,000 featuring diabetes mellitus and optic neuropathy, associated to mutations in the WFS1 gene. Wfs1-/- mouse model shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and histopathology of the retina and optic nerve. Electroretinogram and visual evoked potentials (VEPs were performed in Wfs1-/- and Wfs1+/+ mice at 3, 6, 9 and 12 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC abundance was determined from Brn3a immunolabeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Endoplasmic reticulum stress was assessed using immunoglobulin binding protein (BiP, protein disulfide isomerase (PDI and inositol-requiring enzyme 1 alpha (Ire1α markers. Electroretinograms amplitudes were slightly reduced and latencies increased with time in Wfs1-/- mice. Similarly, VEPs showed decreased N+P amplitudes and increased N-wave latency. Analysis of unfolded protein response signaling revealed an activation of endoplasmic reticulum stress in Wfs1-/- mutant mouse retinas. Altogether, progressive VEPs alterations with minimal neuronal cell loss suggest functional alteration of the action potential in the Wfs1-/- optic pathways.

  17. No association between wolframin gene H611R polymorphism and mood disorders: evidence from 2,570 subjects.

    Science.gov (United States)

    Tang, Xiao-Wu; Wang, Juan; Zou, Yan-Feng

    2015-02-01

    In the past few decades, a number of studies have investigated the association of the wolframin (WFS1) gene H611R polymorphism with mood disorders, but the findings are not always consistent. The objective of the present study is to assess the association between WFS1 gene H611R polymorphism and mood disorders by using a meta-analysis. A comprehensive literature search of PubMed, Excerpta Medica Database, Elsevier Science Direct and China National Knowledge Infrastructure databases was conducted to identify relevant articles, with the last report up to April 15, 2014. Pooled odds ratio (OR) with 95% confidence interval (CI) was estimated. Seven studies including 1318 cases and 1252 controls were selected from potentially relevant articles. This meta-analysis showed that there was no significant association between WFS1 gene H611R polymorphism and mood disorders (R vs. H: OR = 0.93, 95% CI = 0.82-1.05, P = 0.22; HR+ RR vs. HH: OR = 0.98, 95% CI = 0.82-1.17, P = 0.80; RR vs. HH+ HR: OR = 0.84, 95% CI = 0.67-1.04, P = 0.11; RR vs. HH: OR = 0.86, 95% CI = 0.67-1.10, P = 0.24; HR vs. HH: OR = 1.03, 95% CI = 0.78-1.36, P = 0.83). In subgroup analyses by ethnicity, we did not detect any significant association of this polymorphism with mood disorders in Caucasian and Asian populations (P > 0.05). In subgroup analyses by types of mood disorders, we also did not detect any significant association of this polymorphism with bipolar disorder or major depressive disorder (P > 0.05). The results of this meta-analysis suggest that there is no association between WFS1 gene H611R polymorphism and mood disorders.

  18. Circadian rhythms and food anticipatory behavior in Wfs1-deficient mice

    DEFF Research Database (Denmark)

    Luuk, Hendrik; Fahrenkrug, Jan; Hannibal, Jens

    2012-01-01

    in significantly lower body weight and reduced wheel-running activity. Circadian rhythmicity of behavior was normal in Wfs1-deficient mice under ad libitum feeding apart from elongated free-running period in constant light. The amount of food anticipatory activity induced by restricted feeding......The dorsomedial hypothalamic nucleus (DMH) has been proposed as a candidate for the neural substrate of a food-entrainable oscillator. The existence of a food-entrainable oscillator in the mammalian nervous system was inferred previously from restricted feeding-induced behavioral rhythmicity...... reduced or otherwise altered food anticipatory activity. Wfs1 immunoreactivity in DMH was found almost exclusively in the compact part. Restricted feeding induced c-Fos immunoreactivity primarily in the ventral and lateral aspects of DMH and it was similar in both genotypes. Wfs1-deficiency resulted...

  19. Wfs1-deficient mice display altered function of serotonergic system and increased behavioural response to antidepressants

    Directory of Open Access Journals (Sweden)

    Tanel eVisnapuu

    2013-07-01

    Full Text Available It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT and noradrenaline (NA reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioural despair. The tail suspension test (TST and forced swimming test (FST were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 minutes tobrightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.

  20. Identification of a novel WFS1 homozygous nonsense mutation in Jordanian children with Wolfram syndrome

    OpenAIRE

    Khaldon Bodoor; Osama Batiha; Ayman Abu-Awad; Khaldon Al-Sarihin; Haya Ziad; Yousef Jarun; Aya Abu-sheikha; Sara Abu Jalboush; Khoulod S. Alibrahim

    2016-01-01

    Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder characterized by the presentation of early onset type I diabetes mellitus and optic atrophy with later onset diabetes insipidus and deafness. WFS1 gene was identified on chromosome 4p16.1 as the gene responsible for WS disease given that most of the WS patients were found to carry mutations in this gene. This study was carried out to investigate the molecular spectrum of WFS1 gene in Jordanian families. Molecular a...

  1. Progression of low-frequency sensorineural hearing loss (DFNA6/14-WFS1).

    NARCIS (Netherlands)

    Pennings, R.J.E.; Bom, S.J.H.; Cryns, K.; Flothmann, K.; Huygen, P.L.M.; Kremer, J.M.J.; Camp, G. van; Cremers, C.W.R.J.

    2003-01-01

    OBJECTIVE: To assess the audiometric profile and speech recognition characteristics in affected members of 2 families with DFNA6/14 harboring heterozygous mutations in the WFS1 gene that cause an autosomal dominant nonsyndromic sensorineural hearing impairment trait. DESIGN: Family study. SETTING:

  2. Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified

    DEFF Research Database (Denmark)

    Hansen, Lars; Eiberg, Hans Rudolf Lytchoff; Barrett, Timothy

    2005-01-01

    Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing...

  3. Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1.

    Science.gov (United States)

    Duan, Lian; Li, Qian; Tong, An-Li; Mao, Jiang-Feng; Yu, Miao; Yuan, Tao; Chai, Xiao-Feng; Gu, Feng

    2018-01-01

    Wolfram syndrome (WS) is a rare, degenerative, and hereditary disorder characterized by ear diabetes mellitus (DM) and optic atrophy (OA). We aim to characterize clinical features in Chinese patients who had been poorly studied until now. We performed a retrospective review of patients with WS seen in the Peking Union Medical College Hospital from 2002 to 2017. Data including demographic data, clinical presentations, examination results, family history, and genetic analysis were described. Six patients with WS were identified, meeting the diagnostic criteria of the coincidence of DM and OA before 15 years old or the existence of two WFS1 mutations. All were male, with the median age of 14.5 years (range 10-19 years). Blood glucose impairment, OA, and diabetes insipidus were present in all (100%), hearing impairment in four (66.7%), urological abnormalities in four (66.7%), neurological abnormalities in one (16.7%), and endocrine disorder in one (16.7%). Rare presentation includes cataract, glaucoma, and spina bifida occulta. Diabetes was insulin-dependent and not ketosis onset, with antibody to glutamic acid decarboxylase and islet cell negative. Genetic analysis revealed mutations in WFS1 in three patients. A novel frameshift mutation (p.Asp151Glufs*93) was identified in exon 4 of WFS1 . Our series of WS patients indicated that WS is a degenerative disease with a wide and variable spectrum, characterized by ear non-autoimmune DM and bilateral OA. Genetic analysis is recommended when suspected of WS.

  4. Cataract as a phenotypic marker for a mutation in WFS1, the Wolfram syndrome gene.

    Science.gov (United States)

    Titah, Salah Mohamed Cherif; Meunier, Isabelle; Blanchet, Catherine; Lopez, Severine; Rondouin, Gerard; Lenaers, Guy; Amati-Bonneau, Patrizia; Reynier, Pascal; Paquis-Flucklinger, Veronique; Hamel, Christian P

    2012-01-01

    Wolfram syndrome (WS) or diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) (OMIM 222300) is an inherited neurodegenerative disease characterized by diabetes mellitus and optic atrophy as the 2 major criteria, followed later in life by deafness, diabetes insipidus, and various signs of neurologic impairment. The presence of a cataract has been variably mentioned in WS. Two members of a family had thorough ophthalmic examination and their DNA was screened for mutations in mitochondrial DNA, WFS1, OPA1, and OPA3 genes. We report a patient who first had surgery for bilateral cataract at age 5 and who subsequently presented typical signs of WS, i.e., diabetes mellitus, optic atrophy with reduced visual acuity at 20/400 on both eyes at age 22, and mild deafness. The patient was found to be a compound heterozygote for 2 truncating mutations in WFS1, the major WS gene. She carried the previously reported c.1231_1233 delCT and a novel c.2431_2465dup35 mutation. She also was heterozygote for a novel OPA1 sequence variant, c.929A>G in exon 9, whose pathogenicity remains uncertain. The patient's mother was a heterozygous carrier of the c.2431_2465dup35 mutation. She did not have diabetes mellitus or optic atrophy but had bilateral polar cataract. She did not carry the OPA1 sequence variant. Cataract could be a marker for the WFS1 heterozygosity in this family, namely the c.2431_2465dup35 mutation.

  5. Identification of a novel mutation in WFS1 in a family affected by low-frequency hearing impairment

    Energy Technology Data Exchange (ETDEWEB)

    Kunz, Juergen; Marquez-Klaka, Ben; Uebe, Steffen; Volz-Peters, Anja; Berger, Roswitha; Rausch, Peter

    2003-04-09

    Previously we confirmed linkage of autosomal dominantly inherited low-frequency sensorineural hearing impairment (LFSNHI) in a German family to the genetic locus DFNA6/DFNA14 on chromosome 4p16.3 close to the markers D4S432 and D4S431. Analysis of data from the Human Genome Project, showed that WFS1 is located in this region. Mutations in WFS1 are known to be responsible for Wolfram syndrome (DIDMOAD, MIM no. 606201), which follows an autosomal recessive trait. Studies in low-frequency hearing loss families showed that mutations in WFS1 were responsible for the phenotype. In all affected family members analysed, we detected a missense mutation in WFS1 (K705N) and therefore confirm the finding that the majority of mutations responsible for LFSNHI are missense mutations which localise to the C-terminal domain of the protein.

  6. A novel mutation of WFS1 gene in a Chinese patient with Wolfram syndrome: a case report.

    Science.gov (United States)

    Li, Min; Liu, Jia; Yi, Huan; Xu, Li; Zhong, Xiufeng; Peng, Fuhua

    2018-03-17

    Wolfram syndrome (WS), caused by mutations of the Wolfram syndrome 1 (WFS1) gene on chromosome 4p16.1, is an autosomal recessive disorder characterized by diabetes insipidus (DI), neuro-psychiatric disorders, hearing deficit, and urinary tract anomalies. Here we report a 11-year-old Chinese boy who presented with visual loss, was suspected with optic neuritis (ON) or neuromyelitis optica (NMO) and referred to our department for further diagnosis. Finally he was diagnosed with WS because of diabetes mellitus (DM) and optic atrophy (OA). Eight exons and flanking introns of WFS1 gene were analyzed by sequencing. A novel mutation c.1760G > A in WFS1 gene of exon 8 was identified. This report reviews a case of WS associated with a novel mutation, c.1760G > A in WFS1 gene of exon 8, and emphasizes that WS should be taken into account for juveniles with visual loss and diabetes mellitus.

  7. Identification of a novel mutation in WFS1 in a family affected by low-frequency hearing impairment

    International Nuclear Information System (INIS)

    Kunz, Juergen; Marquez-Klaka, Ben; Uebe, Steffen; Volz-Peters, Anja; Berger, Roswitha; Rausch, Peter

    2003-01-01

    Previously we confirmed linkage of autosomal dominantly inherited low-frequency sensorineural hearing impairment (LFSNHI) in a German family to the genetic locus DFNA6/DFNA14 on chromosome 4p16.3 close to the markers D4S432 and D4S431. Analysis of data from the Human Genome Project, showed that WFS1 is located in this region. Mutations in WFS1 are known to be responsible for Wolfram syndrome (DIDMOAD, MIM no. 606201), which follows an autosomal recessive trait. Studies in low-frequency hearing loss families showed that mutations in WFS1 were responsible for the phenotype. In all affected family members analysed, we detected a missense mutation in WFS1 (K705N) and therefore confirm the finding that the majority of mutations responsible for LFSNHI are missense mutations which localise to the C-terminal domain of the protein

  8. Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic beta-cells.

    Science.gov (United States)

    Hatanaka, Masayuki; Tanabe, Katsuya; Yanai, Akie; Ohta, Yasuharu; Kondo, Manabu; Akiyama, Masaru; Shinoda, Koh; Oka, Yoshitomo; Tanizawa, Yukio

    2011-04-01

    Wolfram syndrome is an autosomal recessive disorder characterized by juvenile-onset insulin-dependent diabetes mellitus and optic atrophy. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER) resident transmembrane protein. The Wfs1-null mouse exhibits progressive insulin deficiency causing diabetes. Previous work suggested that the function of the WFS1 protein is connected to unfolded protein response and to intracellular Ca(2+) homeostasis. However, its precise molecular function in pancreatic β-cells remains elusive. In our present study, immunofluorescent and electron-microscopic analyses revealed that WFS1 localizes not only to ER but also to secretory granules in pancreatic β-cells. Intragranular acidification was assessed by measuring intracellular fluorescence intensity raised by the acidotrophic agent, 3-[2,4-dinitroanilino]-3'-amino-N-methyldipropyramine. Compared with wild-type β-cells, there was a 32% reduction in the intensity in WFS1-deficient β-cells, indicating the impairment of granular acidification. This phenotype may, at least partly, account for the evidence that Wfs1-null islets have impaired proinsulin processing, resulting in an increased circulating proinsulin level. Morphometric analysis using electron microscopy evidenced that the density of secretory granules attached to the plasma membrane was significantly reduced in Wfs1-null β-cells relative to that in wild-type β-cells. This may be relevant to the recent finding that granular acidification is required for the priming of secretory granules preceding exocytosis and may partly explain the fact that glucose-induced insulin secretion is profoundly impaired in young prediabetic Wfs1-null mice. These results thus provide new insights into the molecular mechanisms of β-cell dysfunction in patients with Wolfram syndrome.

  9. Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.

    Science.gov (United States)

    Matsunaga, Kimie; Tanabe, Katsuya; Inoue, Hiroshi; Okuya, Shigeru; Ohta, Yasuharu; Akiyama, Masaru; Taguchi, Akihiko; Kora, Yukari; Okayama, Naoko; Yamada, Yuichiro; Wada, Yasuhiko; Amemiya, Shin; Sugihara, Shigetaka; Nakao, Yuzo; Oka, Yoshitomo; Tanizawa, Yukio

    2014-01-01

    Wolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.

  10. Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1

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    Lian Duan

    2018-02-01

    Full Text Available ObjectiveWolfram syndrome (WS is a rare, degenerative, and hereditary disorder characterized by ear diabetes mellitus (DM and optic atrophy (OA. We aim to characterize clinical features in Chinese patients who had been poorly studied until now.MethodsWe performed a retrospective review of patients with WS seen in the Peking Union Medical College Hospital from 2002 to 2017. Data including demographic data, clinical presentations, examination results, family history, and genetic analysis were described.ResultsSix patients with WS were identified, meeting the diagnostic criteria of the coincidence of DM and OA before 15 years old or the existence of two WFS1 mutations. All were male, with the median age of 14.5 years (range 10–19 years. Blood glucose impairment, OA, and diabetes insipidus were present in all (100%, hearing impairment in four (66.7%, urological abnormalities in four (66.7%, neurological abnormalities in one (16.7%, and endocrine disorder in one (16.7%. Rare presentation includes cataract, glaucoma, and spina bifida occulta. Diabetes was insulin-dependent and not ketosis onset, with antibody to glutamic acid decarboxylase and islet cell negative. Genetic analysis revealed mutations in WFS1 in three patients. A novel frameshift mutation (p.Asp151Glufs*93 was identified in exon 4 of WFS1.ConclusionOur series of WS patients indicated that WS is a degenerative disease with a wide and variable spectrum, characterized by ear non-autoimmune DM and bilateral OA. Genetic analysis is recommended when suspected of WS.

  11. c.376G>A mutation in WFS1 gene causes Wolfram syndrome without deafness.

    Science.gov (United States)

    Safarpour Lima, Behnam; Ghaedi, Hamid; Daftarian, Narsis; Ahmadieh, Hamid; Jamshidi, Javad; Khorrami, Mehdi; Noroozi, Rezvan; Sohrabifar, Nasim; Assarzadegan, Farhad; Hesami, Omid; Taghavi, Shaghayegh; Ahmadifard, Azadeh; Atakhorrami, Minoo; Rahimi-Aliabadi, Simin; Shahmohammadibeni, Neda; Alehabib, Elham; Andarva, Monavvar; Darvish, Hossein; Emamalizadeh, Babak

    2016-02-01

    Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn't cause deafness in affected individuals. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. A novel mutation in the WFS1 gene identified in a Taiwanese family with low-frequency hearing impairment

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    Chung Shing-Fang

    2007-05-01

    Full Text Available Abstract Background Wolfram syndrome gene 1 (WFS1 accounts for most of the familial nonsyndromic low-frequency sensorineural hearing loss (LFSNHL which is characterized by sensorineural hearing losses equal to and below 2000 Hz. The current study aimed to contribute to our understanding of the molecular basis of LFSNHL in an affected Taiwanese family. Methods The Taiwanese family with LFSNHL was phenotypically characterized using audiologic examination and pedigree analysis. Genetic characterization was performed by direct sequencing of WFS1 and mutation analysis. Results Pure tone audiometry confirmed that the family members affected with LFSNHL had a bilateral sensorineural hearing loss equal to or below 2000 Hz. The hearing loss threshold of the affected members showed no progression, a characteristic that was consistent with a mutation in the WFS1 gene located in the DFNA6/14/38 locus. Pedigree analysis showed a hereditarily autosomal dominant pattern characterized by a full penetrance. Among several polymorphisms, a missense mutation Y669H (2005T>C in exon 8 of WFS1 was identified in members of a Taiwanese family diagnosed with LFSNHL but not in any of the control subjects. Conclusion We discovered a novel heterozygous missense mutation in exon 8 of WFS1 (i.e., Y669H which is likely responsible for the LFSNHL phenotype in this particular Taiwanese family.

  13. Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.

    Directory of Open Access Journals (Sweden)

    Kimie Matsunaga

    Full Text Available BACKGROUND: Wolfram syndrome (WFS is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1. However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. METHODOLOGY: The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. PRINCIPAL FINDINGS: Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49% having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5% had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5% had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. CONCLUSION/SIGNIFICANCE: This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may

  14. Identification of unsuspected Wolfram syndrome cases through clinical assessment and WFS1 gene screening in type 1 diabetes mellitus patients.

    Science.gov (United States)

    Blanco-Aguirre, Maria E; la Parra, David Rivera-De; Tapia-Garcia, Hugo; Gonzalez-Rodriguez, Johanna; Welschen, Daniela; Welskin, Daniela; Arroyo-Yllanes, Maria Estela; Escudero, Irineo; Nuñez-Hernandez, Jorge A; Medina-Bravo, Patricia; Zenteno, Juan C

    2015-07-15

    Wolfram syndrome (WS) is a severe autosomal recessive pleiotropic disease primarily characterized by the association of juvenile-onset diabetes mellitus and optic atrophy. Earlier reports have shown that a proportion of WS cases may remain unrecognized due to misdiagnosis as type 1 diabetes mellitus (T1DM). The objectives of this work were to estimate the prevalence of patients fulfilling clinical criteria for WS in a cohort of subjects diagnosed as T1DM and to identify causal WFS1 gene mutations in those individuals meeting clinical criteria for the disease. A cohort of 131 unrelated Mexican T1DM patients was collected, including 77 females and 54 males. Additional clinical anomalies suggesting WS were identified through review of medical files, detailed physical examination and/or specialized tests. WFS1 gene analysis was performed using exon-by-exon PCR amplification and direct Sanger sequencing on genomic DNA from patients reaching WS clinical criteria. Clinical criteria for a WS diagnosis were reached in 6 probands, corresponding to a 4.58% frequency of the disease. WFS1 mutations were identified in 4 out of 5 (80%) individuals fulfilling WS clinical criteria, including two homozygous, one compound heterozygous, and one patient with a single allele mutation. No WFS1 mutations were identified in the remaining subject. In our cohort, approximately 6% of cases diagnosed as T1DM were in fact patients with Wolfram syndrome. WFS1 mutations were identified in 4 out of 5 individuals (80%) fulfilling clinical criteria for WS. Clinical and genetic analyses of large cohorts of T1DM patients from different ethnic origins would help to better estimate the occurrence of WS and will lead to a better management of such patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila.

    Science.gov (United States)

    Sakakibara, Yasufumi; Sekiya, Michiko; Fujisaki, Naoki; Quan, Xiuming; Iijima, Koichi M

    2018-01-01

    Wolfram syndrome (WS), caused by loss-of-function mutations in the Wolfram syndrome 1 gene (WFS1), is characterized by juvenile-onset diabetes mellitus, bilateral optic atrophy, and a wide spectrum of neurological and psychiatric manifestations. WFS1 encodes an endoplasmic reticulum (ER)-resident transmembrane protein, and mutations in this gene lead to pancreatic β-cell death induced by high levels of ER stress. However, the mechanisms underlying neurodegeneration caused by WFS1 deficiency remain elusive. Here, we investigated the role of WFS1 in the maintenance of neuronal integrity in vivo by knocking down the expression of wfs1, the Drosophila homolog of WFS1, in the central nervous system. Neuronal knockdown of wfs1 caused age-dependent behavioral deficits and neurodegeneration in the fly brain. Knockdown of wfs1 in neurons and glial cells resulted in premature death and significantly exacerbated behavioral deficits in flies, suggesting that wfs1 has important functions in both cell types. Although wfs1 knockdown alone did not promote ER stress, it increased the susceptibility to oxidative stress-, excitotoxicity- or tauopathy-induced behavioral deficits, and neurodegeneration. The glutamate release inhibitor riluzole significantly suppressed premature death phenotypes induced by neuronal and glial knockdown of wfs1. This study highlights the protective role of wfs1 against age-associated neurodegeneration and furthers our understanding of potential disease-modifying factors that determine susceptibility and resilience to age-associated neurodegenerative diseases.

  16. Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila.

    Directory of Open Access Journals (Sweden)

    Yasufumi Sakakibara

    2018-01-01

    Full Text Available Wolfram syndrome (WS, caused by loss-of-function mutations in the Wolfram syndrome 1 gene (WFS1, is characterized by juvenile-onset diabetes mellitus, bilateral optic atrophy, and a wide spectrum of neurological and psychiatric manifestations. WFS1 encodes an endoplasmic reticulum (ER-resident transmembrane protein, and mutations in this gene lead to pancreatic β-cell death induced by high levels of ER stress. However, the mechanisms underlying neurodegeneration caused by WFS1 deficiency remain elusive. Here, we investigated the role of WFS1 in the maintenance of neuronal integrity in vivo by knocking down the expression of wfs1, the Drosophila homolog of WFS1, in the central nervous system. Neuronal knockdown of wfs1 caused age-dependent behavioral deficits and neurodegeneration in the fly brain. Knockdown of wfs1 in neurons and glial cells resulted in premature death and significantly exacerbated behavioral deficits in flies, suggesting that wfs1 has important functions in both cell types. Although wfs1 knockdown alone did not promote ER stress, it increased the susceptibility to oxidative stress-, excitotoxicity- or tauopathy-induced behavioral deficits, and neurodegeneration. The glutamate release inhibitor riluzole significantly suppressed premature death phenotypes induced by neuronal and glial knockdown of wfs1. This study highlights the protective role of wfs1 against age-associated neurodegeneration and furthers our understanding of potential disease-modifying factors that determine susceptibility and resilience to age-associated neurodegenerative diseases.

  17. Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome

    DEFF Research Database (Denmark)

    Luuk, H.; Koks, S.; Plaas, M.

    2008-01-01

    Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. Patients with Wolfram syndrome display considerable clinical pleiomorphism, and symptoms such as neurological complications and psychiatric...... and psychiatric symptoms found in Wolfram syndrome. Enrichment of Wfs1 protein in the central extended amygdala suggests a role in the modulation of anxiety and fear Udgivelsesdato: 2008/8/20...

  18. [Research progress of mutational spectrum and pathophysiology of WFS1 gene in Wolfram syndrome and nonsyndromic low frequency sensorineural hearing loss].

    Science.gov (United States)

    Shi, S M; Han, Y H; Wang, H B

    2016-09-07

    Compound homozygous or heterozygous mutations in WFS 1 can lead to autosomal recessive Wolfram syndrome (WS), and heterozygous mutations in WFS 1 can lead to autosomal dominant non-syndromic low frequency sensorineural hearing loss (LFSNHL). In addition, mutations in the WFS region has relationship with diabetes and psychiatric diseases. In this paper, we provide an overview of genetic research with different phenotypes, including WS and LFSNHL.

  19. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

    DEFF Research Database (Denmark)

    Rendtorff, Nanna D; Lodahl, Marianne; Boulahbel, Houda

    2011-01-01

    Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare...... that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome....

  20. Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms.

    Science.gov (United States)

    Sobhani, Maryam; Tabatabaiefar, Mohammad Amin; Rajab, Asadollah; Kajbafzadeh, Abdol-Mohammad; Noori-Daloii, Mohammad Reza

    2013-10-10

    Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder that represents a likely source of childhood diabetes especially among countries in the consanguinity belt. The main responsible gene is WFS1 for which over one hundred mutations have been reported from different ethnic groups. The aim of this study was to identify the molecular etiology of WS and to perform a possible genotype-phenotype correlation in Iranian kindred. An Iranian family with two patients was clinically studied and WS was suspected. Genetic linkage analysis via 5 STR markers was carried out. For identification of mutations, DNA sequencing of WFS1 including all the exons, exon-intron boundaries and the promoter was performed. Linkage analysis indicated linkage to the WFS1 region. After DNA sequencing of WFS1, one novel pathogenic mutation, which causes frameshift alteration c.2177_2178insTCTTC (or c.2173_2177dupTCTTC) in exon eight, was found. The genotype-phenotype correlation analysis suggests that the presence of the homozygous mutation may be associated with early onset of disease symptoms. This study stresses the necessity of considering the molecular analysis of WFS1 in childhood diabetes with some symptoms of WS. © 2013 Elsevier B.V. All rights reserved.

  1. Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

    DEFF Research Database (Denmark)

    Sparsø, T; Andersen, G; Albrechtsen, Anders

    2008-01-01

    .025) and decreased 30-min serum insulin levels (p = 0.047) after an oral glucose load. In glucose-tolerant individuals the same allele was associated with increased fasting serum insulin concentration (p = 0.019) and homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.026). To study the complex...... interaction of WFS1 rs734312 on insulin release and insulin resistance we introduced Hotelling's T (2) test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR when stratified according to glucose tolerance status around the means of each WFS1...... rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation on the insulinogenic index and HOMA-IR was significantly associated with the traits (p = 0.0017). CONCLUSIONS/INTERPRETATION: Type 2 diabetes-associated risk alleles of WFS1...

  2. Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome

    DEFF Research Database (Denmark)

    Luuk, H.; Koks, S.; Plaas, M.

    2008-01-01

    , and central auditory pathway. Wf1 expression was also detected in numerous brainstem nuclei and in laminae VIII and IX of the spinal cord. Wfs1-positive nerve fibers were found in the medial forebrain bundle, reticular part of the substantia nigra, globus pallidus, posterior caudate putamen, lateral lemniscus...

  3. Association of the WFS1 gene with disease progression in children with new onset T1D. Results from the Hvidoere study group on childhood diabetes

    DEFF Research Database (Denmark)

    Nielsen, L.B.; Andersen, M.L.M.; Svensson, Jannete

    2010-01-01

    variants the Wolfram syndrome. The aim of this study was to investigate the impact of a common genetic variant (rs10010131) of the WFS1 gene on disease progression in a group of children newly diagnosed with T1D. Methods: The study is a multicenter longitudinal investigation with 18 participating...

  4. Identification of one novel causative mutation in exon 4 of WFS1 gene in two Italian siblings with classical DIDMOAD syndrome phenotype.

    Science.gov (United States)

    Rigoli, Luciana; Lombardo, Fortunato; Salzano, Giuseppina; Di Bella, Chiara; Messina, Maria Francesca; De Luca, Filippo; Iafusco, Dario

    2013-09-10

    The aim of the present paper is to describe a novel missense mutation (G107R) of WFS1 gene that was unexpectedly detected, in two siblings from Southern Italy, outside exon 8; a very unusual finding which has previously been reported only twice in Italian patients with Wolfram syndrome (WS). Although in Spanish pedigrees' WFS1 mutations are frequently located in exon 4, this finding is very infrequent in other pedigrees, particularly in Italian patients. a) our report of two siblings with one novel WSF1 mutation (G107R) expands the molecular spectrum of WS; b) this is the 3rd report of Italian patients harbouring one mutation outside exon 8 and the 2nd with one mutation in exon 4; c) on the basis of the present observations, and literature data we can infer that mutation locations outside exon 8 do not seem to be clearly associated with peculiar phenotype expressions of WFS1 gene. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Dominant ER Stress-InducingWFS1Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.

    Science.gov (United States)

    De Franco, Elisa; Flanagan, Sarah E; Yagi, Takuya; Abreu, Damien; Mahadevan, Jana; Johnson, Matthew B; Jones, Garan; Acosta, Fernanda; Mulaudzi, Mphele; Lek, Ngee; Oh, Vera; Petz, Oliver; Caswell, Richard; Ellard, Sian; Urano, Fumihiko; Hattersley, Andrew T

    2017-07-01

    Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome-causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome. © 2017 by the American Diabetes Association.

  6. Association of aggression with a novel microRNA binding site polymorphism in the wolframin gene.

    Science.gov (United States)

    Kovacs-Nagy, Reka; Elek, Zsuzsanna; Szekely, Anna; Nanasi, Tibor; Sasvari-Szekely, Maria; Ronai, Zsolt

    2013-06-01

    Rare mutations in the WFS1 gene lead to Wolfram syndrome, a severe multisystem disorder with progressive neurodegeneration and diabetes mellitus causing life-threatening complications and premature death. Only a few association studies using small clinical samples tested the possible effects of common WFS1 gene variants on mood disorders and suicide, the non-clinical spectrum has not been studied yet. Self-report data on Aggression, Impulsiveness, Anxiety, and Depression were collected from a large (N = 801) non-psychiatric sample. Single nucleotide polymorphisms (SNPs) were selected to provide an adequate coverage of the entire WFS1 gene, as well as to include putative microRNA binding site polymorphisms. Molecular analysis of the assumed microRNA binding site variant was performed by an in vitro reporter-gene assay of the cloned 3' untranslated region with coexpression of miR-668. Among the 17 WFS1 SNPs, only the rs1046322, a putative microRNA (miR-668) binding site polymorphism showed significant association with psychological dimensions after correction for multiple testing: those with the homozygous form of the minor allele reported higher aggression on the Buss-Perry Aggression Questionnaire (P = 0.0005). Functional effect of the same SNP was also demonstrated in a luciferase reporter system: the minor A allele showed lower repression compared to the major G allele, if co-expressed with miR-668. To our knowledge, this is the first report describing a microRNA binding site polymorphism of the WFS1 gene and its association with human aggression based on a large, non-clinical sample. Copyright © 2013 Wiley Periodicals, Inc.

  7. Clinical and Molecular Genetic Analysis in Three Children with Wolfram Syndrome: A Novel WFS1 Mutation (c.2534T>A).

    Science.gov (United States)

    Çelmeli, Gamze; Türkkahraman, Doğa; Çürek, Yusuf; Houghton, Jayne; Akçurin, Sema; Bircan, İffet

    2017-03-01

    Wolfram syndrome (WS) is an autosomal recessive disorder caused by mutations in WFS1 gene. The clinical features include diabetes insipidus, diabetes mellitus (DM), optic atrophy, deafness, and other variable clinical manifestations. In this paper, we present the clinical and genetic characteristics of 3 WS patients from 3 unrelated Turkish families. Clinical characteristics of the patients and the age of onset of symptoms were quite different in each pedigree. The first two cases developed all symptoms of the disease in their first decade of life. The heterozygous father of case 2 was symptomatic with bilateral deafness. The first ocular finding of one patient (patient 3) was bilateral cataract which was accompanying DM as a first feature of the syndrome. In this patient's family, there were two members with features suggestive of WS. Previously known homozygous mutations, c.460+1G>A in intron 4 and c.1885C>T in exon 8, were identified in these cases. A novel homozygous c.2534T>A mutation was also detected in the exon 8 of WFS1 gene. Because of the rarity and heterogeneity of WS, detection of specific and nonspecific clinical signs including ocular findings and family history in non-autoimmune, insulinopenic diabetes cases should lead to a tentative diagnosis of WS. Genetic testing is required to confirm the diagnosis.

  8. A p.(Glu809Lys) Mutation in the WFS1 Gene Associated with Wolfram-like Syndrome: A Case Report.

    Science.gov (United States)

    Prochazkova, Dagmar; Hruba, Zuzana; Konecna, Petra; Skotakova, Jarmila; Fajkusova, Lenka

    2016-12-01

    Wolfram-like syndrome (WFSL) is a rare autosomal dominant disease characterised by congenital progressive hearing loss, diabetes mellitus, and optic atrophy. The patient was a boy with the juvenile form of diabetes mellitus and findings which clinically matched the symptoms of Wolfram syndrome. At the age of 3 1/4 years, diabetes mellitus was diagnosed in this boy who also had severe psychomotor retardation, failure to thrive, a dysmorphic face with Peters anomaly type 3 (i.e. posterior central defect with stromal opacity of the cornea, adhering stripes of the iris, and cataract with corneolenticular adhesion), congenital glaucoma, megalocornea, severe hearing impairment, a one-sided deformity of the auricle with atresia of the bony and soft external auditory canal, non-differentiable eardrum, missing os incus, hypothyreosis, and nephrocalcinosis. Molecular-genetic examinations revealed a de novo mutation p.(Glu809Lys) in the WFS1 gene. No mutations were detected in the biological parents. The mutation p.(Glu809Lys) in the WFS1 gene is associated with WFSL.

  9. Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility

    Science.gov (United States)

    Haghighi, Amirreza; Haghighi, Alireza; Setoodeh, Aria; Saleh-Gohari, Nasrollah; Astuti, Dewi; Barrett, Timothy G

    2013-01-01

    Wolfram syndrome (WFS) is a neurodegenerative genetic condition characterized by juvenile-onset of diabetes mellitus and optic atrophy. We studied clinical features and the molecular basis of severe WFS (neurodegenerative complications) in two consanguineous families from Iran. A clinical and molecular genetic investigation was performed in the affected and healthy members of two families. The clinical diagnosis of WFS was confirmed by the existence of diabetes mellitus and optic atrophy in the affected patients, who in addition had severe neurodegenerative complications. Sequencing of WFS1 was undertaken in one affected member from each family. Targeted mutations were tested in all members of relevant families. Patients had most of the reported features of WFS. Two affected males in the first family had fathered unaffected children. We identified two homozygous mutations previously reported with apparently milder phenotypes: family 1: c.631G>A (p.Asp211Asn) in exon 5, and family 2: c.1456C>T (p.Gln486*) in exon 8. Heterozygous carriers were unaffected. This is the first report of male Wolfram patients who have successfully fathered children. Surprisingly, they also had almost all the complications associated with WFS. Our report has implications for genetic counseling and family planning advice for other affected families. PMID:22781099

  10. Significant expressivity of Wolfram syndrome: phenotypic assessment of two known and one novel mutation in the WFS1 gene in three Iranian families.

    Science.gov (United States)

    Sobhani, Maryam; Tabatabaiefar, Mohammad Amin; Rajab, Asadollah; Kajbafzadeh, Abdol-Mohammad; Noori-Daloii, Mohammad Reza

    2014-11-01

    Wolfram syndrome also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is a rare neurodegenerative autosomal recessive disorder. There is evidence of variable expressivity both in patients and heterozygous carriers. In this study, we describe three Persian Wolfram syndrome families with differences in the age of onset, signs and symptoms of the disease. We clinically evaluated affected families for verifying WS clinical diagnosis. After linkage analysis via 5 STR markers, molecular analysis for WFS1 was performed by direct sequencing for patients and available family members. Three homozygous mutations were identified including c.1885 C>T, c.2205C>A both in exon 8 and c.460+1G>A in intron 4. The mutation c.2205C>A was found to be novel. We report interesting phenotype-genotype correlations: homozygous c.1885C>T and c.2205C>A variants were correlated with quite different disease severity and onset in the siblings. We report a rare case of WS with homozygous c.1885C>T who is married and has a healthy child. c.460+1G>A showed a possible partial dominant inheritance put forth by a heterozygous parent showing partial WS symptoms while her daughter displayed typical WS symptoms. Due to variable expressivity, detailed clinical examination and molecular diagnostics should be used to confirm WS and a more exact recurrence risk data.

  11. Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility.

    Science.gov (United States)

    Haghighi, Amirreza; Haghighi, Alireza; Setoodeh, Aria; Saleh-Gohari, Nasrollah; Astuti, Dewi; Barrett, Timothy G

    2013-03-01

    Wolfram syndrome (WFS) is a neurodegenerative genetic condition characterized by juvenile-onset of diabetes mellitus and optic atrophy. We studied clinical features and the molecular basis of severe WFS (neurodegenerative complications) in two consanguineous families from Iran. A clinical and molecular genetic investigation was performed in the affected and healthy members of two families. The clinical diagnosis of WFS was confirmed by the existence of diabetes mellitus and optic atrophy in the affected patients, who in addition had severe neurodegenerative complications. Sequencing of WFS1 was undertaken in one affected member from each family. Targeted mutations were tested in all members of relevant families. Patients had most of the reported features of WFS. Two affected males in the first family had fathered unaffected children. We identified two homozygous mutations previously reported with apparently milder phenotypes: family 1: c.631G>A (p.Asp211Asn) in exon 5, and family 2: c.1456C>T (p.Gln486*) in exon 8. Heterozygous carriers were unaffected. This is the first report of male Wolfram patients who have successfully fathered children. Surprisingly, they also had almost all the complications associated with WFS. Our report has implications for genetic counseling and family planning advice for other affected families.

  12. Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in Type 2 Diabetes in a Chinese population

    Directory of Open Access Journals (Sweden)

    Zhou Xianghai

    2010-05-01

    Full Text Available Abstract Background Recently, several genome-wide and candidate gene association studies have identified many novel genetic loci for type 2 diabetes (T2D; among these genes, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 are the most important. We aimed to determine the effects of these genetic loci associated with T2D in the Chinese Han population of China. Methods Single-nucleotide polymorphisms (SNPs in or near CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 genes were genotyped in a case-control Chinese Han sample living in Beijing, China involving 1024 patients with T2D and 1005 control subjects. Results In Chinese Han, we replicated the associations between 7 genetic loci and T2D, with risk allele-specific odds ratios (ORs as follows: 1.27 (95% CI, 1.11-1.45; p = 0.0008 for CDKAL1-rs10946398, 1.26 (95% CI, 1.08-1.47; p = 0.003 for IGF2BP2-rs4402960, 1.19 (95% CI, 1.04-1.37; p = 0.009 for SLC30A8-rs13266634, 1.22 (95% CI, 1.06-1.41; p = 0.005 for CDKN2A/B-rs10811661, 1.20 (95% CI, 1.01-1.42; p = 0.03 for HHEX-rs5015480, 1.37 (95% CI, 1.19-1.69; p = 1.0 × 10-4 for KCNQ1-rs2237892, and 1.24 (95% CI, 1.01-1.52; p = 0.046 for FTO-rs8050136 after adjustment for age, gender, and body mass index. Not only did an association between WFS1-rs6446482 and early-onset T2D exist in the subgroup analysis, but TCF2-rs7501939 and WFS1-rs6446482 were also confirmed to confer risk for T2D in this meta-analysis. Moreover, the relationship between FTO-rs8050136 and body mass index, together with the effect of CDKAL1-rs10946398 on beta cell function, was also observed in the control individuals. Conclusions Our findings support the important contribution of these genetic loci to susceptibility for T2D in the Chinese Han population in Beijing of China.

  13. Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

    Science.gov (United States)

    Cheurfa, N; Brenner, G M; Reis, A F; Dubois-Laforgue, D; Roussel, R; Tichet, J; Lantieri, O; Balkau, B; Fumeron, F; Timsit, J; Marre, M; Velho, G

    2011-03-01

    We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

  14. A new mutation in WFS1 gene (C.1522-1523delTA, Y508fsX421) may be responsible for early appearance of clinical features of Wolfram syndrome and suicidal behaviour.

    Science.gov (United States)

    Aluclu, Mehmet Ufuk; Bahceci, Mithat; Tuzcu, Alpaslan; Arikan, Senay; Gokalp, Deniz

    2006-12-01

    Wolfram syndrome (WS) is an autosomal recessive disorder characterized by the association of juvenile-onset diabetes mellitus and optic atrophy. It is also known by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). We diagnosed Wolfram syndrome in 2 male siblings and determined a new mutation (c. 1522-1523delTA, Y508fsX421). Both affected siblings were homozygous, other family members were heterozygous. Dilated renal outflow tracts in the third decade, and neuropsychiatric disorders including bipolar disorder and neurosensorial deafness appear in the fourth decade in ordinary WS, whereas these features appeared in second decade in our patients. This mutation may be responsible for early appearance of dilated renal outflow tracts and multiple neurological abnormalities. Psychiatric disturbances such as suicide were reported at increased frequency in Wolfram patients and in heterozygous carriers. Suicidal behaviour occurred in our patients when they were yet 11 and 13 years old. Therefore, our findings may indicate that there may be a relationship between this WFS1 mutation and mood disorder such as suicidal behaviour. We determined a new mutation (c. 1522-1523delTA, Y508fsX421) in WS1 gene in 2 siblings with Wolfram syndrome. This mutation may be responsible for early appearance of clinical features of Wolfram syndrome, and there may be a relationship between this mutation and suicidal behaviour.

  15. False diagnosis of type 1 diabetes mellitus and its complications in Wolfram syndrome--is it the reason for the low number of reported cases of this abnormality?

    Science.gov (United States)

    Homa, Katarzyna; Stefański, Adam; Zmysłowska, Agnieszka; Molęda, Piotr; Bryśkiewicz, Marta Ewa; Majkowska, Liliana

    2014-01-01

    Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a rare autosomal recessive syndrome (1/770,000 in the United Kingdom), characterised by juvenile onset of diabetes mellitus, optic nerve atrophy, diabetes insipidus, sensorineural deafness, renal tract and neurological abnormalities, and primary gonadal atrophy. WS is caused mainly by biallelic mutations in the WFS1 gene, which encodes wolframin. Wide tissue distribution of wolframin and many mutations in the wolframin gene resulting in Wolfram syndrome may contribute to different phenotypes and the unusual combinations of clinical features. We describe a female patient with Wolfram syndrome diagnosed at the age of 25, with a previous false diagnosis of type 1 diabetes mellitus and misdiagnosed diabetic complications. The patient was found to be a compound heterozygote for two novel mutations in exon 8 of WFS1 gene: a 2-bp deletion AT at nt 1539 leading to a frameshift (Y513fs) and a single-base substitution 1174C > T resulting in a stop codon (Q392X). A detailed analysis of the patient's medical history and a review of the literature suggest that many cases of Wolfram syndrome may remain undiagnosed due to misdiagnosis as type 1 diabetes mellitus and incorrect interpretation of clinical symptoms of neurodegenerative abnormalities, especially in their early stages.

  16. Differential promoter activity by nucleotide substitution at a type 2 diabetes genome-wide association study signal upstream of the wolframin gene.

    Science.gov (United States)

    Ryu, Jihye; Lee, Chaeyoung

    2016-03-01

    Functional knowledge of most genetic variants identified from genome-wide association studies (GWAS) for type 2 diabetes (T2D) is limited. A recent T2D GWAS revealed an association signal (rs4689388) upstream of the gene encoding Wolfram syndrome 1 (WFS1) whose intrinsic nucleotide variants had been previously associated with T2D in several candidate gene analyses. The aim of the present study was to identify functional variants of the GWAS signal. Promoter activity of luciferase reporter constructs was compared with haplotypes including variants composing a linkage disequilibrium block in the vicinity of rs4689388 in HEK293 and HepG2 cells. Promoter activity was highest with the most frequent haplotype (H1; ATCGT) and lowest with second most frequent haplotype (H2; GATCG), whose nucleotide alleles were all complementary to those of H1. Further analysis with artificial haplotypes revealed differential transcriptional activity by nucleotide substitution of rs4320200, rs13107806, or rs13127445 (P WFS1 by nucleotide substitution. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  17. Partial deletion 11q

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Tommerup, N; Sørensen, F B

    1995-01-01

    We describe the cytogenetic findings and the dysmorphic features in a stillborn girl with a large de novo terminal deletion of the long arm of chromosome 11. The karyotype was 46,XX,del(11)(q21qter). By reviewing previous reports of deletion 11q, we found that cleft lip and palate are most...... frequently seen in proximal 11q deletions involving 11q21. Telomeric staining using the PRINS technique demonstrated normal telomeric sequences in the deleted chromosome 11....

  18. Partial deletion 11q

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Tommerup, N; Sørensen, F B

    1995-01-01

    We describe the cytogenetic findings and the dysmorphic features in a stillborn girl with a large de novo terminal deletion of the long arm of chromosome 11. The karyotype was 46,XX,del(11)(q21qter). By reviewing previous reports of deletion 11q, we found that cleft lip and palate are most...

  19. Schizophrenia and chromosomal deletions

    Energy Technology Data Exchange (ETDEWEB)

    Lindsay, E.A.; Baldini, A. [Baylor College of Medicine, Houston, TX (United States); Morris, M. A. [Univ. of Geneva School of Medicine, NY (United States)] [and others

    1995-06-01

    Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

  20. Quantum deletion: Beyond the no-deletion principle

    International Nuclear Information System (INIS)

    Adhikari, Satyabrata

    2005-01-01

    Suppose we are given two identical copies of an unknown quantum state and we wish to delete one copy from among the given two copies. The quantum no-deletion principle restricts us from perfectly deleting a copy but it does not prohibit us from deleting a copy approximately. Here we construct two types of a 'universal quantum deletion machine' which approximately deletes a copy such that the fidelity of deletion does not depend on the input state. The two types of universal quantum deletion machines are (1) a conventional deletion machine described by one unitary operator and (2) a modified deletion machine described by two unitary operators. Here it is shown that the modified deletion machine deletes a qubit with fidelity 3/4, which is the maximum limit for deleting an unknown quantum state. In addition to this we also show that the modified deletion machine retains the qubit in the first mode with average fidelity 0.77 (approx.) which is slightly greater than the fidelity of measurement for two given identical states, showing how precisely one can determine its state [S. Massar and S. Popescu, Phys. Rev. Lett. 74, 1259 (1995)]. We also show that the deletion machine itself is input state independent, i.e., the information is not hidden in the deleting machine, and hence we can delete the information completely from the deletion machine

  1. Molecular characterization of WFS1 in patients with Wolfram syndrome.

    NARCIS (Netherlands)

    Ouweland, J.M.W. van den; Cryns, K.; Pennings, R.J.E.; Walraven, I.; Janssen, G.M.; Maassen, J.A.; Veldhuijzen, B.F.; Arntzenius, A.B.; Lindhout, D.; Cremers, C.W.R.J.; Camp, G. van; Dikkeschei, L.D.

    2003-01-01

    Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

  2. Molecular characterization of WFS1 in patients with Wolfram syndrome

    NARCIS (Netherlands)

    Van den Ouweland, JMW; Cryns, K; Pennings, RJE; Walraven, [No Value; Janssen, GMC; Maassen, JA; Veldhuijzen, BFE; Arntzenius, AB; Lindhout, D; Cremers, CWRJ; Van Camp, G; Dikkeschei, LD

    Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

  3. (AJST) GENERALISED DELETION DESIGNS

    African Journals Online (AJOL)

    th row if the t-th level is deleted from factor Fj in the preliminary design d-p to obtain d and xss j is an s x s permutation matrix with 1 in the aj - th column of the o-th row. We shall also write j j a j j. * a. cDPDc d j j. ′. ′= (3.2) where cj is a contrast ...

  4. Deletions of the mitochondrial genome.

    Science.gov (United States)

    Harding, A E; Hammans, S R

    1992-01-01

    Single large deletions of mitochondrial DNA are found in the muscle of about 40% of patients with mitochondrial myopathies, and are detectable in both blood and muscle in Pearson syndrome. In mitochondrial myopathies, there is a close association between the presence of deletions and involvement of extra-ocular muscles, together with other features of the Kearns-Sayre syndrome. Deletions appear to arise as fresh mutations in the vast majority of patients and are often flanked by direct repeats up to 13 nucleotides in length. They should affect translation of all mitochondrially encoded components of the respiratory chain, but there is evidence to suggest that intramitochondrial complementation occurs in some cases.

  5. Strategies for state-dependent quantum deleting

    International Nuclear Information System (INIS)

    Song Wei; Yang Ming; Cao Zhuoliang

    2004-01-01

    A quantum state-dependent quantum deleting machine is constructed. We obtain a upper bound of the global fidelity on N-to-M quantum deleting from a set of K non-orthogonal states. Quantum networks are constructed for the above state-dependent quantum deleting machine when K=2. Our deleting protocol only involves a unitary interaction among the initial copies, with no ancilla. We also present some analogies between quantum cloning and deleting

  6. Pregnancy: Comparison among Physiological and Pathological States

    Directory of Open Access Journals (Sweden)

    Angela Lucariello

    2014-01-01

    Full Text Available The WFS1 gene, encoding a transmembrane glycoprotein of the endoplasmic reticulum called wolframin, is mutated in Wolfram syndrome, an autosomal recessive disorder defined by the association of diabetes mellitus, optic atrophy, and further organ abnormalities. Disruption of the WFS1 gene in mice causes progressive β-cell loss in the pancreas and impaired stimulus-secretion coupling in insulin secretion. However, little is known about the physiological functions of this protein. We investigated the immunohistochemical expression of wolframin in human placenta throughout pregnancy in normal women and diabetic pregnant women. In normal placenta, there was a modulation of wolframin throughout pregnancy with a strong level of expression during the first trimester and a moderate level in the third trimester of gestation. In diabetic women, wolframin expression was strongly reduced in the third trimester of gestation. The pattern of expression of wolframin in normal placenta suggests that this protein may be required to sustain normal rates of cytotrophoblast cell proliferation during the first trimester of gestation. The decrease in wolframin expression in diabetic placenta suggests that this protein may participate in maintaining the physiologic glucose homeostasis in this organ.

  7. 76 FR 9555 - Procurement List; Proposed Deletions

    Science.gov (United States)

    2011-02-18

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed deletions from the Procurement...'Day Act (41 U.S.C. 46- 48c) in connection with the products proposed for deletion from the Procurement...

  8. 78 FR 56679 - Procurement List; Deletions

    Science.gov (United States)

    2013-09-13

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Deletions from the Procurement List. SUMMARY: This action deletes products from the Procurement List previously furnished by nonprofit agencies employing...

  9. 1p36 deletion syndrome: an update

    Directory of Open Access Journals (Sweden)

    Jordan VK

    2015-08-01

    Full Text Available Valerie K Jordan,1 Hitisha P Zaveri,2 Daryl A Scott1,2 1Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Abstract: Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes. Keywords: chromosome 1p36, chromosome deletion, 1p36 deletion syndrome, monosomy 1p36

  10. 78 FR 68823 - Procurement List Deletions

    Science.gov (United States)

    2013-11-15

    ...'Day Act (41 U.S.C. 8501-8506) in connection with the products and services deleted from the... Center, Chicago, IL. Service Type/Location: Janitorial/Custodial Service, Gamelin USARC, 10 Asylum Road... COMMITTEE FOR PURCHASE FROM PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Deletions...

  11. Seven gene deletions in seven days

    DEFF Research Database (Denmark)

    Ingemann Jensen, Sheila; Lennen, Rebecca; Herrgard, Markus

    2015-01-01

    genes and a rhamnose inducible flippase recombinase was constructed to facilitate fast marker-free deletions. To further speed up the procedure, we integrated the arabinose inducible lambda Red recombineering genes and the rhamnose inducible FLP into the genome of E. coli K-12 MG1655. This system...... in which four to seven genes were deleted in E. coli W and E. coli K-12. The growth rate of an E. coli K-12 quintuple deletion strain was significantly improved in the presence of high concentrations of acetate and NaCl. In conclusion, we have generated a method that enables efficient and simultaneous...... deletion of multiple genes in several E. coli variants. The method enables deletion of up to seven genes in as little as seven days....

  12. Probabilistic cloning and deleting of quantum states

    International Nuclear Information System (INIS)

    Feng Yuan; Zhang Shengyu; Ying Mingsheng

    2002-01-01

    We construct a probabilistic cloning and deleting machine which, taking several copies of an input quantum state, can output a linear superposition of multiple cloning and deleting states. Since the machine can perform cloning and deleting in a single unitary evolution, the probabilistic cloning and other cloning machines proposed in the previous literature can be thought of as special cases of our machine. A sufficient and necessary condition for successful cloning and deleting is presented, and it requires that the copies of an arbitrarily presumed number of the input states are linearly independent. This simply generalizes some results for cloning. We also derive an upper bound for the success probability of the cloning and deleting machine

  13. Genetics Home Reference: distal 18q deletion syndrome

    Science.gov (United States)

    ... Health Conditions Distal 18q deletion syndrome Distal 18q deletion syndrome Printable PDF Open All Close All Enable ... view the expand/collapse boxes. Description Distal 18q deletion syndrome is a chromosomal condition that occurs when ...

  14. Genetics Home Reference: proximal 18q deletion syndrome

    Science.gov (United States)

    ... Health Conditions Proximal 18q deletion syndrome Proximal 18q deletion syndrome Printable PDF Open All Close All Enable ... view the expand/collapse boxes. Description Proximal 18q deletion syndrome is a chromosomal condition that occurs when ...

  15. 19 CFR 142.49 - Deletion of C-4 Code.

    Science.gov (United States)

    2010-04-01

    .... Entry filers may delete C-4 Codes from Line Release by notifying the port director in writing on a Deletion Data Loading Sheet. Such notification shall state the C-4 Code which is to be deleted, the port... TREASURY (CONTINUED) ENTRY PROCESS Line Release § 142.49 Deletion of C-4 Code. (a) By Customs. A port...

  16. 78 FR 17641 - Procurement List; Proposed Addition and Deletion

    Science.gov (United States)

    2013-03-22

    ... Addition and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed Addition to and Deletion from the Procurement List. SUMMARY: The Committee is proposing to add a..., Washington, DC Deletion The following product is proposed for deletion from the Procurement List: Product...

  17. 46 CFR 67.171 - Deletion; requirement and procedure.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Deletion; requirement and procedure. 67.171 Section 67...; Requirement for Exchange, Replacement, Deletion, Cancellation § 67.171 Deletion; requirement and procedure. (a... provided in § 67.161, and the vessel is subject to deletion from the roll of actively documented vessels...

  18. 78 FR 54871 - Procurement List; Proposed Additions and Deletion

    Science.gov (United States)

    2013-09-06

    ... Additions and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed additions to and deletions from the Procurement List. SUMMARY: The Committee is proposing to add... by the Defense Commissary Agency. Deletion The following product is proposed for deletion from the...

  19. Rapid deletion production in fungi via Agrobacterium mediated transformation of OSCAR deletion contructs.

    Science.gov (United States)

    Precise deletion of gene(s) of interest, while leaving the rest of the genome unchanged, provides the ideal product to determine that particular gene’s function in the living organism. In this protocol we describe the OSCAR method of precise and rapid deletion plasmid construction. OSCAR relies on t...

  20. Somatic mosaicism for a DMD gene deletion

    Energy Technology Data Exchange (ETDEWEB)

    Saito, Kayoko; Ikeya, Kiyoko; Kondo, Eri [Tokyo Women`s Medical College (Japan)] [and others

    1995-03-13

    Mosaicism is a mixed state, with two cell populations of different genetic origins caused by a cell mutation occurring after fertilization. In the present case, DNA analysis of lymphocytes led to a DMD diagnosis before death. Postmortem immunocytochemical and DNA analysis showed somatic mosaicism. At age 18 years, blood lymphocyte DNA analysis showed a DMD gene deletion, upstream from exon 7 to the 5{prime} end containing both muscle and brain promoters. As the patient`s mother and elder sister had no deletions, he was considered to have a new mutation. Immunocytochemical studies of postmortem tissues showed that dystrophin was absent from the tongue, deltoid, intercostal, psoas and rectus femoris muscles, but there was a mix of dystrophin-positive and negative fibers in the rectus abdominis, cardiac, temporalis and sternocleidomastoid muscles. All diaphragm cells were dystrophin positive. Polymerase chain reaction (PCR) amplification from all tissues except the temporalis and sternocleidomastoid muscles, diaphragm and kidney, in which no deletion was found, showed the deletion from at least exon 6 to the 5{prime} end containing both muscle and brain promoters. In this case, a genomic deletion of the DMD gene contributed to the formation of tissues derived from both ectoderm and endoderm, and cells of mesodermal origin showed genotypic and phenotypic heterogeneity. Our results indicate a mutation of the present case may have occurred just before the period of germ layer formation. 34 refs., 7 figs.

  1. Wolfram syndrome 1 and Wolfram syndrome 2.

    Science.gov (United States)

    Rigoli, Luciana; Di Bella, Chiara

    2012-08-01

    Wolfram syndrome 1 (WS1) is an autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DI DM OA D syndrome) associated with other variable clinical manifestations. The causative gene for WS1 (WFS1) encoding wolframin maps to chromosome 4p16.1. Wolframin has an important function in maintaining the homeostasis of the endoplasmic reticulum (ER) in pancreatic β cells. Recently, another causative gene, CISD2, has been identified in patients with a type of Wolfram syndrome (WS2) resulting in early optic atrophy, diabetes mellitus, deafness, decreased lifespan, but not diabetes insipidus. The CISD2-encoded protein ERIS (endoplasmic reticulum intermembrane small protein) also localizes to ER, but does not interact directly with wolframin. ERIS maps to chromosome 4q22. Numerous studies have shown an interesting similarity between WFS1 and CISD2 genes. Experimental studies demonstrated that the Cisd2 knockout (Cisd2) mouse shows premature aging and typical symptoms of Wolfram syndrome. These researches provide interesting insight into the relation of neurodegenerative diseases, mitochondrial disorders, and autophagy and are useful for the pathophysiological understanding of both Wolfram syndrome and mitochondrial-mediated premature aging. The knowledge of WS1 and WS2 pathogenesis, and of the interactions between WFS1 and CISD2 genes, is useful for accurate diagnostic classification and for diagnosis of presymptomatic individuals.

  2. 9q22 Deletion - First Familial Case

    Directory of Open Access Journals (Sweden)

    Yamamoto Toshiyuki

    2011-06-01

    Full Text Available Abstract Background Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400 due to haploinsufficiency of the PTCH1 gene (MIM *601309. Methods and Results We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K. The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337 which causing both brachydactyly type 1 (MIM #113000 and Robinow syndrome (MIM #268310, and the immunologically active SYK gene (MIM *600085. The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations. Conclusions This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling.

  3. Deletion 22q13.3 syndrome

    Directory of Open Access Journals (Sweden)

    Phelan Mary C

    2008-05-01

    Full Text Available Abstract The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The diagnosis of deletion 22q13 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH or array comparative genomic hybridization (CGH is recommended for confirmation. Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like affect (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders, cerebral palsy. Genetic counseling is recommended and parental laboratory studies should be considered to identify cryptic rearrangements and detect parental mosaicism. Prenatal diagnosis should be offered for future pregnancies in those families with inherited rearrangements

  4. Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

    NARCIS (Netherlands)

    Wheeler, Heather E.; Gamazon, Eric R.; Frisina, Robert D.; Perez-Cervantes, Carlos; El Charif, Omar; Mapes, Brandon; Fossa, Sophie D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Fung, Chunkit; Kollmannsberger, Christian; Kim, Jeri; Mushiroda, Taisei; Kubo, Michiaki; Ardeshir-Rouhani-Fard, Shirin; Einhorn, Lawrence H.; Cox, Nancy J.; Dolan, M. Eileen; Travis, Lois B.

    2017-01-01

    Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).Experimental Design: We performed a genome-wide association study (GWAS) of CAO using

  5. Some analogies between quantum cloning and quantum deleting

    International Nuclear Information System (INIS)

    Qiu Daowen

    2002-01-01

    We further verify the impossibility of deleting an arbitrary unknown quantum state, and also show it is impossible to delete two nonorthogonal quantum states as a consequence of unitarity of quantum mechanics. A quantum approximate (deterministic) deleting machine and a probabilistic (exact) deleting machine are constructed. The estimation for the global fidelity characterizing the efficiency of the quantum approximate deleting is given. We then demonstrate that unknown nonorthogonal states chosen from a set with their multiple copies can evolve into a linear superposition of multiple deletions and failure branches by a unitary process if and only if the states are linearly independent. It is notable that the proof for necessity is somewhat different from Pati's [Phys. Rev. Lett. 83, 2849 (1999)]. Another deleting machine for the input states that are unnecessarily linearly independent is also presented. The bounds on the success probabilities of these deleting machines are derived. So we expound some preliminary analogies between quantum cloning and deleting

  6. Genetic forms of neurohypophyseal diabetes insipidus.

    Science.gov (United States)

    Rutishauser, Jonas; Spiess, Martin; Kopp, Peter

    2016-03-01

    Neurohypophyseal diabetes insipidus is characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although in most patients non-hereditary causes underlie the disorder, genetic forms have long been recognized and studied both in vivo and in vitro. In most affected families, the disease is transmitted in an autosomal dominant manner, whereas autosomal recessive forms are much less frequent. Both phenotypes can be caused by mutations in the vasopressin-neurophysin II (AVP) gene. In transfected cells expressing dominant mutations, the mutated hormone precursor is retained in the endoplasmic reticulum, where it forms fibrillar aggregates. Autopsy studies in humans and a murine knock-in model suggest that the dominant phenotype results from toxicity to vasopressinergic neurons, but the mechanisms leading to cell death remain unclear. Recessive transmission results from AVP with reduced biologic activity or the deletion of the locus. Genetic neurohypophyseal diabetes insipidus occurring in the context of diabetes mellitus, optic atrophy, and deafness is termed DIDMOAD or Wolfram syndrome, a genetically and phenotypically heterogeneous autosomal recessive disorder caused by mutations in the wolframin (WFS 1) gene. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Variable immune deficiency related to deletion size in chromosome 22q11.2 deletion syndrome.

    Science.gov (United States)

    Crowley, Blaine; Ruffner, Melanie; McDonald McGinn, Donna M; Sullivan, Kathleen E

    2018-01-17

    The clinical features of 22q11.2 deletion syndrome include virtually every organ of the body. This review will focus on the immune system and the differences related to deletion breakpoints. A hypoplastic thymus was one of the first features described in this syndrome and low T cell counts, as a consequence of thymic hypoplasia, are the most commonly described immunologic feature. These are most prominently seen in early childhood and can be associated with increased persistence of viruses. Later in life, evidence of T cell exhaustion may be seen and secondary deficiencies of antibody function have been described. The relationship of the immunodeficiency to the deletion breakpoints has been understudied due to the infrequent analysis of people carrying smaller deletions. This manuscript will review the immune deficiency in 22q11.2 deletion syndrome and describe differences in the T cell counts related to the deletion breakpoints. Distal, non-TBX1 inclusive deletions, were found to be associated with better T cell counts. Another new finding is the relative preservation of T cell counts in those patients with a 22q11.2 duplication. © 2018 Wiley Periodicals, Inc.

  8. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects.

    Science.gov (United States)

    Varela, Monica Castro; Kok, Fernando; Otto, Paulo Alberto; Koiffmann, Celia Priszkulnik

    2004-12-01

    Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

  9. Nature of frequent deletions in CEBPA.

    Science.gov (United States)

    Fuchs, Ota; Kostecka, Arnost; Provaznikova, Dana; Krasna, Blazena; Brezinova, Jana; Filkukova, Jitka; Kotlin, Roman; Kouba, Michal; Kobylka, Petr; Neuwirtova, Radana; Jonasova, Anna; Caniga, Miroslav; Schwarz, Jiri; Markova, Jana; Maaloufova, Jacqueline; Sponerova, Dana; Novakova, Ludmila; Cermak, Jaroslav

    2009-01-01

    C/EBPalpha (CCAAT/enhancer binding protein alpha) belongs to the family of leucine zipper transcription factors and is necessary for transcriptional control of granulocyte, adipocyte and hepatocyte differentiation, glucose metabolism and lung development. C/EBPalpha is encoded by an intronless gene. CEBPA mutations cause a myeloid differentiation block and were detected in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma and non-Hodgkin's lymphoma (NHL) patients. In this study we identified in 41 individuals from 824 screened individuals (290 AML patients, 382 MDS patients, 56 NHL patients and 96 healthy individuals) a single class of 23 deletions in CEBPA gene which involved a direct repeat of at least 2 bp. These mutations are characterised by the loss of one of two same repeats at the ends of deleted sequence. Three most frequent repeats included in these deletions in CEBPA gene are CGCGAG (493-498_865-870), GCCAAGCAGC (508-517_907-916) and GG (486-487_885-886), all according to GenBank accession no. NM_004364.2. A mechanism for deletion formation between two repetitive sequences can be recombination events in the repair process. Double-stranded cut in DNA can initiate these recombination events of adjacent DNA sequences.

  10. Obtaining a Proportional Allocation by Deleting Items

    NARCIS (Netherlands)

    Dorn, B.; de Haan, R.; Schlotter, I.; Röthe, J.

    2017-01-01

    We consider the following control problem on fair allocation of indivisible goods. Given a set I of items and a set of agents, each having strict linear preference over the items, we ask for a minimum subset of the items whose deletion guarantees the existence of a proportional allocation in the

  11. 22q11.2 deletion syndrome

    NARCIS (Netherlands)

    McDonald-McGinn, Donna M.; Sullivan, Kathleen E.; Marino, Bruno; Philip, Nicole; Swillen, Ann; Vorstman, Jacob A S; Zackai, Elaine H.; Emanuel, Beverly S.; Vermeesch, Joris R.; Morrow, Bernice E.; Scambler, Peter J.; Bassett, Anne S.

    2015-01-01

    22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of

  12. Sequence analysis of 17 NRXN1 deletions

    DEFF Research Database (Denmark)

    Hoeffding, Louise Kristine Enggaard; Hansen, Thomas; Ingason, Andrés

    2014-01-01

    into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism...

  13. Union-Find with Constant Time Deletions

    DEFF Research Database (Denmark)

    Alstrup, Stephen; Thorup, Mikkel; Gørtz, Inge Li

    2014-01-01

    operations performed, and α_M/N_(n) is a functional inverse of Ackermann’s function. They left open the question whether delete operations can be implemented more efficiently than find operations, for example, in o(log n) worst-case time. We resolve this open problem by presenting a relatively simple...

  14. Delayed chromosomal instability caused by large deletion

    International Nuclear Information System (INIS)

    Ojima, M.; Suzuki, K.; Kodama, S.; Watanabe, M.

    2003-01-01

    Full text: There is accumulating evidence that genomic instability, manifested by the expression of delayed phenotypes, is induced by X-irradiation but not by ultraviolet (UV) light. It is well known that ionizing radiation, such as X-rays, induces DNA double strand breaks, but UV-light mainly causes base damage like pyrimidine dimers and (6-4) photoproducts. Although the mechanism of radiation-induced genomic instability has not been thoroughly explained, it is suggested that DNA double strand breaks contribute the induction of genomic instability. We examined here whether X-ray induced gene deletion at the hprt locus induces delayed instability in chromosome X. SV40-immortalized normal human fibroblasts, GM638, were irradiated with X-rays (3, 6 Gy), and the hprt mutants were isolated in the presence of 6-thioguanine (6-TG). A 2-fold and a 60-fold increase in mutation frequency were found by 3 Gy and 6 Gy irradiation, respectively. The molecular structure of the hprt mutations was determined by multiplex polymerase chain reaction of nine exons. Approximately 60% of 3 Gy mutants lost a part or the entire hprt gene, and the other mutants showed point mutations like spontaneous mutants. All 6 Gy mutants show total gene deletion. The chromosomes of the hprt mutants were analyzed by Whole Human Chromosome X Paint FISH or Xq telomere FISH. None of the point or partial gene deletion mutants showed aberrations of X-chromosome, however total gene deletion mutants induced translocations and dicentrics involving chromosome X. These results suggest that large deletion caused by DNA double strand breaks destabilizes chromosome structure, which may be involved in an induction of radiation-induced genomic instability

  15. 78 FR 29119 - Procurement List; Additions and Deletion

    Science.gov (United States)

    2013-05-17

    ... and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and Deletion from the Procurement List. SUMMARY: This action adds products and services to the... Activity: Washington Headquarters Services (WHS), Acquisition Directorate, Washington, DC. Deletion On 4/5...

  16. 75 FR 41451 - Procurement List; Proposed Additions and Deletion

    Science.gov (United States)

    2010-07-16

    ... Additions and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed additions to and deletion from the Procurement List. SUMMARY: The Committee is proposing to add..., Mission and Installation Contracting Command--Carlisle Barracks, Carlisle, PA. Deletion Regulatory...

  17. Genetics Home Reference: 2q37 deletion syndrome

    Science.gov (United States)

    ... Twitter Home Health Conditions 2q37 deletion syndrome 2q37 deletion syndrome Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description 2q37 deletion syndrome is a condition that can affect many ...

  18. Genetics Home Reference: 1p36 deletion syndrome

    Science.gov (United States)

    ... Twitter Home Health Conditions 1p36 deletion syndrome 1p36 deletion syndrome Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description 1p36 deletion syndrome is a disorder that typically causes severe ...

  19. 5 CFR 1631.17 - Deletion of exempted information.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Deletion of exempted information. 1631.17... Deletion of exempted information. Where requested records contain matters which are exempted under 5 U.S.C... disclosed by the Board with deletions. To each such record, the Board shall attach a written justification...

  20. 75 FR 56995 - Procurement List Proposed Additions and Deletion

    Science.gov (United States)

    2010-09-17

    ... Additions and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed Additions to and Deletion From the Procurement List. SUMMARY: The Committee is proposing to add... aggregated by the Defense Logistics Agency Troop Support, Philadelphia, PA. Deletion Regulatory Flexibility...

  1. 5 CFR 2502.18 - Deletion of exempted information.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Deletion of exempted information. 2502.18... Charges for Search and Reproduction § 2502.18 Deletion of exempted information. Where requested records... the remainder of the records, they shall be disclosed by the Office with deletions. To each such...

  2. 78 FR 75912 - Procurement List; Addition and Deletion

    Science.gov (United States)

    2013-12-13

    ... and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Addition to and deletion from the Procurement List. SUMMARY: This action adds a service to the Procurement...: General Services Administration, Fort Worth, TX Deletion On 11/1/2013 (78 FR 65618), the Committee for...

  3. 78 FR 27369 - Procurement List; Additions and Deletion

    Science.gov (United States)

    2013-05-10

    ... and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and Deletion from the Procurement List. SUMMARY: This action adds products to the Procurement..., Philadelphia, PA. Deletion On 4/5/2013 (78 FR 20622-20623), the Committee for Purchase From People Who Are...

  4. Genetics Home Reference: 22q11.2 deletion syndrome

    Science.gov (United States)

    ... Health Conditions 22q11.2 deletion syndrome 22q11.2 deletion syndrome Printable PDF Open All Close All Enable ... view the expand/collapse boxes. Description 22q11.2 deletion syndrome (which is also known by several other ...

  5. 75 FR 7450 - Procurement List: Proposed Addition and Deletion

    Science.gov (United States)

    2010-02-19

    ... Addition and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed addition to and deletion from Procurement List. SUMMARY: The Committee is proposing to add to the... W6BA ACA, FT CARSON, COLORADO. Deletion Regulatory Flexibility Act Certification I certify that the...

  6. 77 FR 20795 - Procurement List Proposed Addition and Deletion

    Science.gov (United States)

    2012-04-06

    ... Addition and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed Addition to and Deletion from the Procurement List. SUMMARY: The Committee is proposing to add a.... Deletion Regulatory Flexibility Act Certification I certify that the following action will not have a...

  7. 36 CFR 1275.58 - Deletion of restricted portions.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Deletion of restricted... HISTORICAL MATERIALS OF THE NIXON ADMINISTRATION Access by the Public § 1275.58 Deletion of restricted... materials after the deletion of the portions which are restricted under this § 1275.50 or § 1275.52. ...

  8. Characterization of five partial deletions of the factor VIII gene

    International Nuclear Information System (INIS)

    Youssoufian, H.; Antonarakis, S.E.; Aronis, S.; Tsiftis, G.; Phillips, D.G.; Kazazian, H.H. Jr.

    1987-01-01

    Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. By using cloned DNA probes, the authors have characterized the following five different partial deletions of the factor VIII gene from a panel of 83 patients with hemophilia A: (i) a 7-kilobase (kb) deletion that eliminates exon 6; (ii) a 2.5-kb deletion that eliminates 5' sequences of exon 14; (iii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliminates exons 23-25; and (v) a 5.5-kb deletion that eliminates exon 22. The first four deletions are associated with severe hemophilia A. By contrast, the last deletion is associated with moderate disease, possibly because of in-frame splicing from adjacent exons. None of those patients with partial gene deletions had circulating inhibitors to factor VIII. One deletion occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of the maternal grandfather. These observations demonstrate that de novo deletions of X-linked genes can occur in either male or female gametes

  9. 75 FR 69638 - Procurement List; Additions and Deletion

    Science.gov (United States)

    2010-11-15

    ... and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and deletion from the Procurement List. SUMMARY: This action adds products and a service to the...), DENVER, CO. Deletion On 9/17/2010 (75 FR 56995-56996), the Committee for Purchase From People Who Are...

  10. 76 FR 60810 - Procurement List; Proposed Additions and Deletion

    Science.gov (United States)

    2011-09-30

    ... Additions and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed Additions to and Deletion from the Procurement List. SUMMARY: The Committee is proposing to add... Activity: Department of Energy, Idaho Operations Office, Idaho Falls, ID. DELETION Regulatory Flexibility...

  11. 44 CFR 5.27 - Deletion of identifying details.

    Science.gov (United States)

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Deletion of identifying... Availability of General Agency Information, Rules, Orders, Policies, and Similar Material § 5.27 Deletion of..., interpretation, or staff manual or instruction. However, the justification for each deletion will be explained...

  12. 29 CFR 1610.20 - Deletion of exempted matters.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Deletion of exempted matters. 1610.20 Section 1610.20 Labor... Production or Disclosure Under 5 U.S.C. 552 § 1610.20 Deletion of exempted matters. Where requested records... the remainder of the records, they shall be disclosed by the Commission with deletions. To each such...

  13. 75 FR 41449 - Procurement List Additions and Deletion

    Science.gov (United States)

    2010-07-16

    ... and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and deletion from the Procurement List. SUMMARY: This action adds products and services to the... of the Air Force, FA6643 HQ AFRES LGC, Robins AFB, GA Deletion On 5/28/2010 (75 FR 29994-29995), the...

  14. 49 CFR 7.6 - Deletion of identifying detail.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Deletion of identifying detail. 7.6 Section 7.6... To Be Made Public by DOT § 7.6 Deletion of identifying detail. Whenever it is determined to be... the deletion will accompany the record published or made available for inspection. ...

  15. 76 FR 5142 - Procurement List; Additions and Deletion

    Science.gov (United States)

    2011-01-28

    ... and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and deletion from the Procurement List. SUMMARY: This action adds services to the Procurement.... Contracting Activity: Department of Transportation, Federal Aviation Administration, Jamaica, NY. Deletion On...

  16. Genetics Home Reference: 22q13.3 deletion syndrome

    Science.gov (United States)

    ... Health Conditions 22q13.3 deletion syndrome 22q13.3 deletion syndrome Printable PDF Open All Close All Enable ... view the expand/collapse boxes. Description 22q13.3 deletion syndrome , which is also commonly known as Phelan- ...

  17. Probabilistic phylogenetic inference with insertions and deletions.

    Directory of Open Access Journals (Sweden)

    Elena Rivas

    2008-09-01

    Full Text Available A fundamental task in sequence analysis is to calculate the probability of a multiple alignment given a phylogenetic tree relating the sequences and an evolutionary model describing how sequences change over time. However, the most widely used phylogenetic models only account for residue substitution events. We describe a probabilistic model of a multiple sequence alignment that accounts for insertion and deletion events in addition to substitutions, given a phylogenetic tree, using a rate matrix augmented by the gap character. Starting from a continuous Markov process, we construct a non-reversible generative (birth-death evolutionary model for insertions and deletions. The model assumes that insertion and deletion events occur one residue at a time. We apply this model to phylogenetic tree inference by extending the program dnaml in phylip. Using standard benchmarking methods on simulated data and a new "concordance test" benchmark on real ribosomal RNA alignments, we show that the extended program dnamlepsilon improves accuracy relative to the usual approach of ignoring gaps, while retaining the computational efficiency of the Felsenstein peeling algorithm.

  18. Submicroscopic deletions at 22q11.2: Variability of the clinical picture and delineation of a commonly deleted region

    Energy Technology Data Exchange (ETDEWEB)

    Lindsay, E.A.; Shaffer, L.G.; Greenberg, F. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1995-03-27

    DiGeorge anomaly (DGA) and velo-cardio-facial syndrome (VCFS) are frequently associated with monosomy of chromosome region 22q11. Most patients have a submicroscopic deletion, recently estimated to be at least 1-2 Mb. It is not clear whether individuals who present with only some of the features of these conditions have the deletion, and if so, whether the size of the deletion varies from those with more classic phenotypes. We have used fluorescence in situ hybridization (FISH) to assess the deletion status of 85 individuals referred to us for molecular analysis, with a wide range of DGA-like or VCFS-like clinical features. The test probe used was the cosmid sc11.1, which detects two loci about 2 Mb apart in 22q11.2. Twenty-four patients carried the deletion. Of the deleted patients, most had classic DGA or VCFS phenotypes, but 6 deleted patients had mild phenotypes, including 2 with minor facial anomalies and velopharyngeal incompetence as the only presenting signs. Despite the great phenotypic variability among the deleted patients, none had a deletion smaller than the 2-Mb region defined by sc11.1. Smaller deletions were not detected in patients with particularly suggestive phenotypes who were not deleted for sc11.1, even when tested with two other probes from the DGA/VCFS region. 24 refs., 2 figs., 2 tabs.

  19. Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy

    DEFF Research Database (Denmark)

    Bisgaard, A-M; Kirchhoff, M; Nielsen, J E

    2008-01-01

    A deletion on one chromosome and a mutant allele on the other may cause an autosomal recessive disease. We report on two patients with mental retardation, dysmorphic features and low catalytic activity of arylsulfatase A. One patient had a pathogenic mutation in the arylsulfatase A gene (ARSA......) and succumbed to metachromatic leukodystrophy (MLD). The other patient had a pseudoallele, which does not lead to MLD. The presenting clinical features and low arylsulfatase A activity were explained, in each patients, by a deletion of 22q13 and, thereby, of one allele of ARSA....

  20. Targeted gene deletion in Zygosaccharomyces bailii.

    Science.gov (United States)

    Mollapour, M; Piper, P

    2001-01-30

    Yeasts of the genus Zygosaccharomyces are notable agents of large-scale food spoilage. Despite the economic importance of these organisms, little is known about the stress adaptations whereby they adapt to many of the more severe conditions of food preservation. In this study it was shown that genes of Z. bailii, a yeast notable for its high resistances to food preservatives and ethanol, can be isolated by complementation of the corresponding mutant strains of Saccharomyces cerevisiae. It was also discovered that the acquisition by S. cerevisiae of a single small Z. bailii gene (ZbYME2) was sufficient for the former yeast to acquire the ability to degrade two major food preservatives, benzoic acid and sorbic acid. Using DNA cassettes containing dominant selectable markers and methods originally developed for performing gene deletions in S. cerevisiae, the two copies of ZbYME2 in the Z. bailii genome were sequentially deleted. The resulting Zbyme2/Zbyme2 homozygous deletant strain had lost any ability to utilize benzoate as sole carbon source and was more sensitive to weak acid preservatives during growth on glucose. Thus, ZbYME2, probably the nuclear gene for a mitochondrial mono-oxygenase function, is essential for Z. bailii to degrade food preservatives. This ability to catabolize weak acid preservatives is a significant factor contributing to the preservative resistance of Z. bailii under aerobic conditions. This study is the first to demonstrate that it is possible to delete in Z. bailii genes that are suspected as being important for growth of this organism in preserved foods and beverages. With the construction of further mutant of Z. bailii strains, a clearer picture should emerge of how this yeast adapts to the conditions of food preservation. This information will, in turn, allow the design of new preservation strategies. GenBank Accession Nos: ZbURA3 (AF279259), ZbTIM9 (AF279260), ZbYME2 (AF279261), ZbTRP1 (AF279262), ZbHHT1(AF296170). Copyright 2000 John

  1. Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment

    Science.gov (United States)

    2012-01-01

    Background Hepatitis B virus (HBV), because of its error-prone viral polymerase, has a high mutation rate leading to widespread substitutions, deletions, and insertions in the HBV genome. Deletions may significantly change viral biological features complicating the progression of liver diseases. However, the clinical conditions correlating to the accumulation of deleted mutants remain unclear. In this study, we explored HBV deletion patterns and their association with disease status and antiviral treatment by performing whole genome sequencing on samples from 51 hepatitis B patients and by monitoring changes in deletion variants during treatment. Clone sequencing was used to analyze preS regions in another cohort of 52 patients. Results Among the core, preS, and basic core promoter (BCP) deletion hotspots, we identified preS to have the highest frequency and the most complex deletion pattern using whole genome sequencing. Further clone sequencing analysis on preS identified 70 deletions which were classified into 4 types, the most common being preS2. Also, in contrast to the core and BCP regions, most preS deletions were in-frame. Most deletions interrupted viral surface epitopes, and are possibly involved in evading immuno-surveillance. Among various clinical factors examined, logistic regression showed that antiviral medication affected the accumulation of deletion mutants (OR = 6.81, 95% CI = 1.296 ~ 35.817, P = 0.023). In chronic carriers of the virus, and individuals with chronic hepatitis, the deletion rate was significantly higher in the antiviral treatment group (Fisher exact test, P = 0.007). Particularly, preS2 deletions were associated with the usage of nucleos(t)ide analog therapy (Fisher exact test, P = 0.023). Dynamic increases in preS1 or preS2 deletions were also observed in quasispecies from samples taken from patients before and after three months of ADV therapy. In vitro experiments demonstrated that preS2 deletions alone

  2. Method for introducing unidirectional nested deletions

    Science.gov (United States)

    Dunn, J.J.; Quesada, M.A.; Randesi, M.

    1999-07-27

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment. More specifically, the method comprises providing a recombinant DNA construct comprising a DNA segment of interest inserted in a cloning vector. The cloning vector has an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment of interest. The recombinant DNA construct is then contacted with the protein pII encoded by gene II of phage f1 thereby generating a single-stranded nick. The nicked DNA is then contacted with E. coli Exonuclease III thereby expanding the single-stranded nick into a single-stranded gap. The single-stranded gapped DNA is then contacted with a single-strand-specific endonuclease thereby producing a linearized DNA molecule containing a double-stranded deletion corresponding in size to the single-stranded gap. The DNA treated in this manner is then incubated with DNA ligase under conditions appropriate for ligation. Also disclosed is a method for producing single-stranded DNA probes. In this embodiment, single-stranded gapped DNA, produced as described above, is contacted with a DNA polymerase in the presence of labeled nucleotides to fill in the gap. This DNA is then linearized by digestion with a restriction enzyme which cuts outside the DNA segment of interest. The product of this digestion is then denatured to produce a labeled single-stranded nucleic acid probe. 1 fig.

  3. Deletion of ultraconserved elements yields viable mice

    Energy Technology Data Exchange (ETDEWEB)

    Ahituv, Nadav; Zhu, Yiwen; Visel, Axel; Holt, Amy; Afzal, Veena; Pennacchio, Len A.; Rubin, Edward M.

    2007-07-15

    Ultraconserved elements have been suggested to retainextended perfect sequence identity between the human, mouse, and ratgenomes due to essential functional properties. To investigate thenecessities of these elements in vivo, we removed four non-codingultraconserved elements (ranging in length from 222 to 731 base pairs)from the mouse genome. To maximize the likelihood of observing aphenotype, we chose to delete elements that function as enhancers in amouse transgenic assay and that are near genes that exhibit markedphenotypes both when completely inactivated in the mouse as well as whentheir expression is altered due to other genomic modifications.Remarkably, all four resulting lines of mice lacking these ultraconservedelements were viable and fertile, and failed to reveal any criticalabnormalities when assayed for a variety of phenotypes including growth,longevity, pathology and metabolism. In addition more targeted screens,informed by the abnormalities observed in mice where genes in proximityto the investigated elements had been altered, also failed to revealnotable abnormalities. These results, while not inclusive of all thepossible phenotypic impact of the deleted sequences, indicate thatextreme sequence constraint does not necessarily reflect crucialfunctions required for viability.

  4. Are there ethnic differences in deletions in the dystrophin gene?

    Energy Technology Data Exchange (ETDEWEB)

    Banerjee, M.; Verma, I.C. [All India Inst. of Medical Sciences, New Delhi (India)

    1997-01-20

    We studied 160 cases of Duchenne muscular dystrophy (DMD) drawn from all parts of India, using multiplex PCR of 27 exons. Of these, 103 (64.4%) showed intragenic deletions. Most (69.7%) of the deletions involved exons 45-51. The phenotype of cases with deletion of single exons did not differ significantly from those with deletion of multiple exons. The distribution of deletions in studies from different countries was variable, but this was accounted for either by the small number of cases studied, or by fewer exons analyzed. It is concluded that there is likely to be no ethnic difference with respect to deletions in the DMD gene. 38 refs., 2 figs., 3 tabs.

  5. Clival encephalocele and 5q15 deletion: a case report.

    Science.gov (United States)

    Puvabanditsin, Surasak; Malik, Imran; Garrow, Eugene; Francois, Lissa; Mehta, Rajeev

    2015-03-01

    A preterm neonate presenting with respiratory distress after birth was found to have a clival encephalocele, which is a variant of a basal encephalocele, and hypoplasia of the cerebellum. Genetic studies revealed a small deletion of the long arm of chromosome 5: 5q15 deletion. We report a rare variant of a basal encephalocele with a cerebellar malformation and 5q15 deletion. © The Author(s) 2014.

  6. Panchromatic cooperative hyperspectral adaptive wide band deletion repair method

    Science.gov (United States)

    Jiang, Bitao; Shi, Chunyu

    2018-02-01

    In the hyperspectral data, the phenomenon of stripe deletion often occurs, which seriously affects the efficiency and accuracy of data analysis and application. Narrow band deletion can be directly repaired by interpolation, and this method is not ideal for wide band deletion repair. In this paper, an adaptive spectral wide band missing restoration method based on panchromatic information is proposed, and the effectiveness of the algorithm is verified by experiments.

  7. NPL deletion policy for RCRA-regulated TSD facilities finalized

    International Nuclear Information System (INIS)

    Anon.

    1995-01-01

    Under a new policy published by EPA on March 20, 1995, certain sites may be deleted from the National Priorities List (NPL) and deferred to RCRA corrective action. To be deleted from the NPL, a site must (1) be regulated under RCRA as a treatment, storage, or disposal (TSD) facility and (2) meet the four criteria specified by EPA. The new NPL deletion policy, which does not pertain to federal TSD facilities, became effective on April 19, 1995. 1 tab

  8. A Comparative Study of Quantum and Classical Deletion

    International Nuclear Information System (INIS)

    Shen Yao; Hao Liang; Long Guilu

    2010-01-01

    Here in this letter, we study the difference between quantum and classical deletion. We point out that the linear mapping deletion operation used in the impossibility proof for quantum systems applies also to classical system. The general classical deletion operation is a combined operation of measurement and transformation, i.e., first read the state and then transfer the state to the standard blank state. Though both quantum information and classical information can be deleted in an open system, quantum information cannot be recovered while classical information can be recovered. (general)

  9. Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

    Science.gov (United States)

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-11-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

  10. "I feel stupid I can't delete..."::a study of users' cloud deletion practices and coping strategies

    OpenAIRE

    Ramokapane, Kopo Marvin; Rashid, Awais; Such, Jose

    2017-01-01

    Deletion of data from cloud storage and services is an important aspect of privacy and security. But how easy or simple a task is it for users to complete? Cloud users' deletion practices, challenges and coping strategies have not been well studied to date. We undertook an exploratory study to better understand this issue. Through in-depth semi-structured interviews and use of deletion scenarios with 26 subjects, we explored several key questions: why and when cloud users would like to delete...

  11. AZFc deletion detected in a newborn with prenatally diagnosed Yq deletion.

    Science.gov (United States)

    Tóth, A; Tardy, E P; Gombos, S; Hajdu, K; Bátorfi, J; Krausz, C

    2001-04-01

    A case of prenatally diagnosed Yq deletion is described. Fluorescence in situ hybridisation (FISH) was used to identify the abnormal chromosome and to exclude mosaicism. Based on the cytogenetic result and the ultrasound investigation the pregnancy was continued. A newborn with normal male genitalia was delivered. Microdeletion analysis of the Yq showed the absence of the AZFc region. This type of deletion has been described as being associated with azoospermia or oligozoospermia with a progressive decrease of sperm number over time. Long-term andrological follow-up of the newborn will be necessary with eventual cryoconservation of sperm at early adulthood. The present report proposes that AZF analysis combined with FISH has an important role in accurate genetic counselling in sex chromosome anomalies. Copyright 2001 John Wiley & Sons, Ltd.

  12. Linguistic and Psychomotor Development in Children with Chromosome 14 Deletions

    Science.gov (United States)

    Zampini, Laura; D'Odorico, Laura; Zanchi, Paola; Zollino, Marcella; Neri, Giovanni

    2012-01-01

    The present study focussed on a specific type of rare genetic condition: chromosome 14 deletions. Children with this genetic condition often show developmental delays and brain and neurological problems, although the type and severity of symptoms varies depending on the size and location of the deleted genetic material. The specific aim of the…

  13. Hepatic mitochondrial DNA deletion in alcoholics: association with microvesicular steatosis.

    Science.gov (United States)

    Fromenty, B; Grimbert, S; Mansouri, A; Beaugrand, M; Erlinger, S; Rötig, A; Pessayre, D

    1995-01-01

    Alcohol abuse may lead to microvesicular steatosis, a lesion ascribed to impaired mitochondrial function. Because alcohol abuse leads to reactive oxygen species in the hepatic mitochondria, it may damage mitochondrial DNA. The aim of this study was to look for the presence of the "common" 4977-base pair deletion in the hepatic mitochondrial DNA of alcoholic patients and age-matched, nonalcoholic controls. Hepatic DNA was subjected to two polymerase chain reactions that amplified non-deleted and deleted mitochondrial DNA, respectively. The deletion was found in 6 of 10 alcoholics with microvesicular steatosis, 2 of 17 alcoholic patients with macrovacuolar steatosis, but in none of 12 patients with acute alcoholic hepatitis, 11 patients with alcoholic cirrhosis, or 62 nonalcoholic patients of comparable ages with various other liver diseases or normal liver histology. In all patients with the deletion, restriction fragments of deleted mitochondrial DNA co-migrated with those of reference Pearson bone marrow-pancreas syndrome patients with the common mitochondrial DNA deletion. The common deletion is frequent in the hepatic DNA of alcoholic patients with microvesicular steatosis. Alcohol-induced mitochondrial DNA damage may contribute to the occurrence of this lesion in some alcoholics.

  14. Lack of association of insertion/deletion polymorphism in ...

    African Journals Online (AJOL)

    In the present preliminary study the insertion/deletion polymorphism within angiotensin converting enzyme gene is not likely to be associated with nephropathy in type 2 diabetic patients of Punjabi population of Pakistan. Key words: Angiotensin converting enzymes, insertion/deletion polymorphism, albuminuria and type 2 ...

  15. Coexistence of 9p Deletion Syndrome and Autism Spectrum Disorder

    Science.gov (United States)

    Günes, Serkan; Ekinci, Özalp; Ekinci, Nuran; Toros, Fevziye

    2017-01-01

    Deletion or duplication of the short arm of chromosome 9 may lead to a variety of clinical conditions including craniofacial and limb abnormalities, skeletal malformations, mental retardation, and autism spectrum disorder. Here, we present a case report of 5-year-old boy with 9p deletion syndrome and autism spectrum disorder.

  16. Mitochondrial DNA deletions in patients with chronic suppurative otitis media.

    Science.gov (United States)

    Tatar, Arzu; Tasdemir, Sener; Sahin, Ibrahim; Bozoglu, Ceyda; Erdem, Haktan Bagis; Yoruk, Ozgur; Tatar, Abdulgani

    2016-09-01

    The aim of this study was to investigate the 4977 and 7400 bp deletions of mitochondrial DNA in patients with chronic suppurative otitis media and to indicate the possible association of mitochondrial DNA deletions with chronic suppurative otitis media. Thirty-six patients with chronic suppurative otitis media were randomly selected to assess the mitochondrial DNA deletions. Tympanomastoidectomy was applied for the treatment of chronic suppurative otitis media, and the curettage materials including middle ear tissues were collected. The 4977 and 7400 bp deletion regions and two control regions of mitochondrial DNA were assessed by using the four pair primers. DNA was extracted from middle ear tissues and peripheral blood samples of the patients, and then polymerase chain reactions (PCRs) were performed. PCR products were separated in 2 % agarose gel. Seventeen of 36 patients had the heterozygote 4977 bp deletion in the middle ear tissue but not in peripheral blood. There wasn't any patient who had the 7400 bp deletion in mtDNA of their middle ear tissue or peripheral blood tissue. The patients with the 4977 bp deletion had a longer duration of chronic suppurative otitis media and a higher level of hearing loss than the others (p otitis media and the reactive oxygen species can cause the mitochondrial DNA deletions and this may be a predisposing factor to sensorineural hearing loss in chronic suppurative otitis media. An antioxidant drug as a scavenger agent may be used in long-term chronic suppurative otitis media.

  17. Phosphatase and tensin homologue deleted on chromosome 10 ...

    African Journals Online (AJOL)

    Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor gene deleted or mutated in many human cancers such as glioblastoma, spinal tumors, prostate, bladder, adrenals, thyroid, breast, endometrium, and colon cancers. They result from loss of heterozygosity (LOH) for the PTEN ...

  18. Generalised deletion designs | Gachii | African Journal of Science ...

    African Journals Online (AJOL)

    In this paper asymmetrical single replicate factorial designs are constructed from symmetrical single replicate factorial designs using the deletion technique. The study is along the lines of Voss(1986), Chauhan(1989) and Gachii and Odhiambo(1997). We give results for the general order deletion designs of the form sn-m1(s ...

  19. 24 CFR 990.155 - Addition and deletion of units.

    Science.gov (United States)

    2010-04-01

    ... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Addition and deletion of units. 990.155 Section 990.155 Housing and Urban Development Regulations Relating to Housing and Urban...; Computation of Eligible Unit Months § 990.155 Addition and deletion of units. (a) Changes in public housing...

  20. 4977-bp mitochondrial DNA deletion in infertile patients with varicocele.

    Science.gov (United States)

    Gashti, N G; Salehi, Z; Madani, A H; Dalivandan, S T

    2014-04-01

    Varicocele is the abnormal inflexion and distension of veins of the pampiniform plexus within spermatic cord and is one of the amendable causes of male infertility. It can increase reactive oxygen species (ROS) production in semen and cause oxidative stress. The purpose of this study was to analyse spermatozoa mtDNA 4977-bp deletion in infertile men with varicocele. To detect 4977-bp deletion in spermatozoa mtDNA, semen samples of 60 infertile patients with clinical varicocele and 90 normal men from northern Iran were prepared. After extraction of spermatozoa total DNA, Gap polymerase chain reaction (Gap PCR) was performed. 4977-bp deletion was observed in 81.66% of patients with varicocele, while approximately 15.55% of controls had this deletion. As spermatozoa from patients with varicocele had a high frequency of occurrence of 4977-bp deletion in mtDNA [OR = 24.18, 95% confidence interval (CI) = 10.15-57.57, P deletion in spermatozoa and cause infertility in north Iranian men. However, to determine the relation between sperm mtDNA 4977-bp deletion and varicocele-induced infertility, larger population-based studies are needed. It is concluded that there is an association between sperm mtDNA 4977-bp deletion and varicocele-induced infertility in the population studied. © 2013 Blackwell Verlag GmbH.

  1. 34 CFR 5.16 - Deletion of identifying details.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Deletion of identifying details. 5.16 Section 5.16 Education Office of the Secretary, Department of Education AVAILABILITY OF INFORMATION TO THE PUBLIC PURSUANT TO PUB. L. 90-23 (Eff. until 7-14-10) What Records Are Available § 5.16 Deletion of identifying...

  2. 76 FR 27999 - Procurement List; Addition and Deletion

    Science.gov (United States)

    2011-05-13

    ... and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Addition to and Deletion from the Procurement List. SUMMARY: This action adds a service to the Procurement... USA ROCK ISL Arsenal, Rock Island, IL. [[Page 28000

  3. 42 CFR 401.118 - Deletion of identifying details.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 2 2010-10-01 2010-10-01 false Deletion of identifying details. 401.118 Section 401.118 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... Deletion of identifying details. When CMS publishes or otherwise makes available an opinion or order...

  4. Solid-phase nested deletion: a new subcloning-less method for generating nested deletions.

    Science.gov (United States)

    Yohda, M; Kato, N; Endo, I

    1995-08-31

    We have developed a new subcloning-less method for generating nested deletions which we have termed Solid-Phase Nested Deletion. The basic procedure for this method is as follows. The target DNA fragment is cloned in the multiple cloning site of a cloning vector, pUC or its derivatives, and amplified by PCR using a set of primers, one of which is 5'-biotinylated. The amplified DNA is partially digested by a restriction enzyme with a 4-base recognition sequence. The digested DNA is ligated with a synthetic adapter DNA. Monodiverse beads coupled with streptavidin (Dynabeads M-280 streptavidin) are added to the mixture and the biotinylated DNA fragments are separated by applying magnetic field. The unidirectionally deleted DNA fragments are recovered by PCR from the magnetic beads, and size-fractionated by agarose gel electrophoresis. The DNA fragments are amplified by PCR and used for sequencing. We demonstrate the potential of this method using a 4878-bp EcoRI fragment of lambda phage DNA.

  5. Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

    DEFF Research Database (Denmark)

    Abbott, Geoffrey W; Jepps, Thomas A

    2016-01-01

    ) subunits. We investigated the effects of targeted germline Kcne4 deletion on mesenteric artery reactivity in adult male and female mice. Kcne4 deletion increased mesenteric artery contractility in response to α-adrenoceptor agonist methoxamine, and decreased responses to Kv7.2-7.5 channel activator ML213......, in male but not female mice. In contrast, Kcne4 deletion markedly decreased vasorelaxation in response to isoprenaline in both male and female mice. Kcne4 expression was 2-fold lower in the female versus the male mouse mesenteric artery, and Kcne4 deletion elicited only moderate changes of other Kcne...... transcripts, with no striking sex-specific differences. However, Kv7.4 protein expression in females was twice that in males, and was reduced in both sexes by Kcne4 deletion. Our findings confirm a crucial role for KCNE4 in regulation of Kv7 channel activity to modulate vascular tone, and provide the first...

  6. Attenuation of monkeypox virus by deletion of genomic regions

    Science.gov (United States)

    Lopera, Juan G.; Falendysz, Elizabeth A.; Rocke, Tonie E.; Osorio, Jorge E.

    2015-01-01

    Monkeypox virus (MPXV) is an emerging pathogen from Africa that causes disease similar to smallpox. Two clades with different geographic distributions and virulence have been described. Here, we utilized bioinformatic tools to identify genomic regions in MPXV containing multiple virulence genes and explored their roles in pathogenicity; two selected regions were then deleted singularly or in combination. In vitro and in vivostudies indicated that these regions play a significant role in MPXV replication, tissue spread, and mortality in mice. Interestingly, while deletion of either region led to decreased virulence in mice, one region had no effect on in vitro replication. Deletion of both regions simultaneously also reduced cell culture replication and significantly increased the attenuation in vivo over either single deletion. Attenuated MPXV with genomic deletions present a safe and efficacious tool in the study of MPX pathogenesis and in the identification of genetic factors associated with virulence.

  7. Role of DNA deletion length in mutation and cell survival

    International Nuclear Information System (INIS)

    Braby, L.A.; Morgan, T.L.

    1992-01-01

    A model is presented which is based on the assumption that malignant transformation, mutation, chromosome aberration, and reproductive death of cells are all manifestations of radiation induced deletions in the DNA of the cell, and that the size of the deletion in relation to the spacing of essential genes determines the consequences of that deletion. It is assumed that two independent types of potentially lethal lesions can result in DNA deletions, and that the relative numbers of these types of damage is dependent on radiation quality. The repair of the damage reduces the length of a deletion, but does not always eliminate it. The predictions of this model are in good agreement with a wide variety of experimental evidence. (author)

  8. Ku80-deleted cells are defective at base excision repair

    International Nuclear Information System (INIS)

    Li, Han; Marple, Teresa; Hasty, Paul

    2013-01-01

    Graphical abstract: - Highlights: • Ku80-deleted cells are hypersensitive to ROS and alkylating agents. • Cells deleted for Ku80, but not Ku70 or Lig4, have reduced BER capacity. • OGG1 rescues hypersensitivity to H 2 O 2 and paraquat in Ku80-mutant cells. • Cells deleted for Ku80, but not Lig4, are defective at repairing AP sites. • Cells deleted for Ku80, but not Lig4 or Brca2 exon 27, exhibit increased PAR. - Abstract: Ku80 forms a heterodimer with Ku70, called Ku, that repairs DNA double-strand breaks (DSBs) via the nonhomologous end joining (NHEJ) pathway. As a consequence of deleting NHEJ, Ku80-mutant cells are hypersensitive to agents that cause DNA DSBs like ionizing radiation. Here we show that Ku80 deletion also decreased resistance to ROS and alkylating agents that typically cause base lesions and single-strand breaks (SSBs). This is unusual since base excision repair (BER), not NHEJ, typically repairs these types of lesions. However, we show that deletion of another NHEJ protein, DNA ligase IV (Lig4), did not cause hypersensitivity to these agents. In addition, the ROS and alkylating agents did not induce γ-H2AX foci that are diagnostic of DSBs. Furthermore, deletion of Ku80, but not Lig4 or Ku70, reduced BER capacity. Ku80 deletion also impaired BER at the initial lesion recognition/strand scission step; thus, involvement of a DSB is unlikely. Therefore, our data suggests that Ku80 deletion impairs BER via a mechanism that does not repair DSBs

  9. Frequency of KLK3 gene deletions in the general population.

    Science.gov (United States)

    Rodriguez, Santiago; Al-Ghamdi, Osama A; Guthrie, Philip Ai; Shihab, Hashem A; McArdle, Wendy; Gaunt, Tom; Alharbi, Khalid K; Day, Ian Nm

    2017-07-01

    Background One of the kallikrein genes ( KLK3) encodes prostate-specific antigen, a key biomarker for prostate cancer. A number of factors, both genetic and non-genetic, determine variation of serum prostate-specific antigen concentrations in the population. We have recently found three KLK3 deletions in individuals with very low prostate-specific antigen concentrations, suggesting a link between abnormally reduced KLK3 expression and deletions of KLK3. Here, we aim to determine the frequency of kallikrein gene 3 deletions in the general population. Methods The frequency of KLK3 deletions in the general population was estimated from the 1958 Birth Cohort sample ( n = 3815) using amplification ratiometry control system. In silico analyses using PennCNV were carried out in the same cohort and in NBS-WTCCC2 in order to provide an independent estimation of the frequency of KLK3 deletions in the general population. Results Amplification ratiometry control system results from the 1958 cohort indicated a frequency of KLK3 deletions of 0.81% (3.98% following a less stringent calling criterion). From in silico analyses, we found that potential deletions harbouring the KLK3 gene occurred at rates of 2.13% (1958 Cohort, n = 2867) and 0.99% (NBS-WTCCC2, n = 2737), respectively. These results are in good agreement with our in vitro experiments. All deletions found were in heterozygosis. Conclusions We conclude that a number of individuals from the general population present KLK3 deletions in heterozygosis. Further studies are required in order to know if interpretation of low serum prostate-specific antigen concentrations in individuals with KLK3 deletions may offer false-negative assurances with consequences for prostate cancer screening, diagnosis and monitoring.

  10. Ku80-deleted cells are defective at base excision repair

    Energy Technology Data Exchange (ETDEWEB)

    Li, Han [The University of Texas Health Science Center at San Antonio, The Institute of Biotechnology, The Department of Molecular Medicine, 15355 Lambda Drive, San Antonio, TX 78245-3207 (United States); Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029 (Spain); Marple, Teresa [The University of Texas Health Science Center at San Antonio, The Institute of Biotechnology, The Department of Molecular Medicine, 15355 Lambda Drive, San Antonio, TX 78245-3207 (United States); Hasty, Paul, E-mail: hastye@uthscsa.edu [The University of Texas Health Science Center at San Antonio, The Institute of Biotechnology, The Department of Molecular Medicine, 15355 Lambda Drive, San Antonio, TX 78245-3207 (United States); Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029 (Spain)

    2013-05-15

    Graphical abstract: - Highlights: • Ku80-deleted cells are hypersensitive to ROS and alkylating agents. • Cells deleted for Ku80, but not Ku70 or Lig4, have reduced BER capacity. • OGG1 rescues hypersensitivity to H{sub 2}O{sub 2} and paraquat in Ku80-mutant cells. • Cells deleted for Ku80, but not Lig4, are defective at repairing AP sites. • Cells deleted for Ku80, but not Lig4 or Brca2 exon 27, exhibit increased PAR. - Abstract: Ku80 forms a heterodimer with Ku70, called Ku, that repairs DNA double-strand breaks (DSBs) via the nonhomologous end joining (NHEJ) pathway. As a consequence of deleting NHEJ, Ku80-mutant cells are hypersensitive to agents that cause DNA DSBs like ionizing radiation. Here we show that Ku80 deletion also decreased resistance to ROS and alkylating agents that typically cause base lesions and single-strand breaks (SSBs). This is unusual since base excision repair (BER), not NHEJ, typically repairs these types of lesions. However, we show that deletion of another NHEJ protein, DNA ligase IV (Lig4), did not cause hypersensitivity to these agents. In addition, the ROS and alkylating agents did not induce γ-H2AX foci that are diagnostic of DSBs. Furthermore, deletion of Ku80, but not Lig4 or Ku70, reduced BER capacity. Ku80 deletion also impaired BER at the initial lesion recognition/strand scission step; thus, involvement of a DSB is unlikely. Therefore, our data suggests that Ku80 deletion impairs BER via a mechanism that does not repair DSBs.

  11. Tau deletion promotes brain insulin resistance.

    Science.gov (United States)

    Marciniak, Elodie; Leboucher, Antoine; Caron, Emilie; Ahmed, Tariq; Tailleux, Anne; Dumont, Julie; Issad, Tarik; Gerhardt, Ellen; Pagesy, Patrick; Vileno, Margaux; Bournonville, Clément; Hamdane, Malika; Bantubungi, Kadiombo; Lancel, Steve; Demeyer, Dominique; Eddarkaoui, Sabiha; Vallez, Emmanuelle; Vieau, Didier; Humez, Sandrine; Faivre, Emilie; Grenier-Boley, Benjamin; Outeiro, Tiago F; Staels, Bart; Amouyel, Philippe; Balschun, Detlef; Buee, Luc; Blum, David

    2017-08-07

    The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients. © 2017 Marciniak et al.

  12. Dermatoglyphic Profile in 22q Deletion Syndrome

    Science.gov (United States)

    Martín, B.; Fañanás, L.; Gutiérrez, B.; Chow, E.W.C.; Bassett, A.S.

    2011-01-01

    A genetic subtype of schizophrenia has been described in 22q11 Deletion syndrome. Previous studies have described an excess of dermatoglyphic alterations in schizophrenia, such as low a–b ridge counts (ABRCs), a high frequency of ridge dissociations, and increased dermatoglyphic fluctuating asymmetry. Little is known however, about the dermatoglyphic profile of 22qDS subjects showing psychotic symptoms and its similarity to the previously reported anomalies in schizophrenia. We studied the palmar dermatoglyphics of 22 subjects with 22qDS of predominantly Caucasian origin, 15 of whom had psychotic illness, and in 84 healthy controls of similar ethnicity. We observed higher values for total ATD angle in cases than in controls (P = 0.04). In addition, there was an excess of radial figures in the hypothenar area in cases, especially in the left hand. Interestingly, greater fluctuating asymmetry, determined by the absolute difference between right and left ABRC, was observed in 22qDS subjects compared to controls (P = 0.05). However, no differences were found for ABRCs and frequency of dissociations. Despite the small sample size, the palmprints analyzed suggest the existence of an altered dermatoglyphic profile in 22qDS, involving: (i) ATD angle amplitude, (ii) presence of radial loops in the hypothenar area, and (iii) an increment of fluctuating asymmetry. The first two features are similar to those found in other genetic syndromes associated with low IQ, while high levels of fluctuating asymmetry have often been reported in schizophrenia. PMID:15211630

  13. Optimization of Internally Deleted Dystrophin Constructs.

    Science.gov (United States)

    Reza, Mojgan; Laval, Steve H; Roos, Andreas; Carr, Stephanie; Lochmüller, Hanns

    2016-10-01

    Duchenne muscular dystrophy (DMD) is a severe, genetic muscle disease caused by the absence of the sarcolemmal protein dystrophin. Gene replacement therapy is considered a potential strategy for the treatment of DMD, aiming to restore the missing protein. Although the elements of the dystrophin molecule have been identified and studies in transgenic mdx mice have explored the importance of a number of these structural domains, the resulting modified dystrophin protein products that have been developed so far are only partially characterized in relation to their structure and function in vivo. To optimize a dystrophin cDNA construct for therapeutic application we designed and produced four human minidystrophins within the packaging capacity of lentiviral vectors. Two novel minidystrophins retained the centrally located neuronal nitric oxide synthase (nNOS)-anchoring domain in order to achieve sarcolemmal nNOS restoration, which is lost in most internally deleted dystrophin constructs. Functionality of the resulting truncated dystrophin proteins was investigated in muscle of adult dystrophin-deficient mdx mice followed by a battery of detailed immunohistochemical and morphometric tests. This initial assessment aimed to determine the overall suitability of various constructs for cloning into lentiviral vectors for ex vivo gene delivery to stem cells for future preclinical studies.

  14. Gibson Deletion: a novel application of isothermal in vitro recombination.

    Science.gov (United States)

    Kalva, Swara; Boeke, Jef D; Mita, Paolo

    2018-01-01

    Recombinant DNA technology is today a fundamental tool for virtually all biological research fields. Among the many techniques available for the construction of a "custom DNA" molecule, the isothermal in vitro assembly, or Gibson assembly, allows for an efficient, one-step, scarless recombination-based assembly. Here, we apply and characterize the use of Gibson assembly for the deletion of DNA sequences around a DNA cut. This method, that we named "Gibson Deletion", can be used to easily substitute or delete one or more restriction sites within a DNA molecule. We show that Gibson Deletion is a viable method to delete up to 100 nucleotides from the DNA ends of a cleavage site. In addition, we found that Gibson Deletion can be performed using single strand DNA with the same efficiency as using double strand DNA molecules. Gibson Deletion is a novel, easy and convenient application of isothermal in vitro assembly, that performs with high efficiency and can be implemented for a broad range of applications.

  15. Performance of quantum cloning and deleting machines over coherence

    Science.gov (United States)

    Karmakar, Sumana; Sen, Ajoy; Sarkar, Debasis

    2017-10-01

    Coherence, being at the heart of interference phenomena, is found to be an useful resource in quantum information theory. Here we want to understand quantum coherence under the combination of two fundamentally dual processes, viz., cloning and deleting. We found the role of quantum cloning and deletion machines with the consumption and generation of quantum coherence. We establish cloning as a cohering process and deletion as a decohering process. Fidelity of the process will be shown to have connection with coherence generation and consumption of the processes.

  16. Precise mapping of 17 deletion breakpoints within the central hotspot deletion region (introns 50 and 51) of the DMD gene.

    Science.gov (United States)

    Esposito, Gabriella; Tremolaterra, Maria Roberta; Marsocci, Evelina; Tandurella, Igor Cm; Fioretti, Tiziana; Savarese, Maria; Carsana, Antonella

    2017-12-01

    Exon deletions in the human DMD gene, which encodes the dystrophin protein, are the molecular defect in 50-70% of cases of Duchenne/Becker muscular dystrophies. Deletions are preferentially clustered in the 5' (exons 2-20) and the central (exons 45-53) region of DMD, likely because local DNA structure predisposes to specific breakage or recombination events. Notably, innovative therapeutic strategies may rescue dystrophin function by homology-based specific targeting of sequences within the central DMD hot spot deletion region. To further study molecular mechanisms that generate such frequent genome variations and to identify residual intronic sequences, we sequenced 17 deletion breakpoints within introns 50 and 51 of DMD and analyzed the surrounding genomic architecture. There was no breakpoint clustering within the introns nor extensive homology between sequences adjacent to each junction. However, at or near the breakpoint, we found microhomology, short tandem repeats, interspersed repeat elements and short sequence stretches that predispose to DNA deletion or bending. Identification of such structural elements contributes to elucidate general mechanisms generating deletion within the DMD gene. Moreover, precise mapping of deletion breakpoints and localization of repeated elements are of interest, because residual intronic sequences may be targeted by therapeutic strategies based on genome editing correction.

  17. 22q11.2 deletion syndrome

    Science.gov (United States)

    McDonald-McGinn, Donna M.; Sullivan, Kathleen E.; Marino, Bruno; Philip, Nicole; Swillen, Ann; Vorstman, Jacob A. S.; Zackai, Elaine H.; Emanuel, Beverly S.; Vermeesch, Joris R.; Morrow, Bernice E.; Scambler, Peter J.; Bassett, Anne S.

    2016-01-01

    22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population. PMID:27189754

  18. Heme oxygenase-1 deletion affects stress erythropoiesis.

    Directory of Open Access Journals (Sweden)

    Yu-An Cao

    Full Text Available Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1 deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/- or hmox(+/+ bone marrow cells, we evaluated (i the erythrocyte parameters in the peripheral blood; (ii the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii the patterns of histological iron staining; and (iv the number of Mac-1(+-cells expressing TNF-α. In the spleens of mice that received hmox(+/- cells, we show (i decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii increases in the insoluble iron levels and decreases in the soluble iron levels; (iii increased numbers of Mac-1(+-cells expressing TNF-α; and (iv decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

  19. Multigene deletions in lung adenocarcinomas from irradiated and control mice

    International Nuclear Information System (INIS)

    Zhang, Y.; Woloschak, G.E.

    1996-01-01

    K-ras codon 12 point mutations mRb and p53 gene deletions were examined in tissues from 120 normal lungs and lung adenocarcinomas that were Formalin-treated and paraffin-embedded 25 years ago. The results showed that 12 of 60 (20%) lung adenocarcinomas had mRb deletions. All lung adenocarcinomas that were initially found bearing deleted mRb had p53 deletions (15 of 15; 100%). A significantly higher mutation frequency for K-ras codon 12 point mutations was also found in the lung adenocarcinomas from mice exposed to 24 once-weekly neutron irradiation (10 of 10; 100%) compared with those exposed to 24 or 60 once-weekly γ-ray doses (5 of 10; 50%). The data suggested that p53 and K-ras gene alterations were two contributory factors responsible for the increased incidence of lung adenocarcinoma in B6CF 1 male mice exposed to protracted neutron radiation

  20. Non-deletion mutations in Egyptian patients with Duchenne ...

    African Journals Online (AJOL)

    . Molecular analysis included Polymerase Chain Reaction (PCR) followed by multiplex ligation-dependent probe amplification (MLPA) to those patients with no deletion by PCR. Direct sequencing of the whole dystrophin gene was done to ...

  1. Additions and deletions to the known cerambycidae (Coleoptera) of Bolivia

    Science.gov (United States)

    An additional 137 species and two tribes are added to the known cerambycid fauna of Bolivia while 12 species are deleted. Comments and statistics regarding the growth of knowledge on the Bolivian Cerambycid fauna and species endemicity are included....

  2. Improved detection of small deletions in complex pools of DNA

    Science.gov (United States)

    Edgley, Mark; D’Souza, Anil; Moulder, Gary; McKay, Sheldon; Shen, Bin; Gilchrist, Erin; Moerman, Donald; Barstead, Robert

    2002-01-01

    About 40% of the genes in the nematode Caenorhabditis elegans have homologs in humans. Based on the history of this model system, it is clear that the application of genetic methods to the study of this set of genes would provide important clues to their function in humans. To facilitate such genetic studies, we are engaged in a project to derive deletion alleles in every gene in this set. Our standard methods make use of nested PCR to hunt for animals in mutagenized populations that carry deletions at a given locus. The deletion bearing animals exist initially in mixed populations where the majority of the animals are wild type at the target. Therefore, the production of the PCR fragment representing the deletion allele competes with the production of the wild type fragment. The size of the deletion fragment relative to wild type determines whether it can compete to a level where it can be detected above the background. Using our standard conditions, we have found that when the deletion is 600 bp, they do not work well to detect mutants with smaller deletions. Here we report a new strategy to detect small deletion alleles in complex DNA pools. Our new strategy is a modification of our standard PCR based screens. In the first round of the nested PCR, we include a third PCR primer between the two external primers. The presence of this third primer leads to the production of three fragments from wild type DNA. We configure the system so that two of these three fragments cannot serve as a template in the second round of the nested PCR. The addition of this third primer, therefore, handicaps the amplification from wild type template. On the other hand, the amplification of mutant fragments where the binding site for the third primer is deleted is unabated. Overall, we see at least a 500-fold increase in the sensitivity for small deletion fragments using our new method. Using this new method, we report the recovery of new deletion alleles within 12 C.elegans genes. PMID

  3. The significance of chromosome deletions in atomic-bomb survivors

    International Nuclear Information System (INIS)

    Tanaka, Kimio; Shigeta, Chiharu; Oguma, Nobuo; Kamada, Nanao; Deng, Z.; Niimi, Masanobu; Aisaka, Tadaichi.

    1986-01-01

    In 39 A-bomb survivors 40 years after exposure at ≤ 1,000 m from ground zero, the frequency and features of chromosome deletions in peripheral lymphocytes were examined using a differential staining technique. Simultaneously, in vitro irradiation experiment with Cf-252 was made to infer chromosome aberrations occuring immediately after exposure. Californium-252 with 100 rad induced dicentric and ring chromosomes in 40 % of the cells and acentric fragments in 44 %. Among the A-bomb survivors, chromosome aberrations were observed in 651 (21 %) of the total 3,136 cells. There were 146 cells with deletions (22 % of abnormal cells; 5 % of the total cells), and 10 cells with acentric fragment (0.3 % of the total cells). The figure for deletions was far higher than that reported in the literature. A large number of deletions were seen in chromosomes no.4, no.21, and no.22, and a few deletions in chromosomes no.7 and no.20. Significance of chromosome deletions is discussed. (Namekawa, K.)

  4. Wolfram syndrome in the Polish population: novel mutations and genotype-phenotype correlation.

    Science.gov (United States)

    Zmyslowska, A; Borowiec, M; Antosik, K; Szalecki, M; Stefanski, A; Iwaniszewska, B; Jedrzejczyk, M; Pietrzak, I; Mlynarski, W

    2011-11-01

    Wolfram syndrome is a rare form of diabetes mellitus associated with optic atrophy and disorders of different organs (e.g. diabetes insipidus, hearing loss, ataxia, anaemia and many others). This syndrome is caused by recessive mutations in the wolframin gene (WFS1) localized on chromosome 4p16·1. The aim of this study was to identify the causative mutations in WFS1 in a group of Polish patients with suspected Wolfram syndrome. Nine patients with clinical symptoms consistent with Wolfram syndrome (at least diabetes mellitus and optic atrophy) and 22 first-degree relatives were examined. The molecular analysis was carried out by direct sequencing of the exons, the exon-intron junctions, and the 5' and 3' untranslated regions of WFS1. Nine different mutations in WFS1 (five of them novel) were identified in the nine patients. Six patients were homozygous for the following mutations: V412fs, S443R, W539X, V659fs. They developed diabetes at a mean age of 5·2 years. Three patients were compound-heterozygous for the following mutations: S167fs, Q392X, Y513fs, W648X, V779G. They developed diabetes at a mean age of 6·5 years. Mean age of diagnosis of diabetes among the Polish patients was typical for Wolfram syndrome; however, compound-heterozygous patients were slightly older at diabetes onset. © 2011 Blackwell Publishing Ltd.

  5. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype.

    Science.gov (United States)

    Rohayem, Julia; Ehlers, Christian; Wiedemann, Bärbel; Holl, Reinhard; Oexle, Konrad; Kordonouri, Olga; Salzano, Giuseppina; Meissner, Thomas; Burger, Walter; Schober, Edith; Huebner, Angela; Lee-Kirsch, Min Ae

    2011-07-01

    To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation. The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. WSD was diagnosed earlier than type 1 diabetes (5.4±3.8 vs. 7.9±4.2 years; P7.5% (P=0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P=0.028). Endoplasmic reticulum stress-mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.

  6. 41 CFR 51-2.3 - Notice of proposed addition or deletion.

    Science.gov (United States)

    2010-07-01

    ... addition or deletion. 51-2.3 Section 51-2.3 Public Contracts and Property Management Other Provisions... or deletion. At least 30 days prior to the Committee's consideration of the addition or deletion of a... Register announcing the proposed addition or deletion and providing interested persons an opportunity to...

  7. 10 CFR 9.19 - Segregation of exempt information and deletion of identifying details.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Segregation of exempt information and deletion of... Information Act Regulations § 9.19 Segregation of exempt information and deletion of identifying details. (a... deletions are made from parts of the record by computer, the amount of information deleted will be indicated...

  8. Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss.

    NARCIS (Netherlands)

    Bespalova, I.N.; Camp, G. van; Bom, S.J.H.; Brown, D.J.; Cryns, K.; Wan, A.T. de; Erson, A.E.; Flothmann, K.; Kunst, H.P.M.; Kurnool, P.; Sivakumaran, T.A.; Cremers, C.W.R.J.; Leal, S.M.; Burmeister, M.; Lesperance, M.M.

    2001-01-01

    Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have

  9. Novel Targets for the Diagnosis and Treatment of Breast Cancer Identified by Genomic Analysis

    Science.gov (United States)

    2006-12-01

    containing 3 5q15 2.24 3419 202069_s_at IDH3A isocitrate dehydrogenase 3 (NAD+) alpha 15q25.1-q25.2 2.21 7466 202908_at WFS1 Wolfram syndrome 1 ( wolframin ...protein 15q21.1 3.11 27236 218230_at ARFIP1 ADP-ribosylation factor interacting protein 1 (arfaptin 1) 4q31.3 3.06 9236 221511_x_at CPR8 cell cycle...of genetic interactions . In addition, we Table 2 Tentative subcellular annotation for probe sets with predicted localization Predicted location Total

  10. Association of Wolfram syndrome with Fallot tetralogy in a girl.

    Science.gov (United States)

    Korkmaz, Hüseyin A; Demir, Korcan; Hazan, Filiz; Yıldız, Melek; Elmas, Özlem N; Özkan, Behzat

    2016-06-01

    Wolfram syndrome (DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a rare neurodegenerative disorder. Mutations of the WFS1 (wolframin) on chromosome 4 are responsible for the clinical manifestations in majority of patients with Wolfram syndrome. Wolfram syndrome is also accompanied by neurologic and psychiatric disorders, urodynamic abnormalities, restricted joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotrophic hypogonadism in males and diabetic microvascular disorders. There are very limited data in the literature regarding cardiac malformations associated in children with Wolfram syndrome. A 5-year-old girl with Wolfram syndrome and tetralogy of Fallot is presented herein. Sociedad Argentina de Pediatría.

  11. Molecular studies of deletions at the human steroid sulfatase locus

    Energy Technology Data Exchange (ETDEWEB)

    Shapiro, L.J.; Yen, P.; Pomerantz, D.; Martin, E.; Rolewic, L.; Mohandas, T. (Univ. of California, Los Angeles (USA))

    1989-11-01

    The human steroid sulfatase gene (STS) is located on the distal X chromosome short arm close to the pseudoautosomal region but in a segment of DNA that is unique to the X chromosome. In contrast to most X chromosome-encoded genes, STS expression is not extinguished during the process of X chromosome inactivation. Deficiency of STS activity produced the syndrome of X chromosome-linked ichthyosis, which is one of the most common inborn errors of metabolism in man. Approximately 90% of STS{sup {minus}} individuals have large deletions at the STS locus. The authors and others have found that the end points of such deletions are heterogeneous in their location. One recently ascertained subject was observed to have a 40-kilobase deletion that is entirely intragenic, permitting the cloning and sequencing of the deletion junction. Studies of this patient and of other X chromosome sequences in other subjects permit some insight into the mechanism(s) responsible for generating frequent deletions on the short arm of the X chromosome.

  12. Amino-acid composition after loop deletion drives domain swapping.

    Science.gov (United States)

    Nandwani, Neha; Surana, Parag; Udgaonkar, Jayant B; Das, Ranabir; Gosavi, Shachi

    2017-10-01

    Rational engineering of a protein to enable domain swapping requires an understanding of the sequence, structural and energetic factors that favor the domain-swapped oligomer over the monomer. While it is known that the deletion of loops between β-strands can promote domain swapping, the spliced sequence at the position of the loop deletion is thought to have a minimal role to play in such domain swapping. Here, two loop-deletion mutants of the non-domain-swapping protein monellin, frame-shifted by a single residue, were designed. Although the spliced sequence in the two mutants differed by only one residue at the site of the deletion, only one of them (YEIKG) promoted domain swapping. The mutant containing the spliced sequence YENKG was entirely monomeric. This new understanding that the domain swapping propensity after loop deletion may depend critically on the chemical composition of the shortened loop will facilitate the rational design of domain swapping. © 2017 The Protein Society.

  13. The Yeast Deletion Collection: A Decade of Functional Genomics

    Science.gov (United States)

    Giaever, Guri; Nislow, Corey

    2014-01-01

    The yeast deletion collections comprise >21,000 mutant strains that carry precise start-to-stop deletions of ∼6000 open reading frames. This collection includes heterozygous and homozygous diploids, and haploids of both MATa and MATα mating types. The yeast deletion collection, or yeast knockout (YKO) set, represents the first and only complete, systematically constructed deletion collection available for any organism. Conceived during the Saccharomyces cerevisiae sequencing project, work on the project began in 1998 and was completed in 2002. The YKO strains have been used in numerous laboratories in >1000 genome-wide screens. This landmark genome project has inspired development of numerous genome-wide technologies in organisms from yeast to man. Notable spinoff technologies include synthetic genetic array and HIPHOP chemogenomics. In this retrospective, we briefly describe the yeast deletion project and some of its most noteworthy biological contributions and the impact that these collections have had on the yeast research community and on genomics in general. PMID:24939991

  14. Molecular studies of deletions at the human steroid sulfatase locus

    International Nuclear Information System (INIS)

    Shapiro, L.J.; Yen, P.; Pomerantz, D.; Martin, E.; Rolewic, L.; Mohandas, T.

    1989-01-01

    The human steroid sulfatase gene (STS) is located on the distal X chromosome short arm close to the pseudoautosomal region but in a segment of DNA that is unique to the X chromosome. In contrast to most X chromosome-encoded genes, STS expression is not extinguished during the process of X chromosome inactivation. Deficiency of STS activity produced the syndrome of X chromosome-linked ichthyosis, which is one of the most common inborn errors of metabolism in man. Approximately 90% of STS - individuals have large deletions at the STS locus. The authors and others have found that the end points of such deletions are heterogeneous in their location. One recently ascertained subject was observed to have a 40-kilobase deletion that is entirely intragenic, permitting the cloning and sequencing of the deletion junction. Studies of this patient and of other X chromosome sequences in other subjects permit some insight into the mechanism(s) responsible for generating frequent deletions on the short arm of the X chromosome

  15. Scalable Design of Paired CRISPR Guide RNAs for Genomic Deletion.

    Directory of Open Access Journals (Sweden)

    Carlos Pulido-Quetglas

    2017-03-01

    Full Text Available CRISPR-Cas9 technology can be used to engineer precise genomic deletions with pairs of single guide RNAs (sgRNAs. This approach has been widely adopted for diverse applications, from disease modelling of individual loci, to parallelized loss-of-function screens of thousands of regulatory elements. However, no solution has been presented for the unique bioinformatic design requirements of CRISPR deletion. We here present CRISPETa, a pipeline for flexible and scalable paired sgRNA design based on an empirical scoring model. Multiple sgRNA pairs are returned for each target, and any number of targets can be analyzed in parallel, making CRISPETa equally useful for focussed or high-throughput studies. Fast run-times are achieved using a pre-computed off-target database. sgRNA pair designs are output in a convenient format for visualisation and oligonucleotide ordering. We present pre-designed, high-coverage library designs for entire classes of protein-coding and non-coding elements in human, mouse, zebrafish, Drosophila melanogaster and Caenorhabditis elegans. In human cells, we reproducibly observe deletion efficiencies of ≥50% for CRISPETa designs targeting an enhancer and exonic fragment of the MALAT1 oncogene. In the latter case, deletion results in production of desired, truncated RNA. CRISPETa will be useful for researchers seeking to harness CRISPR for targeted genomic deletion, in a variety of model organisms, from single-target to high-throughput scales.

  16. A Rare Syndrome of Deletion in 2 Siblings

    Directory of Open Access Journals (Sweden)

    Aravindhan Veerapandiyan MBBS

    2017-08-01

    Full Text Available The Glutamate receptor, ionotropic, delta 2 gene codes for an ionotropic glutamate delta-2 receptor, which is selectively expressed in cerebellar Purkinje cells, and facilitates cerebellar synapse organization and transmission. The phenotype associated with the deletion of Glutamate receptor, ionotropic, delta 2 gene in humans was initially defined in 2013. In this case report, the authors describe 2 brothers who presented with developmental delay, tonic upward gaze, nystagmus, oculomotor apraxia, hypotonia, hyperreflexia, and ataxia. They were found to have a homozygous intragenic deletion within the Glutamate receptor, ionotropic, delta 2 gene at exon 2. Our patients serve as an addition to the literature of previously reported children with this rare clinical syndrome associated with Glutamate receptor, ionotropic, delta 2 deletion.

  17. Physiological characterisation of acuB deletion in Aspergillus niger

    DEFF Research Database (Denmark)

    Meijer, Susan Lisette; De Jongh, Willem Adriaan; Olsson, Lisbeth

    2009-01-01

    that a basal level of FacB activity exists under glucose-repressive conditions. In the present study, the effect of deletion of acuB on the physiology of A. niger was assessed. Differences in organic acid and acetate production, enzyme activities and extracellular amino and non-amino organic acid production...... pathways that are not directly involved in acetate metabolism are influenced by acuB deletion. Clear differences in organic acid consumption and production were detected between the a dagger acuB and reference strain. However, the hypothesis that AcuB is responsible for basal AcuA activity necessary...... for activation of acetate metabolic pathways, even during growth on glucose, could not be confirmed. The experiments demonstrated that also when acuB was deleted, no acetate was formed. Therefore, AcuB cannot be the only activator of AcuA, and another control mechanism has to be available for activating AcuA....

  18. The diagnosis and molecular analysis of a novel 21.9kb deletion (Qinzhou type deletion) causing α+ thalassemia.

    Science.gov (United States)

    Long, Ju; Yan, Shanhuo; Lao, Kegan; Pang, Wanrong; Ye, Xuehe; Sun, Lei

    2014-04-01

    α-Thalassemia is a common single-gene genetic disease that can cause Hb Bart's hydrops fetalis and Hb H disease in tropical and subtropical regions. When examining conventional thalassemia genes, an only detected --(SEA) genotype sample needs further analysis. In doing so, we found a novel 21.9kb deletion (Qinzhou type deletion). The deletion position of the novel 21.9kb deletion is from 14373bp to 36299bp of the α-globin gene cluster (NG_000006.1); thus, there exists a 21927bp sequence deletion, into which a 29bp sequence is added. After sequence analysis, a group of Gap-PCR primers were synthesized to diagnose this novel thalassemia genotype. Through pedigree analysis, we deduced that the propositus obtained the novel alleles from her mother. The genotype of this propositus is --(SEA)/-α(21.9) and its phenotype conforms to the characteristics of Hb H disease, establishing that the combination between -α(21.9) genotype and α(0) genotype can lead to Hb H disease. By molecular analysis, we established that this case fits the characteristic of an α(+) thalassemia genotype. © 2013.

  19. Dissecting the phenotypes of Dravet syndrome by gene deletion.

    Science.gov (United States)

    Rubinstein, Moran; Han, Sung; Tai, Chao; Westenbroek, Ruth E; Hunker, Avery; Scheuer, Todd; Catterall, William A

    2015-08-01

    Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Nav1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Nav1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Nav1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Nav1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Nav1.1 in parvalbumin-expressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context-dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types. © The Author (2015). Published by Oxford University Press on

  20. Viable deletions of the M13 complementary strand origin

    OpenAIRE

    Kim, Myoung Hee; Hines, Jane C.; Ray, Dan S.

    1981-01-01

    The single-stranded DNA of bacteriophage M13 is converted to a duplex replicative form by a mechanism involving RNA-primed initiation at a single unique site on the viral DNA. The DNA sequence that specifies the RNA primer is contained largely within one of two adjacent hairpin structures protected from DNase degradation by RNA polymerase. We have used in vitro techniques to construct a series of M13 mutants having deletions in the region of the complementary strand origin. Deletions of the d...

  1. Polymorphism of angiotensin converting enzyme (insertion/deletion ...

    Indian Academy of Sciences (India)

    and electrolyte balance, and blood pressure (Malik et al. 1997) contains a ... of diverse population groups with a variable prevalence of hypertension .... group were in HWE. The 287-bp insertion/deletion polymorphism located in intron 16 of ACE gene was detected by PCR analysis in the three ethnic groups. The insertion ...

  2. Oncolytic Replication of E1b-Deleted Adenoviruses

    Directory of Open Access Journals (Sweden)

    Pei-Hsin Cheng

    2015-11-01

    Full Text Available Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viralmRNAexport, and cell cycle disruption.

  3. Commentary: The Thrill of Professionalization and the Agony of Deletes

    Science.gov (United States)

    Waite, Susan Field; Leavell, Judy A.

    2006-01-01

    Although some teacher educators hoped that the creation and use of standards would help to professionalize teaching, the discourse of standards and accountability is now being used to erode teacher education. Many teacher educators who anticipated the thrill of professionalization through standards are now experiencing the agony of deletes,…

  4. Case-Deletion Diagnostics for Nonlinear Structural Equation Models

    Science.gov (United States)

    Lee, Sik-Yum; Lu, Bin

    2003-01-01

    In this article, a case-deletion procedure is proposed to detect influential observations in a nonlinear structural equation model. The key idea is to develop the diagnostic measures based on the conditional expectation of the complete-data log-likelihood function in the EM algorithm. An one-step pseudo approximation is proposed to reduce the…

  5. Angiotensin-converting enzyme insertion/deletion gene ...

    Indian Academy of Sciences (India)

    Angiotensin-converting enzyme insertion/deletion gene polymorphism in cystic fibrosis patients. Sabrine Oueslati Sondess Hadj Fredj Hajer Siala Amina Bibi Hajer Aloulou Lamia Boughamoura Khadija Boussetta Sihem Barsaoui Taieb Messaoud. Research Note Volume 95 Issue 1 March 2016 pp 193-196 ...

  6. Induced pluripotent stem cells with a mitochondrial DNA deletion.

    Science.gov (United States)

    Cherry, Anne B C; Gagne, Katelyn E; McLoughlin, Erin M; Baccei, Anna; Gorman, Bryan; Hartung, Odelya; Miller, Justine D; Zhang, Jin; Zon, Rebecca L; Ince, Tan A; Neufeld, Ellis J; Lerou, Paul H; Fleming, Mark D; Daley, George Q; Agarwal, Suneet

    2013-07-01

    In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here, we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases. Copyright © 2013 AlphaMed Press.

  7. Induced pluripotent stem cells with a pathological mitochondrial DNA deletion

    Science.gov (United States)

    Cherry, Anne B. C.; Gagne, Katelyn E.; McLoughlin, Erin M.; Baccei, Anna; Gorman, Bryan; Hartung, Odelya; Miller, Justine D.; Zhang, Jin; Zon, Rebecca L.; Ince, Tan A.; Neufeld, Ellis J.; Lerou, Paul H.; Fleming, Mark D.; Daley, George Q.; Agarwal, Suneet

    2013-01-01

    In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases. PMID:23400930

  8. DSN1 deletion is deleterious to the Saccharomyces cerevisiae while ...

    African Journals Online (AJOL)

    insufficiency and segregational errors in yeast diploid single deletants. Expression of Dsn1p in CHO has been achieved using the pcDNA 3.1/HIS A expression vector. Analysis by DNA sequencing showed no changes in the DSN1 DNA sequence.

  9. The insertion/deletion polymorphism of angiotensin-converting ...

    African Journals Online (AJOL)

    The association between type 2 diabetes mellitus (T2DM) and essential hypertension (EH) is not well understood. Both conditions result from an interaction of multiple genetic (ethnic) and environmental (geographical) factors. One possible genetic determinant is the angiotensin-converting enzyme (ACE) insertion/deletion ...

  10. An angiotensin I-converting enzyme insertion/deletion ...

    Indian Academy of Sciences (India)

    Angiotensin I-converting enzyme (ACE) plays a majorrole in fibrous tissue formation and is highly expressed in lungs. The main aim of this research work was to study the roleof ACE insertion/deletion (I/D) polymorphism, rs4646994, in asthma in Pakistani patients. A total of 854 subjects,including 333 asthma patients and ...

  11. QR in Child Grammar: Evidence from Antecedent-Contained Deletion

    Science.gov (United States)

    Syrett, Kristen; Lidz, Jeffrey

    2009-01-01

    We show that 4-year-olds assign the correct interpretation to antecedent-contained deletion (ACD) sentences because they have the correct representation of these structures. This representation involves Quantifier Raising (QR) of a Quantificational Noun Phrase (QNP) that must move out of the site of the verb phrase in which it is contained to…

  12. The detection of large deletions or duplications in genomic DNA.

    Science.gov (United States)

    Armour, J A L; Barton, D E; Cockburn, D J; Taylor, G R

    2002-11-01

    While methods for the detection of point mutations and small insertions or deletions in genomic DNA are well established, the detection of larger (>100 bp) genomic duplications or deletions can be more difficult. Most mutation scanning methods use PCR as a first step, but the subsequent analyses are usually qualitative rather than quantitative. Gene dosage methods based on PCR need to be quantitative (i.e., they should report molar quantities of starting material) or semi-quantitative (i.e., they should report gene dosage relative to an internal standard). Without some sort of quantitation, heterozygous deletions and duplications may be overlooked and therefore be under-ascertained. Gene dosage methods provide the additional benefit of reporting allele drop-out in the PCR. This could impact on SNP surveys, where large-scale genotyping may miss null alleles. Here we review recent developments in techniques for the detection of this type of mutation and compare their relative strengths and weaknesses. We emphasize that comprehensive mutation analysis should include scanning for large insertions and deletions and duplications. Copyright 2002 Wiley-Liss, Inc.

  13. Catalytic properties of ADAM12 and its domain deletion mutants

    DEFF Research Database (Denmark)

    Jacobsen, Jonas; Visse, Robert; Sørensen, Hans Peter

    2008-01-01

    of pro, catalytic, disintegrin, cysteine-rich, and EGF domains. Here we present a novel activity of recombinant ADAM12-S and its domain deletion mutants on S-carboxymethylated transferrin (Cm-Tf). Cleavage of Cm-Tf occurred at multiple sites, and N-terminal sequencing showed that the enzyme exhibits...

  14. Deletion Mutagenesis and Identification of Causative Mutations in Maize.

    Science.gov (United States)

    Jia, Shangang; Li, Aixia; Zhang, Chi; Holding, David

    2018-01-01

    We describe a method for gamma-irradiation of mature maize seeds to generate mutants with opaque endosperm and reduced kernel fill phenotypes. We also describe methods for mapping mutants and identifying causal gene mutations. Using this method, a population of 1788M2 families and 47 Mo17 × F2s showing stable, segregating, and viable kernel phenotypes was developed. For molecular characterization of the mutants, we utilized a novel functional genomics platform that combines separate Bulked Segregant RNA and exome sequencing data sets (BSREx-seq) to map causative mutations and identify candidate genes within mapping intervals. We also describe the use of exome capture sequencing of F2 mutant and normal pools to perform mapping and candidate gene identification without the need for separate RNA-seq (BSEx-seq). To exemplify the utility of the deletion mutants for functional genomics and provide proof-of-concept for the bioinformatics platform, we summarize the identification of the causative deletion in two mutants. Mutant 937, which was characterized by BSREx-seq, harbors a 6203-bp in-frame deletion covering six exons within the Opaque-1 gene on chromosome 4. Preliminary investigation of opaque mutant 1486 with BSEx-seq shows a tight mapping interval and associated deletion on chromosome 10.

  15. Association of insertion–deletion polymorphism of ACE gene and ...

    African Journals Online (AJOL)

    Introduction: Alzheimer's disease (AD) is a progressive, neurodegenerative disease. Many studies proposed an association of the insertion (I)/deletion (D) polymorphism (indel) in intron 16 of the gene for angiotensin I-converting enzyme (ACE) on chromosome 17q23 with Alzheimer's disease. ACE indel and related ...

  16. 76 FR 16733 - Procurement List; Proposed Additions and Deletions

    Science.gov (United States)

    2011-03-25

    ...-Wagner-O'Day Act (41 U.S.C. 46-48c) in connection with the product and services proposed for deletion... AVIATION, RICHMOND, VA. Services: Service Type/Locations: Janitorial/Custodial. U.S. Army Reserve Center... COMMITTEE FOR PURCHASE FROM PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed...

  17. [An updated review of 1p36 deletion (monosomy) syndrome].

    Science.gov (United States)

    Bello, Sabina; Rodríguez-Moreno, Antonio

    The Monosomy 1p36 deletion syndrome is part of the group of diseases known as Rare Diseases. The objective of the present work is to review the characteristics of Monosomy 1p36 deletion syndrome. The monosomy 1p36 deletion syndrome phenotype includes: dysmorphic craniofacial features; large anterior fontanelle, unibrow, deep-set eyes, epicanthus, wide nasal root/bridge, mandible hypoplasia, abnormal location of the pinna, philtrum and pointed chin; neurological alterations: seizures and hydrocephalus (in some cases). Cerebral malformations: ventricular hypertrophy, increased subarachnoid space, morphological alterations of corpus callosum, cortical atrophy, delays in myelinisation, periventricular leukomalacia and periventricular heterotopia. These alterations produce intellectual disability and delays in motor growth, communication skills, language, social and adaptive behaviour. It is Hearing and vision impairments are also observed in subjects with this syndrome, as well as alterations of cardiac, endocrine and urinary systems and alterations at skin and skeletal level. Approximately 100 cases have been documented since 1981. This rare disease is the most common subtelomeric-micro-deletion syndrome. In situ hybridization with fluorescence (FISH) and array-comparative genomic hybridization (CGH-array) are at present the two best diagnostic techniques. There is currently no effective medical treatment for this disease. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Variations in angiotensin-converting enzyme gene insertion/deletion ...

    Indian Academy of Sciences (India)

    deletion (I/D) polymorphism in the Indian population is poorly known. In order to determine the status of the polymorphism, young unrelated male army recruits were screened. The population had cultural and linguistic differences and lived in an ...

  19. Genetic Counseling for the 22q11.2 Deletion

    Science.gov (United States)

    McDonald-McGinn, Donna M.; Zackai, Elaine H.

    2008-01-01

    Because of advances in palliative medical care, children with the 22q11.2 deletion syndrome are surviving into adulthood. An increase in reproductive fitness will likely follow necessitating enhanced access to genetic counseling for these patients and their families. Primary care physicians/obstetric practitioners are in a unique position to…

  20. Lack of Association of Insertion/Deletion Polymorphism in ...

    African Journals Online (AJOL)

    DRNAQSHAB

    2012-01-19

    Jan 19, 2012 ... associated with nephropathy in type 2 diabetic patients of Punjabi population of Pakistan. Key words: Angiotensin converting enzymes, insertion/deletion polymorphism, albuminuria and type 2 diabetes mellitus. INTRODUCTION. Diabetic nephropathy is a leading cause of diabetic. *Corresponding author.

  1. 77 FR 31335 - Procurement List; Proposed Additions and Deletion

    Science.gov (United States)

    2012-05-25

    .... Services Service Type/Location: Laundry and Dry Cleaning Service, Buckley Air Force Base Lodging & Medical... products and services to the Procurement List that will be furnished by nonprofit agencies employing persons who are blind or have other severe disabilities, and deletes a service previously provided by such...

  2. Effect Alpha Globlin Gene Deletion And Gamma Globin Gene -158 ...

    African Journals Online (AJOL)

    ... have been unable to find a molecular basis for the benign clinical course in all our patients. Other genetic or acquired factors must be hypothesized which ameliorate the clinical condition. Keywords: β- thalassemia, Xmn1 polymorphism, α-globin gene deletion. Egyptian Journal of Biochemistry and Molecular Biology Vol.

  3. Rare copy number deletions predict individual variation in intelligence.

    Directory of Open Access Journals (Sweden)

    Ronald A Yeo

    2011-01-01

    Full Text Available Phenotypic variation in human intellectual functioning shows substantial heritability, as demonstrated by a long history of behavior genetic studies. Many recent molecular genetic studies have attempted to uncover specific genetic variations responsible for this heritability, but identified effects capture little variance and have proven difficult to replicate. The present study, motivated an interest in "mutation load" emerging from evolutionary perspectives, examined the importance of the number of rare (or infrequent copy number variations (CNVs, and the total number of base pairs included in such deletions, for psychometric intelligence. Genetic data was collected using the Illumina 1MDuoBeadChip Array from a sample of 202 adult individuals with alcohol dependence, and a subset of these (N = 77 had been administered the Wechsler Abbreviated Scale of Intelligence (WASI. After removing CNV outliers, the impact of rare genetic deletions on psychometric intelligence was investigated in 74 individuals. The total length of the rare deletions significantly and negatively predicted intelligence (r = -.30, p = .01. As prior studies have indicated greater heritability in individuals with relatively higher parental socioeconomic status (SES, we also examined the impact of ethnicity (Anglo/White vs. Other, as a proxy measure of SES; these groups did not differ on any genetic variable. This categorical variable significantly moderated the effect of length of deletions on intelligence, with larger effects being noted in the Anglo/White group. Overall, these results suggest that rare deletions (between 5% and 1% population frequency or less adversely affect intellectual functioning, and that pleotropic effects might partly account for the association of intelligence with health and mental health status. Significant limitations of this research, including issues of generalizability and CNV measurement, are discussed.

  4. Deletion affecting band 7q36 not associated with holoprosencephaly

    Energy Technology Data Exchange (ETDEWEB)

    Ebrahim, S.A.D.; Krivchenia, E.; Mohamed, A.N. [Wayne State Univ., Detroit, MI (United States)] [and others

    1994-09-01

    Although the appearance of 7q36 aberrations have been postulated to be responsible for holoprosencephaly (HPE), the presence of a de novo 7q36 deletion in fetus without HPE has not been reported. We report the first case of a fetus with 7q36 deletion but lacking HPE. Ultrasound examination of a 25-year-old G3P1 Caucasian female showed small head circumference with microcephaly at 28 weeks. Decreased amniotic fluid volume, bilateral renal dilatation and abnormal facial features were also noted. Chromosome analysis after cordocentesis showed an abnormal female karyotype with a deletion involving the chromosome band 7q36, 46,XX,del(7)(q36). Chromosome studies on the biological parents were normal. In view of the chromosome finding and after extensive counseling, the couple elected to terminate the pregnancy. The chromosome findings were confirmed by fetal blood chromosome analysis at termination. Post-mortem examination confirmed dysmorphic features including a depressed nasal bridge and large flat ears with no lobules, but no cleft lip or palate was noted. Internal abnormalities included a bicuspid pulmonary valve and abnormally located lungs. The brain weighed 190g (249 {plus_minus} 64g expected) and had symmetric cerebral hemispheres without evidence of HPE or other gross or microscopic malformation, except focal cerebellar cortical dysplasia. In summary, our patient showed a deletion of the same chromosomal band implicated in HPE but lacked HPE. This finding indicates that 7q36 deletion may be seen in the absence of HPE and suggests that other genetic mechanisms may be responsible for HPE in this setting.

  5. Redefining phenotypes associated with mitochondrial DNA single deletion.

    Science.gov (United States)

    Mancuso, Michelangelo; Orsucci, Daniele; Angelini, Corrado; Bertini, Enrico; Carelli, Valerio; Comi, Giacomo Pietro; Donati, Maria Alice; Federico, Antonio; Minetti, Carlo; Moggio, Maurizio; Mongini, Tiziana; Santorelli, Filippo Maria; Servidei, Serenella; Tonin, Paola; Toscano, Antonio; Bruno, Claudio; Bello, Luca; Caldarazzo Ienco, Elena; Cardaioli, Elena; Catteruccia, Michela; Da Pozzo, Paola; Filosto, Massimiliano; Lamperti, Costanza; Moroni, Isabella; Musumeci, Olimpia; Pegoraro, Elena; Ronchi, Dario; Sauchelli, Donato; Scarpelli, Mauro; Sciacco, Monica; Valentino, Maria Lucia; Vercelli, Liliana; Zeviani, Massimo; Siciliano, Gabriele

    2015-05-01

    Progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and "KSS spectrum" (a category of which classic KSS represents the most severe extreme). The criteria for "KSS spectrum" include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5% PEO, 31.6% KSS spectrum (including classic KSS 6.6%) and 2.6% Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials.

  6. Velo-cardio-facial syndrome: Frequency and textent of 22q11 deletions

    Energy Technology Data Exchange (ETDEWEB)

    Lindsay, E.A.; Goldberg, R.; Jurecic, V. [and others

    1995-07-03

    Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). In 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions. 22 refs., 2 figs., 1 tab.

  7. Restoration of half the normal dystrophin sequence in a double-deletion Duchenne muscular dystrophy family

    Energy Technology Data Exchange (ETDEWEB)

    Hoop, R.C.; Schwartz, L.S.; Hoffman, E.P. [Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Russo, L.S. [Univ. of Florida, Jacksonville, FL (United States); Riconda, D.L. [Orlando Regional Medical Center, Orlando, FL (United States)

    1994-02-01

    Two male cousins with Duchenne muscular dystrophy were found to have different maternal dystrophin gene haplotypes and different deletion mutations. One propositus showed two noncontiguous deletions-one in the 5{prime}, proximal deletional hotspot region, and the other in the 3{prime}, more distal deletional hotspot region. The second propositus showed only the 5{prime} deletion. Using multiple fluorescent exon dosage and fluorescent multiplex CA repeat linkage analyses, the authors show that the mother of each propositus carries both deletions on the same grandmaternal X chromosome. This paradox is explained by a single recombinational event between the 2 deleted regions of one of the carrier`s dystrophin genes, giving rise to a son with a partially {open_quotes}repaired{close_quotes} gene retaining only the 5{prime} deletion. 20 refs., 4 figs.

  8. p27KIP1 Deletions in Childhood Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Hiroaki Komuro

    1999-08-01

    Full Text Available The p27KIP1 gene, which encodes a cyclin-dependent kinase (CDK inhibitor, has been assigned to chromosome band 12p12, a region often affected by cytogenetically apparent deletions or translocations in childhood acute lymphoblastic leukemia (ALL. As described here, fluorescence in situ hybridization (FISH analysis of 35 primary ALL samples with cytogenetic evidence of 12p abnormalities revealed hemizygous deletions of p27KIP1 in 29 cases. Further analysis of 19 of these cases with two additional gene-specific probes from the 12p region (hematopoietic cell phosphatase, HCP and cyclin D2, CCND2 showed that p27KIP1 is located more proximally on the short arm of chromosome 12 and is deleted more frequently than either HCP or CCND2. Of 16 of these cases with hemizygous deletion of p27KIP1, only eight showed loss of HCP or CCND2, whereas loss of either of the latter two loci was uniformly associated with loss of p27KIP1. Missense mutations or mutations leading to premature termination codons were not detected in the coding sequences of the retained p27KIP1 alleles in any of the 16 ALL cases examined, indicating a lack of homozygous inactivation. By Southern blot analysis, one case of primary T-cell ALL had hemizygous loss of a single p27KIP1 allele and a 34.5-kb deletion, including the second coding exon of the other allele. Despite homozygous inactivation of p27KIP1 in this case, our data suggest that haploinsufficiency for p27KIP1 is the primary consequence of 12p chromosomal deletions in childhood ALL. The oncogenic role of reduced, but not absent, levels of p27KIP1 is supported by recent studies in murine models and evidence that this protein not only inhibits the activity of complexes containing CDK2 and cyclin E, but also promotes the assembly and catalytic activity of CDK4 or CDK6 in complexes with cyclin D.

  9. Sequence homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.

    Directory of Open Access Journals (Sweden)

    Bekim Sadikovic

    2010-12-01

    Full Text Available Mitochondrial DNA (mtDNA deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM, progressive external ophthalmoplegia (PEO, and Kearns-Sayre syndrome (KSS, to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old showed a diffused pattern of deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41. Only 15% (3/20 of the young patients (<6 years old carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17 exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier

  10. Sequence homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.

    Science.gov (United States)

    Sadikovic, Bekim; Wang, Jing; El-Hattab, Ayman W; Landsverk, Megan; Douglas, Ganka; Brundage, Ellen K; Craigen, William J; Schmitt, Eric S; Wong, Lee-Jun C

    2010-12-20

    Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement.

  11. Mitochondrial DNA deletion mutations in adult mouse cardiac side population cells

    Energy Technology Data Exchange (ETDEWEB)

    Lushaj, Entela B., E-mail: lushaj@surgery.wisc.edu [Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792 (United States); Lozonschi, Lucian; Barnes, Maria; Anstadt, Emily; Kohmoto, Takushi [Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792 (United States)

    2012-06-01

    We investigated the presence and potential role of mitochondrial DNA (mtDNA) deletion mutations in adult cardiac stem cells. Cardiac side population (SP) cells were isolated from 12-week-old mice. Standard polymerase chain reaction (PCR) was used to screen for the presence of mtDNA deletion mutations in (a) freshly isolated SP cells and (b) SP cells cultured to passage 10. When present, the abundance of mtDNA deletion mutation was analyzed in single cell colonies. The effect of different levels of deletion mutations on SP cell growth and differentiation was determined. MtDNA deletion mutations were found in both freshly isolated and cultured cells from 12-week-old mice. While there was no significant difference in the number of single cell colonies with mtDNA deletion mutations from any of the groups mentioned above, the abundance of mtDNA deletion mutations was significantly higher in the cultured cells, as determined by quantitative PCR. Within a single clonal cell population, the detectable mtDNA deletion mutations were the same in all cells and unique when compared to deletions of other colonies. We also found that cells harboring high levels of mtDNA deletion mutations (i.e. where deleted mtDNA comprised more than 60% of total mtDNA) had slower proliferation rates and decreased differentiation capacities. Screening cultured adult stem cells for mtDNA deletion mutations as a routine assessment will benefit the biomedical application of adult stem cells.

  12. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions : a European collaborative study

    NARCIS (Netherlands)

    Ryan, AK; Goodship, JA; Wilson, DI; Philip, N; Levy, A; Seidel, H; Schuffenhauer, S; Oechsler, H; Belohradsky, B; Prieur, M; Aurias, A; Raymond, FL; ClaytonSmith, J; Hatchwell, E; McKeown, C; Beemer, FA; Dallapiccola, B; Novelli, G; Hurst, JA; Ignatius, J; Green, AJ; Brueton, L; BrondumNielsen, K; Stewart, F; VanEssen, T; Patton, M; Paterson, J; Scambler, PJ

    1997-01-01

    We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22q11. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight

  13. Differentiated psychopharmacological treatment in three genetic subtypes of 22q11.2 deletion syndrome

    NARCIS (Netherlands)

    Verhoeven, W.M.A.; Egger, J.I.M.; Leeuw, N. de

    2017-01-01

    Introduction: The 22q11.2 deletion syndrome (22q11DS), mostly caused by the common deletion including the TBX- and COMT-genes (LCR22A-D), is highly associated with somatic anomalies. The distal deletion (distal of LCR22D) comprises the MAPK1-gene and is associated with specific heart defects. The

  14. 41 CFR 51-6.8 - Deletion of items from the Procurement List.

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 1 2010-07-01 2010-07-01 true Deletion of items from...-PROCUREMENT PROCEDURES § 51-6.8 Deletion of items from the Procurement List. (a) When a central nonprofit... shall notify the Committee staff immediately. Before reaching a decision to request a deletion of an...

  15. 36 CFR 902.14 - Deletion of nondiscloseable information from requested records.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Deletion of nondiscloseable... AVENUE DEVELOPMENT CORPORATION FREEDOM OF INFORMATION ACT General Administration § 902.14 Deletion of... segregable after deletion of the nondiscloseable portions, will be released. If the information in the...

  16. 46 CFR 67.513 - Application for evidence of deletion from documentation.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Application for evidence of deletion from documentation... AND MEASUREMENT OF VESSELS DOCUMENTATION OF VESSELS Fees § 67.513 Application for evidence of deletion from documentation. An application fee is charged for evidence of deletion from documentation in...

  17. 14 CFR 1206.202 - Deletion of segregable portions of a record.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Deletion of segregable portions of a record... AVAILABILITY OF AGENCY RECORDS TO MEMBERS OF THE PUBLIC Records Available § 1206.202 Deletion of segregable... that indication would harm an interest protected by the exemption in Subpart 3 under which the deletion...

  18. 32 CFR 310.34 - Amendment and deletion of system notices.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Amendment and deletion of system notices. 310.34... (CONTINUED) PRIVACY PROGRAM DOD PRIVACY PROGRAM Publication Requirements § 310.34 Amendment and deletion of... system. (see § 310.32(q)). (c) Deletion of system notices. (1) Whenever a system is discontinued...

  19. 19 CFR 176.22 - Deletion of protest or entry number.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 2 2010-04-01 2010-04-01 false Deletion of protest or entry number. 176.22... Facts § 176.22 Deletion of protest or entry number. If any protest number or entry number is to be... authorized official making and approving the deletion. [T.D. 70-181, 35 FR 13433, Aug. 22, 1970] ...

  20. 47 CFR 76.1601 - Deletion or repositioning of broadcast signals.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 4 2010-10-01 2010-10-01 false Deletion or repositioning of broadcast signals... RADIO SERVICES MULTICHANNEL VIDEO AND CABLE TELEVISION SERVICE Notices § 76.1601 Deletion or... to § 76.1601: No deletion or repositioning of a local commercial television station shall occur...

  1. Detection of mitochondrial DNA deletions in human cells induced by ionizing radiation

    International Nuclear Information System (INIS)

    Liu, Qing-Jie; Feng, Jiang-Bin; Lu, Xue; Li, Yu-Wen; Chen, De-Qing

    2008-01-01

    Full text: Purpose: To screen the novel mitochondrial DNA (mt DNA) deletions induced by ionizing radiation, and analyze the several kinds of mt DNA deletions, known as 3895 bp, 889 bp, 7436 bp or 4934 bp deletions. Methods: Long-range PCR with two pairs of primers, which could amplify the whole human mitochondrial genome, was used to analyze the lymphoblastoid cell line before and after exposed to 10 Gy 60 Co γ-rays. The limited condition PCR was used to certify the possible mt DNA deletion showed by long-range PCR. The PCR products were purified, cloned, sequenced and the sequence result were BLASTed. Regular PCR or nest-PCR were used to analyze the 3895 bp, 889 bp, 7436 bp or 4934 bp deletions before and after radiation exposure. The final PCR products were purified, sequenced and BALSTed on standard human mitochondrial genome sequence database. Results: (1) The predicted bands of mt DNA were observed on the control cell lines, and the possible mt DNA deletions were also detected on the irradiated cell lines. The deletions were certified by the limited condition PCR. The sequence BLAST results of the cloned PCR products showed that two kinds of deletions, 7455 bp deletion (nt 475-7929 in heavy strand) and 9225 bp deletion (nt 7714-369 in heavy strand), which were between two 8 bp direct repeats. Further bioinformatics analysis showed that the two deletions were novel deletions. (2) The 889 bp and 3895 bp deletion were not detected for the cell line samples not exposed to 60 Co γ-rays. The 889 bp and 3895 bp deletions were detected on samples exposed to 10 Gy 60 Co γ-rays. The BALST results showed that the 889 bp and 3895 deletions flanked nt 11688 bp-12576, nt 548 bp-4443, respectively. The 7436 bp deletion levels were not changed much before and after irradiation. (3) The 4934 bp deletions had the same pattern as 7436 bp deletion, but it could induced by radiation. Conclusions: Ionizing radiation could induce the human lymphoblastoid two novel mt DNA

  2. Targeted deletions of cyclooxygenase-2 and atherogenesis in mice

    DEFF Research Database (Denmark)

    Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene

    2010-01-01

    BACKGROUND: Although the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI(2)), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX......-2 in macrophages and T cells (TCs) to atherogenesis. METHODS AND RESULTS: Deletion of macrophage-COX-2 (Mac-COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis...... by approximately 30%. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic...

  3. Combinations of probabilistic and approximate quantum cloning and deleting

    International Nuclear Information System (INIS)

    Qiu Daowen

    2002-01-01

    We first construct a probabilistic and approximate quantum cloning machine (PACM) and then clarify the relation between the PACM and other cloning machines. After that, we estimate the global fidelity of the approximate cloning that improves the previous estimation for the deterministic cloning machine; and also derive a bound on the success probability of producing perfect multiple clones. Afterwards, we further establish a more generalized probabilistic and approximate cloning and deleting machine (PACDM) and discuss the connections of the PACDM to some of the existing quantum cloning and deleting machines. Finally the global fidelity and a bound on the success probability of the PACDM are obtained. Summarily, the quantum devices established in this paper improve and also greatly generalize some of the existing machines

  4. Common Deletion (CD) in mitochondrial DNA of irradiated rat heart

    Energy Technology Data Exchange (ETDEWEB)

    Siqueira, Raquel Gomes; Ferreira-Machado, Samara C.; Almeida, Carlos E.V. de, E-mail: raquelgsiqueira@gmail.com [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biologia Roberto Alcanatara Gomes. Lab. de Ciencias Radiologicas; Silva, Dayse A. da; Carvalho, Elizeu F. de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biologia Roberto Alcanatara Gomes. Lab. de Diagnosticos por DNA; Melo, Luiz D.B. de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biofisica Carlos Chagas Filho. Lab. de Parasitologia Molecular

    2014-05-15

    The purpose of this study was to map the common deletion (CD) area in mtDNA and investigate the levels of this deletion in irradiated heart. The assays were developed in male Wistar rats that were irradiated with three different single doses (5, 10 or 15 Gy) delivered directly to the heart and the analyses were performed at various times post-irradiation (3, 15 or 120 days). The CDs area were sequenced and the CD quantified by real-time PCR. Our study demonstrated that the CD levels progressively decreased from the 3rd until the 15th day after irradiation, and then increased thereafter. Additionally, it was observed that the levels of CD are modulated differently according to the different categories of doses (moderate and high). This study demonstrated an immediate response to ionizing radiation, measured by the presence of mutations in the CD area and a decrease in the CD levels. (author)

  5. Mitochondrial DNA exhibits resistance to induced point and deletion mutations

    Science.gov (United States)

    Valente, William J.; Ericson, Nolan G.; Long, Alexandra S.; White, Paul A.; Marchetti, Francesco; Bielas, Jason H.

    2016-01-01

    The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed MutaTMMouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays. Surprisingly, our results demonstrate mutagen treatment did not increase mitochondrial point or deletion mutation frequencies, despite evidence both compounds increase nuclear DNA mutations and demonstrated B[a]P adduct formation in mtDNA. These findings contradict models of mtDNA mutagenesis that assert the elevated rate of mtDNA mutation stems from damage sensitivity and abridged repair capacity. Rather, our results demonstrate induced mtDNA damage does not readily convert into mutation. These findings suggest robust mitochondrial damage responses repress induced mutations after mutagen exposure. PMID:27550180

  6. Distinct phenotype of PHF6 deletions in females.

    Science.gov (United States)

    Di Donato, N; Isidor, B; Lopez Cazaux, S; Le Caignec, C; Klink, B; Kraus, C; Schrock, E; Hackmann, K

    2014-02-01

    We report on two female patients carrying small overlapping Xq26.2 deletions of 100 kb and 270 kb involving the PHF6 gene. Mutations in PHF6 have been reported in individuals with Borjeson-Forssman-Lehmann syndrome, a condition present almost exclusively in males. Two very recent papers revealed de novo PHF6 defects in seven female patients with intellectual disability and a phenotype resembling Coffin-Siris syndrome (sparse hair, bitemporal narrowing, arched eyebrows, synophrys, high nasal root, bulbous nasal tip, marked clinodactyly with the hypoplastic terminal phalanges of the fifth fingers and cutaneous syndactyly of the toes, Blaschkoid linear skin hyperpigmentation, dental anomalies and occasional major malformations). The clinical presentation of these patients overlaps completely with our first patient, who carries a germline deletion involving PHF6. The second patient has a mosaic deletion and presented with a very mild phenotype of PHF6 loss in females. Our report confirms that PHF6 loss in females results in a recognizable phenotype overlapping with Coffin-Siris syndrome and distinct from Borjeson-Forssman-Lehmann syndrome. We expand the clinical spectrum and provide the first summary of the recommended medical evaluation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  7. SHANK1 Deletions in Males with Autism Spectrum Disorder.

    Science.gov (United States)

    Sato, Daisuke; Lionel, Anath C; Leblond, Claire S; Prasad, Aparna; Pinto, Dalila; Walker, Susan; O'Connor, Irene; Russell, Carolyn; Drmic, Irene E; Hamdan, Fadi F; Michaud, Jacques L; Endris, Volker; Roeth, Ralph; Delorme, Richard; Huguet, Guillaume; Leboyer, Marion; Rastam, Maria; Gillberg, Christopher; Lathrop, Mark; Stavropoulos, Dimitri J; Anagnostou, Evdokia; Weksberg, Rosanna; Fombonne, Eric; Zwaigenbaum, Lonnie; Fernandez, Bridget A; Roberts, Wendy; Rappold, Gudrun A; Marshall, Christian R; Bourgeron, Thomas; Szatmari, Peter; Scherer, Stephen W

    2012-05-04

    Recent studies have highlighted the involvement of rare (number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  8. Deletion of PREPl causes growth impairment and hypotonia in mice.

    Directory of Open Access Journals (Sweden)

    Anna Mari Lone

    Full Text Available Genetic studies of rare diseases can identify genes of unknown function that strongly impact human physiology. Prolyl endopeptidase-like (PREPL is an uncharacterized member of the prolyl peptidase family that was discovered because of its deletion in humans with hypotonia-cystinuria syndrome (HCS. HCS is characterized by a number of physiological changes including diminished growth and neonatal hypotonia or low muscle tone. HCS patients have deletions in other genes as well, making it difficult to tease apart the specific role of PREPL. Here, we develop a PREPL null (PREPL(-/- mouse model to address the physiological role of this enzyme. Deletion of exon 11 from the Prepl gene, which encodes key catalytic amino acids, leads to a loss of PREPL protein as well as lower Prepl mRNA levels. PREPL(-/- mice have a pronounced growth phenotype, being significantly shorter and lighter than their wild type (PREPL(+/+ counterparts. A righting assay revealed that PREPL(-/- pups took significantly longer than PREPL(+/+ pups to right themselves when placed on their backs. This deficit indicates that PREPL(-/- mice suffer from neonatal hypotonia. According to these results, PREPL regulates growth and neonatal hypotonia in mice, which supports the idea that PREPL causes diminished growth and neonatal hypotonia in humans with HCS. These animals provide a valuable asset in deciphering the underlying biochemical, cellular and physiological pathways that link PREPL to HCS, and this may eventually lead to new insights in the treatment of this disease.

  9. Familial 22q11.2 deletion syndrome with autosomal dominant inheritance

    Directory of Open Access Journals (Sweden)

    Bahar Gokturk

    2016-06-01

    Full Text Available 22q11.2 deletion syndrome is the most frequent microdeletion syndrome in humans and caused by hemizygote deletion on only one chromosome. Most of probands have a de novo deletion of 22q11.2, but 8-20% have inherited the 22q11.2 deletion from a parent (autosomal dominant mutation. Genotype-phenotype correlation is weak in this patient group. We aimed to present three members in the same family due to an autosomal dominant inheritance with 22q11.2 deletion and different clinical findings. [Cukurova Med J 2016; 41(2.000: 379-385

  10. Molecular and cytogenetic investigation of Y chromosome deletions over three generations facilitated by intracytoplasmic sperm injection.

    Science.gov (United States)

    Minor, Agata; Wong, Edgar Chan; Harmer, Karynn; Ma, Sai

    2007-08-01

    The azoospermic factor (AZF) region is critical for normal spermatogenesis since microdeletions and partial deletions have been associated with infertility. We investigate the diagnostic ability of karyotyping in detecting clinically relevant Y chromosome deletions. The clinical significance of heterochromatin deletions, microdeletions and partial AZFc deletions is also evaluated. A patient with a Yq deletion, affected by severe oligoasthenoteratozoospermia, underwent intracytoplasmic sperm injection (ICSI) which resulted in the birth of a healthy baby boy. The patient, his father and his son underwent Y chromosome microdeletion and partial AZFc deletion screening. We also studied the aneuploidy rate in the sperm of the patient by fluorescent in situ hybridization. AZF microdeletions were absent in the family. However, microdeletion analysis confirmed that the Yq deletion was limited to the heterochromatin. We found a partial AZFc gr/gr deletion in all three family members. We observed an increased rate of sex chromosome aneuploidy in the infertile patient. Cytogenetic analysis was misleading in identifying the Yq breakpoint. Infertility observed in the patient was associated with the gr/gr partial deletion. However, because of the incomplete penetrance of gr/gr deletions, the consequence of the vertical transmission of the deletion through ICSI remains unknown. Copyright (c) 2007 John Wiley & Sons, Ltd.

  11. Exonic deletions of FXN and early-onset Friedreich ataxia.

    Science.gov (United States)

    Anheim, Mathieu; Mariani, Louise-Laure; Calvas, Patrick; Cheuret, Emmanuel; Zagnoli, Fabien; Odent, Sylvie; Seguela, Claire; Marelli, Cecilia; Fritsch, Marlène; Delaunoy, Jean-Pierre; Brice, Alexis; Dürr, Alexandra; Koenig, Michel

    2012-07-01

    Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene. The remaining patients are compound heterozygous for an expansion and a point mutation. Patients who are compound heterozygous for an exonic deletion and an expansion are exquisitely rare. To describe 6 patients affected with FA due to an exonic deletion mutation (FAexdel) and to compare these 6 patients with FAexdel with 46 patients consecutively diagnosed with typical FA due to homozygous GAA expansion and whose small expansions were within the same range as that of the expansions of the patients with FAexdel. Description of a series. Academic research. Six patients with FAexdel and 46 patients with typical FA. FXN gene analysis, including assessments of GAA expansion and exon sequencing and determination of exonic copy numbers using multiplex ligation-dependent probe amplification. We identified 6 patients with FA who presented with the combination of 1 GAA expansion and 1 FXN exonic deletion. The mean (SD) age at onset of the disease was earlier for patients with FAexdel (7 [4] years [range, 3-12 years]) than for patients with typical FA (15 [5] years [range, 6-30 years]) (P = .001), and the median time to confinement to wheelchair was shorter for patients with FAexdel (20 years) than for patients with typical FA (28 years) (P = .002). There was no difference between the mean (SD) size of the expansion for the patients with FAexdel (780 [256] GAA triplet repeat sequences [range, 340-1070 GAA triplet repeat sequences]) and the mean (SD) size of the short expansion for the patients with typical FA (634 [163] GAA triplet repeat sequences [range, 367-1000 GAA triplet repeat sequences]) (P = .10). The mean disease duration before becoming wheelchair bound was shorter for patients with FAexdel (9 years) than for patients with typical FA (13 years), and the

  12. Generating Bona Fide Mammalian Prions with Internal Deletions.

    Science.gov (United States)

    Munoz-Montesino, Carola; Sizun, Christina; Moudjou, Mohammed; Herzog, Laetitia; Reine, Fabienne; Chapuis, Jérôme; Ciric, Danica; Igel-Egalon, Angelique; Laude, Hubert; Béringue, Vincent; Rezaei, Human; Dron, Michel

    2016-08-01

    Mammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha-helical content, loosing the three alpha-helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C terminus of ovine PrP, since this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating and de novo infectious for naive homologous and wild-type PrP-expressing cells. Moreover, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies other than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha-helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions. Prions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative

  13. Interstitial deletion 5p accompanied by dicentric ring formation of the deleted segment resulting in trisomy 5p13-cen

    Energy Technology Data Exchange (ETDEWEB)

    Schuffenhauer, S.; Daumer-Haas, C.; Murken, J. [Ludwig-Maximilians-Universitaet Muenchen (Germany)] [and others

    1996-10-02

    Karyotypes with an interstitial deletion and a marker chromosome formed from the deleted segment are rare. We identified such a rearrangement in a newborn infant, who presented with macrocephaly, asymmetric square skull, minor facial anomalies, omphalocele, inguinal hernias, hypospadias, and club feet. The karyotype 46,XY,del(5)(pter{r_arrow}p13::cen{r_arrow}qter)/47,XY,+dicr(5)(:p13{r_arrow}cen::p13{r_arrow}cen),del(5)(pter{r_arrow}p13::cen{r_arrow}qter) was identified by banding studies and FISH analysis in the peripheral lymphocytes. One breakpoint on the del(5) maps distal to GDNF, and FISH analysis using an {alpha}-satellite probe suggests that the proximal breakpoint maps within the centromere. The dicentric r(5) consists of two copies of the segment deleted in the del(5), resulting in trisomy of proximal 5p (5p13-cen). The phenotype of the propositus is compared with other trisomy 5p cases and possible mechanisms for the generation of this unique chromosomal rearrangement are discussed. 27 refs., 3 figs.

  14. Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin

    Energy Technology Data Exchange (ETDEWEB)

    Thanh, L.T.; Man, Nguyen Thi; Morris, G.E. [Wales Institute, Clwyd (United Kingdom)] [and others

    1995-08-28

    We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immunohistochemistry or Western blotting with these {open_quotes}exon-specific{close_quotes} mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions in Becker muscular dystrophy patients. The antibodies were mapped to the following exons: exon 45 (2 mAbs), exon 46 (6), exon 47 (1), exons 47/48 (4), exons 48-50 (6), and exon 50 (1). PCR amplification of single exons or groups of exons was used both to produce specific dystrophin immunogens and to map the mAbs obtained. PCR-mediated mutagenesis was also used to identify regions of dystrophin important for mAb binding. Because the mAbs can be used to characterize the dystrophin produced by individual muscle fibres, they will also be useful for studying {open_quotes}revertant{close_quotes} fibres in Duchenne muscle and for monitoring the results of myoblast therapy trials in MD patients with deletions in this region of the dystrophin gene. 27 refs., 7 figs., 3 tabs.

  15. DNA-based detection of chromosome deletion and amplification: diagnostic and mechanistic significance

    International Nuclear Information System (INIS)

    Latt, S.A.; Lalande, M.; Donlon, T.

    1986-01-01

    This paper describes a few of the many possible examples in which application of a molecular cytogenetic approach can ultimately lead to a new, important understanding about the statics and dynamics of human chromosome structure. In the case of retinoblastoma, cytological observations of deletions and linkage analysis have positioned the retinoblastoma locus to bank 13q14. This locus is grossly deleted in some spontaneous tumors. It is still necessary to locate more precisely and characterize the nature of the retinoblastoma locus, as well as the basis for the heterogeneity in deletions removing one copy of this locus. One is left with the possibility that those deletions that may be observed cytologically reflect but the tip of the iceberg of deletions; detection of others may require molecular probes. A related question is the nature of the DNA sequences at the deletion boundaries and the role they play in promoting these deletions

  16. Molecular cytogenetic detection of chromosome 15 deletions in patients with Prader-Willi and Angelman syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Chadwick, D.E.; Weksberg, R.; Shuman, C. [Hospital for Sick Children, Toronto (Canada)] [and others

    1994-09-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct genetic disorders involving alterations of chromosome 15q11-q13. Approximately 75% of individuals with PWS and AS have deletions within 15q11-q13 by molecular analysis. We have evaluated fluorescence in situ hybridization (FISH) for the clinical laboratory detection of del(15)(q11q13) using the cosmid probes D15S11 and GABRB3 (ONCOR, Gaithersburg, NY). 4/4 PWS and 1/1 AS patients previously identified as having cytogenetic deletions were deleted for both probes. In a prospectively ascertained series of 54 patient samples referred to rule out either PWS or AS, 8 were deleted for D15S11 and GABRB3. In addition, an atypical deletion patient with PWS was also identified who was found to be deleted for GABRB3 but not D15S11. The SNRPN locus was also deleted in this patient. Only 4 of the 9 patient samples having molecular cytogenetic deletions were clearly deleted by high resolution banding (HRB) analysis. The microscopic and submicroscopic deletions have been confirmed by dinucleotide (CA) repeat analysis. Microsatellite polymorphism analysis was also used to demonstrate that five non-deletion patients in this series had biparental inheritance of chromosome 15, including region q11-q13. Deletions were not detected by either HRB, FISH or microsatellite polymorphism analysis in samples obtained from parents of the deletion patients. Methylation studies of chromosome 15q11-q13 are in progress for this series of PWS and AS families. FISH analysis of chromosome 15q11-q13 in patients with PWS and AS is a rapid, sensitive and reliable method for deletion detection.

  17. Deletion involving D15S113 in a mother and son without Angelman syndrome: Refinement of the Angelman syndrome critical deletion region

    Energy Technology Data Exchange (ETDEWEB)

    Michaelis, R.C.; Skinner, S.A.; Lethco, B.A. [Greenwood Genetic Center, SC (United States)] [and others

    1995-01-02

    Deletions of 15q11-q13 typically result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The critical deletion region for Angelman syndrome has recently been restricted by a report of an Angelman syndrome patient with a deletion spanning less than 200 kb around the D15S113 locus. We report here on a mother and son with a deletion of chromosome 15 that includes the D15S113 locus. The son has mild to moderate mental retardation and minor anomalies, while the mother has a borderline intellectual deficit and slightly downslanting palpebral fissures. Neither patient has the seizures, excessive laughter and hand clapping, ataxia or the facial anomalies which are characteristic of Angelman syndrome. The proximal boundary of the deletion in our patients lies between the D15S10 and The D15S113 loci. Our patients do not have Angelman syndrome, despite the deletion of the D15S113 marker. This suggests that the Angelman syndrome critical deletion region is now defined as the overlap between the deletion found in the previously reported Angelman syndrome patient and the region that is intact in our patients. 28 refs., 6 figs.

  18. A Tunisian patient with Pearson syndrome harboring the 4.977kb common deletion associated to two novel large-scale mitochondrial deletions.

    Science.gov (United States)

    Ayed, Imen Ben; Chamkha, Imen; Mkaouar-Rebai, Emna; Kammoun, Thouraya; Mezghani, Najla; Chabchoub, Imen; Aloulou, Hajer; Hachicha, Mongia; Fakhfakh, Faiza

    2011-07-29

    Pearson syndrome (PS) is a multisystem disease including refractory anemia, vacuolization of marrow precursors and pancreatic fibrosis. The disease starts during infancy and affects various tissues and organs, and most affected children die before the age of 3years. Pearson syndrome is caused by de novo large-scale deletions or, more rarely, duplications in the mitochondrial genome. In the present report, we described a Pearson syndrome patient harboring multiple mitochondrial deletions which is, in our knowledge, the first case described and studied in Tunisia. In fact, we reported the common 4.977kb deletion and two novel heteroplasmic deletions (5.030 and 5.234kb) of the mtDNA. These deletions affect several protein-coding and tRNAs genes and could strongly lead to defects in mitochondrial polypeptides synthesis, and impair oxidative phosphorylation and energy metabolism in the respiratory chain in the studied patient. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Mouse Rad1 deletion enhances susceptibility for skin tumor development

    Directory of Open Access Journals (Sweden)

    Wang Xiangyuan

    2010-03-01

    Full Text Available Abstract Background Cells are constantly exposed to stresses from cellular metabolites as well as environmental genotoxins. DNA damage caused by these genotoxins can be efficiently fixed by DNA repair in cooperation with cell cycle checkpoints. Unrepaired DNA lesions can lead to cell death, gene mutation and cancer. The Rad1 protein, evolutionarily conserved from yeast to humans, exists in cells as monomer as well as a component in the 9-1-1 protein complex. Rad1 plays crucial roles in DNA repair and cell cycle checkpoint control, but its contribution to carcinogenesis is unknown. Results To address this question, we constructed mice with a deletion of Mrad1. Matings between heterozygous Mrad1 mutant mice produced Mrad1+/+ and Mrad1+/- but no Mrad1-/- progeny, suggesting the Mrad1 null is embryonic lethal. Mrad1+/- mice demonstrated no overt abnormalities up to one and half years of age. DMBA-TPA combinational treatment was used to induce tumors on mouse skin. Tumors were larger, more numerous, and appeared earlier on the skin of Mrad1+/- mice compared to Mrad1+/+ animals. Keratinocytes isolated from Mrad1+/- mice had significantly more spontaneous DNA double strand breaks, proliferated slower and had slightly enhanced spontaneous apoptosis than Mrad1+/+ control cells. Conclusion These data suggest that Mrad1 is important for preventing tumor development, probably through maintaining genomic integrity. The effects of heterozygous deletion of Mrad1 on proliferation and apoptosis of keratinocytes is different from those resulted from Mrad9 heterozygous deletion (from our previous study, suggesting that Mrad1 also functions independent of Mrad9 besides its role in the Mrad9-Mrad1-Mhus1 complex in mouse cells.

  20. Novel large-range mitochondrial DNA deletions and fatal multisystemic disorder with prominent hepatopathy

    International Nuclear Information System (INIS)

    Bianchi, Marzia; Rizza, Teresa; Verrigni, Daniela; Martinelli, Diego; Tozzi, Giulia; Torraco, Alessandra; Piemonte, Fiorella; Dionisi-Vici, Carlo; Nobili, Valerio; Francalanci, Paola; Boldrini, Renata; Callea, Francesco; Santorelli, Filippo Maria; Bertini, Enrico

    2011-01-01

    Highlights: ► Expanded array of mtDNA deletions. ► Pearson syndrome with prominent hepatopathy associated with single mtDNA deletions. ► Detection of deletions in fibroblasts and blood avoids muscle and liver biopsy. ► Look for mtDNA deletions before to study nuclear genes related to mtDNA depletion. -- Abstract: Hepatic involvement in mitochondrial cytopathies rarely manifests in adulthood, but is a common feature in children. Multiple OXPHOS enzyme defects in children with liver involvement are often associated with dramatically reduced amounts of mtDNA. We investigated two novel large scale deletions in two infants with a multisystem disorder and prominent hepatopathy. Amount of mtDNA deletions and protein content were measured in different post-mortem tissues. The highest levels of deleted mtDNA were in liver, kidney, pancreas of both patients. Moreover, mtDNA deletions were detected in cultured skin fibroblasts in both patients and in blood of one during life. Biochemical analysis showed impairment of mainly complex I enzyme activity. Patients manifesting multisystem disorders in childhood may harbour rare mtDNA deletions in multiple tissues. For these patients, less invasive blood specimens or cultured fibroblasts can be used for molecular diagnosis. Our data further expand the array of deletions in the mitochondrial genomes in association with liver failure. Thus analysis of mtDNA should be considered in the diagnosis of childhood-onset hepatopathies.

  1. Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population.

    Science.gov (United States)

    Remes, A M; Majamaa-Voltti, K; Kärppä, M; Moilanen, J S; Uimonen, S; Helander, H; Rusanen, H; Salmela, P I; Sorri, M; Hassinen, I E; Majamaa, K

    2005-03-22

    Large-scale mitochondrial DNA (mtDNA) deletions are associated with clinical conditions such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia in adults and Pearson syndrome in children. Reported case series have suggested that deletions are not uncommon in the population, but their prevalence has not been documented. The authors ascertained patients with clinical features associated with mtDNA deletions in a defined adult population in northern Finland. Buccal epithelial samples were requested from each patient fulfilling the selection criteria, and full-length mtDNA was amplified using the long PCR method. Deletion breakpoints were identified using sequencing. Patients with deletions were examined clinically. The authors identified four patients with single large-scale mtDNA deletions. The prevalence of deletions was calculated to be 1.6/100,000 in the adult population in the province of Northern Ostrobothnia (0.0 to 3.2; 95% CI). Analysis of incident cases from a neighboring province revealed two patients with deletions and yielded a similar population frequency. The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.

  2. Deletion mapping of 22q11 in CATCH22 syndrome: Identification of a second critical region

    Energy Technology Data Exchange (ETDEWEB)

    Kurahashi, Hiroki; Nakayama, Takahiro; Nishisho, Isamu [Osaka Univ. Medical School, Yokohama (Japan)] [and others

    1996-06-01

    The deletion at 22q11.2 implicates a variety of congenital anomaly syndromes, for which the acronym CATCH22 has been proposed . Most patients with these syndromes share the common large deletion spanning 1-2 Mb, while the phenotypic variability of the patients does not seem to correlate with the extent of the deletions. On the basis of the deletions of rare cases with unbalanced translocation, the shortest region of overlap (SRO) had been identified in the most-centromeric region of the common large deletion. One patient (ADU) has been reported to carry a balanced translocation with the breakpoint located in the SRO. Recently, three transcripts were identified at or very close to the ADU breakpoint (ADUBP), making them strong candidates for CATCH22 syndrome. Here, we describe one patient with a unique deletion at 22q11.2 revealed by quantitative hybridization and/or FISH with six DNA markers in the common large deletion. The patient was dizygous at loci within the SRO and hemizygous only at the most-telomeric locus in the common large deletion. This finding suggests that there must be another critical region in the common large deletion besides the breakpoint of the ADU and that haploinsufficiency of genes in this deletion may also play a major role in CATCH22 pathogenesis. 15 refs., 3 figs.

  3. Novel large-range mitochondrial DNA deletions and fatal multisystemic disorder with prominent hepatopathy

    Energy Technology Data Exchange (ETDEWEB)

    Bianchi, Marzia; Rizza, Teresa; Verrigni, Daniela [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Martinelli, Diego [Division of Metabolism, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Tozzi, Giulia; Torraco, Alessandra; Piemonte, Fiorella [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Dionisi-Vici, Carlo [Division of Metabolism, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Nobili, Valerio [Gastroenterology and Liver Unit, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Francalanci, Paola; Boldrini, Renata; Callea, Francesco [Dept. Pathology, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Santorelli, Filippo Maria [UOC Neurogenetica e Malattie Neuromuscolari, Fondazione Stella Maris, Pisa (Italy); Bertini, Enrico [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, ' Bambino Gesu' Children' s Hospital, Rome (Italy); and others

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Expanded array of mtDNA deletions. Black-Right-Pointing-Pointer Pearson syndrome with prominent hepatopathy associated with single mtDNA deletions. Black-Right-Pointing-Pointer Detection of deletions in fibroblasts and blood avoids muscle and liver biopsy. Black-Right-Pointing-Pointer Look for mtDNA deletions before to study nuclear genes related to mtDNA depletion. -- Abstract: Hepatic involvement in mitochondrial cytopathies rarely manifests in adulthood, but is a common feature in children. Multiple OXPHOS enzyme defects in children with liver involvement are often associated with dramatically reduced amounts of mtDNA. We investigated two novel large scale deletions in two infants with a multisystem disorder and prominent hepatopathy. Amount of mtDNA deletions and protein content were measured in different post-mortem tissues. The highest levels of deleted mtDNA were in liver, kidney, pancreas of both patients. Moreover, mtDNA deletions were detected in cultured skin fibroblasts in both patients and in blood of one during life. Biochemical analysis showed impairment of mainly complex I enzyme activity. Patients manifesting multisystem disorders in childhood may harbour rare mtDNA deletions in multiple tissues. For these patients, less invasive blood specimens or cultured fibroblasts can be used for molecular diagnosis. Our data further expand the array of deletions in the mitochondrial genomes in association with liver failure. Thus analysis of mtDNA should be considered in the diagnosis of childhood-onset hepatopathies.

  4. The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome.

    Science.gov (United States)

    Cook, R Kimberley; Christensen, Stacey J; Deal, Jennifer A; Coburn, Rachel A; Deal, Megan E; Gresens, Jill M; Kaufman, Thomas C; Cook, Kevin R

    2012-01-01

    Chromosomal deletions are used extensively in Drosophila melanogaster genetics research. Deletion mapping is the primary method used for fine-scale gene localization. Effective and efficient deletion mapping requires both extensive genomic coverage and a high density of molecularly defined breakpoints across the genome. A large-scale resource development project at the Bloomington Drosophila Stock Center has improved the choice of deletions beyond that provided by previous projects. FLP-mediated recombination between FRT-bearing transposon insertions was used to generate deletions, because it is efficient and provides single-nucleotide resolution in planning deletion screens. The 793 deletions generated pushed coverage of the euchromatic genome to 98.4%. Gaps in coverage contain haplolethal and haplosterile genes, but the sizes of these gaps were minimized by flanking these genes as closely as possible with deletions. In improving coverage, a complete inventory of haplolethal and haplosterile genes was generated and extensive information on other haploinsufficient genes was compiled. To aid mapping experiments, a subset of deletions was organized into a Deficiency Kit to provide maximal coverage efficiently. To improve the resolution of deletion mapping, screens were planned to distribute deletion breakpoints evenly across the genome. The median chromosomal interval between breakpoints now contains only nine genes and 377 intervals contain only single genes. Drosophila melanogaster now has the most extensive genomic deletion coverage and breakpoint subdivision as well as the most comprehensive inventory of haploinsufficient genes of any multicellular organism. The improved selection of chromosomal deletion strains will be useful to nearly all Drosophila researchers.

  5. Angelman syndrome: Validation of molecular cytogenetic analysis of chromosome 15q11-q13 for deletion detection

    Energy Technology Data Exchange (ETDEWEB)

    White, L.; Knoll, J.H.M. [Harvard Medical School, Boston, MA (United States)

    1995-03-13

    In a series of 18 individuals comprising parents of Angelman syndrome (AS) patients and AS patients with large deletions, microdeletions, and no deletions, we utilized fluorescence in situ hybridization (FISH) with genomic phage clones for loci D15S63 and GABRB3 for deletion detection of chromosome 15q11-q13. Utilization of probes at these loci allows detection of common large deletions and permits discrimination of less common small deletions. In all individuals the molecular cytogenetic data were concordant with the DNA deletion analyses. FISH provides an accurate method of deletion detection for chromosome 15q11-q13. 23 refs., 2 figs., 1 tab.

  6. Deletion Mutations in an Australian Series of HNPCC Patients

    Directory of Open Access Journals (Sweden)

    McPhillips Mary

    2005-11-01

    Full Text Available Abstract Hereditary non polyposis colorectal cancer (HNPCC is characterized by the presence of early onset colorectal cancer and other epithelial malignancies. The genetic basis of HNPCC is a deficiency in DNA mismatch repair, which manifests itself as DNA microsatellite instability in tumours. There are four genes involved in DNA mismatch repair that have been linked to HNPCC; these include hMSH2, hMLH1, hMSH6 and hPMS2. Of these four genes hMLH1 and hMSH2 account for the majority of families diagnosed with the disease. Notwithstanding, up to 40 percent of families do not appear to harbour a change in either hMSH2 or hMLH1 that can be detected using standard screening procedures such as direct DNA sequencing or a variety of methods all based on a heteroduplex analysis. In this report we have screened a series of 118 probands that all have the clinical diagnosis of HNPCC for medium to large deletions by the Multiplex Ligation-Dependent Probe Amplification assay (MLPA to determine the frequency of this type of mutation. The results indicate that a significant proportion of Australian HNPCC patients harbour deletion or duplication mutations primarily in hMSH2 but also in hMLH1.

  7. Production planning and coronal stop deletion in spontaneous speech

    Directory of Open Access Journals (Sweden)

    James Tanner

    2017-06-01

    Full Text Available Many phonological processes can be affected by segmental context spanning word boundaries, which often lead to variable outcomes. This paper tests the idea that some of this variability can be explained by reference to production planning. We examine coronal stop deletion (CSD, a variable process conditioned by preceding and upcoming phonological context, in a corpus of spontaneous British English speech, as a means of investigating a number of variables associated with planning: Prosodic boundary strength, word frequency, conditional probability of the following word, and speech rate. From the perspective of production planning, (1 prosodic boundaries should affect deletion rate independently of following context; (2 given the locality of production planning, the effect of the following context should decrease at stronger prosodic boundaries; and (3 other factors affecting planning scope should modulate the effect of upcoming phonological material above and beyond the modulating effect of prosodic boundaries. We build a statistical model of CSD realization, using pause length as a quantitative proxy for boundary strength, and find support for these predictions. These findings are compatible with the hypothesis that the locality of production planning constrains variability in speech production, and have practical implications for work on CSD and other variable processes.

  8. Neuroradiographic findings in 22q11.2 deletion syndrome.

    Science.gov (United States)

    Bohm, Lauren A; Zhou, Tom C; Mingo, Tyler J; Dugan, Sarah L; Patterson, Richard J; Sidman, James D; Roby, Brianne B

    2017-08-01

    22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than half (13/24) of the patients had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), aberrant cortical veins (6/24), polymicrogyria or cortical dysplasia (4/24), inner ear deformities (3/24), hypoplastic internal carotid artery (2/24), and hypoplastic cerebellum (1/24). These findings reveal the types and frequencies of brain malformations in this case series, and suggest that the prevalence of neuroanatomical abnormalities in 22q11.2DS may be underestimated. Understanding indications for imaging and frequently encountered brain malformations will result in early diagnosis and intervention in an effort to optimize patient outcomes. © 2017 Wiley Periodicals, Inc.

  9. Hematological abnormalities and 22q11.2 deletion syndrome

    Directory of Open Access Journals (Sweden)

    Rafael Fabiano Machado Rosa

    2011-01-01

    Full Text Available The 22q11.2 deletion syndrome (22q11DS is a common genetic disease characterized by broad phenotypic variability. Despite the small number of studies describing hematological alterations in individuals with 22q11DS, it appears that these abnormalities are more frequent than previously imagined. Thus, the objective of our study was to report on a patient with 22q11DS presenting thrombocytopenia and large platelets and to review the literature. The patient, a 13-year-old boy, was originally evaluated due to craniofacial dysmorphia and speech delay. He also had a history of behavioral changes, neuropsychomotor delay and recurrent otitis/sinusitis. The identification of a 22q11.2 microdeletion by fluorescent in situ hybridization diagnosed the syndrome. Despite his hematological alterations, he only had a history of epistaxis and bruising of the upper and lower limbs. Assessments of the prothrombin time, thrombin time, partial thromboplastin time, bleeding time, fibrinogen levels and platelet aggregation (including the ristocetin induced platelet aggregation test were all normal. Hematological alterations observed in 22q11DS are directly related to the genetic disorder itself (especially in respect to deletion of the GPIb gene and secondary to some clinical findings, such as immunodeficiency. Macrothrombocytopenia is increasingly being considered a feature of the broad spectrum of 22q11DS and may potentially be a clinical marker for the syndrome.

  10. Files synchronization from a large number of insertions and deletions

    Science.gov (United States)

    Ellappan, Vijayan; Kumari, Savera

    2017-11-01

    Synchronization between different versions of files is becoming a major issue that most of the applications are facing. To make the applications more efficient a economical algorithm is developed from the previously used algorithm of “File Loading Algorithm”. I am extending this algorithm in three ways: First, dealing with non-binary files, Second backup is generated for uploaded files and lastly each files are synchronized with insertions and deletions. User can reconstruct file from the former file with minimizing the error and also provides interactive communication by eliminating the frequency without any disturbance. The drawback of previous system is overcome by using synchronization, in which multiple copies of each file/record is created and stored in backup database and is efficiently restored in case of any unwanted deletion or loss of data. That is, to introduce a protocol that user B may use to reconstruct file X from file Y with suitably low probability of error. Synchronization algorithms find numerous areas of use, including data storage, file sharing, source code control systems, and cloud applications. For example, cloud storage services such as Drop box synchronize between local copies and cloud backups each time users make changes to local versions. Similarly, synchronization tools are necessary in mobile devices. Specialized synchronization algorithms are used for video and sound editing. Synchronization tools are also capable of performing data duplication.

  11. Enhanced N2-fixing ability of a deletion mutant of arctic rhizobia with sainfoin (Onobrychis viciifolia).

    Science.gov (United States)

    Jain, D K; Bordeleau, L M

    1990-12-01

    Mutagenesis provoked by exposure at elevated temperature of the cold-adapted, arctic Rhizobium strain N31 resulted in the generation of five deletion mutants, which exhibited loss of their smaller plasmid (200 kb), whereas the larger plasmid (> 500 kb) was still present in all mutants. Deletion mutants did not show differences from the wild type in the antibiotic resistance pattern, the carbohydrates and organic acids utilization, and the growth rate at low temperature. However, deletion mutants differed from the wild type and among themselves in the ex planta nitrogenase activity, the nodulation index, and the symbiotic effectiveness. The deletion mutant N31.6rif (r) showed higher nodulation index and exhibited higher nitrogenase activity and symbiotic efficiency than the other deletion mutants and the wild type. The process of deletion mutation resulted in the improvement of an arctic Rhizobium strain having an earlier and higher symbiotic nitrogen fixation efficiency than the wild type.

  12. Branchio-oto-renal syndrome caused by partial EYA1 deletion due to LINE-1 insertion

    DEFF Research Database (Denmark)

    Morisada, Naoya; Rendtorff, Nanna Dahl; Nozu, Kandai

    2010-01-01

    multiplex ligation-dependent probe amplification (MLPA) analysis, a heterozygous EYA1 gene deletion comprising at least exons 5 to 7. In her parents, we did not detect any deletion in EYA1 by MLPA, so the deletion was a de novo mutation. PCR analysis and sequencing of patient DNA revealed a heterozygous...... approximately 17 kb EYA1 deletion starting from the eight last bases of exon 4 and proceeding to base 1,217 of intron 7. Furthermore, in place of this deleted region was inserted a 3756-bp-long interspersed nuclear elements-1 (LINE-1, L1). Accordingly, RT-PCR showed that exons 4-7 were not present in EYA1 m......RNA expressed from the mutated allele. Although there are reports of L1 element insertion occurring in various human diseases, this is the first report of a large EYA1 deletion in combination with L1 element insertion....

  13. Toughness Condition for a Graph to Be a Fractional (g,f,n-Critical Deleted Graph

    Directory of Open Access Journals (Sweden)

    Wei Gao

    2014-01-01

    Full Text Available A graph G is called a fractional (g,f-deleted graph if G-{e} admits a fractional (g,f-factor for any e∈E(G. A graph G is called a fractional (g,f,n-critical deleted graph if, after deleting any n vertices from G, the resulting graph is still a fractional (g,f-deleted graph. The toughness, as the parameter for measuring the vulnerability of communication networks, has received significant attention in computer science. In this paper, we present the relationship between toughness and fractional (g,f,n-critical deleted graphs. It is determined that G is fractional (g,f,n-critical deleted if t(G≥((b2-1+bn/a.

  14. The rates and patterns of deletions in the human factor IX gene

    Energy Technology Data Exchange (ETDEWEB)

    Ketterling, R.P.; Vielhaber, E.L.; Lind, T.J.; Thorland, E.C.; Sommer S.S. (Mayo Clinic/Foundation, Rochester, MN (United States))

    1994-02-01

    Deletions are commonly observed in genes with either segments of highly homologous sequences or excessive gene length. However, in the factor IX gene and in most genes, deletions (of [ge]21 bp) are uncommon. The authors have analyzed DNA from 290 families with hemophilia B (203 independent mutations) and have found 12 deletions >20 bp. Eleven of these are >2 kb (range >3-163 kb), and one is 1.1 kb. The junctions of the four deletions that are completely contained within the factor IX gene have been determined. A novel mutation occurred in patient HB128: the data suggest that a 26.8-kb deletion occurred between two segments of alternating purines and pyrimidines and that a 2.3-kb sense strand segment derived from the deleted region was inserted. For a sample of 203 independent mutations, the authors estimate the [open quotes]baseline[close quotes] rates of deletional mutation per base pair per generation as a function of size. The rate for large (>2 kb)I deletions is exceedingly low. For every mutational event in which a given base is at the junction of a large deletion, there are an estimated 58 microdeletions (<20 bp) and 985 single-base substitutions at that base. Analysis of the nine reported deletion junctions in the factor IX gene literature reveals that (i) five are associated with inversion, orphan sequences, or sense strand insertions; (ii) four are simple deletions that display an excess of short direct repeats at their junctions; (iii) there is no dramatic clustering of junctions within the gene; and (iv) with the exception of alternating purines and pyrimidines, deletion junctions are not preferentially associated with repetitive DNA. 58 refs., 5 figs., 5 tabs.

  15. Improved pestalotiollide B production by deleting competing polyketide synthase genes in Pestalotiopsis microspora.

    Science.gov (United States)

    Chen, Longfei; Li, Yingying; Zhang, Qian; Wang, Dan; Akhberdi, Oren; Wei, Dongsheng; Pan, Jiao; Zhu, Xudong

    2017-02-01

    Pestalotiollide B, an analog of dibenzodioxocinones which are inhibitors of cholesterol ester transfer proteins, is produced by Pestalotiopsis microspora NK17. To increase the production of pestalotiollide B, we attempted to eliminate competing polyketide products by deleting the genes responsible for their biosynthesis. We successfully deleted 41 out of 48 putative polyketide synthases (PKSs) in the genome of NK17. Nine of the 41 PKS deleted strains had significant increased production of pestalotiollide B (P polyketides.

  16. Neuronal PTEN deletion in adult cortical neurons triggers progressive growth of cell bodies, dendrites, and axons.

    Science.gov (United States)

    Gallent, Erin A; Steward, Oswald

    2018-05-01

    Deletion of the phosphatase and tensin (PTEN) gene in neonatal mice leads to enlargement of the cell bodies of cortical motoneurons (CMNs) in adulthood (Gutilla et al., 2016). Here, we assessed whether PTEN deletion in adult mice would trigger growth of mature neurons. PTEN was deleted by injecting AAV-Cre into the sensorimotor cortex of adult transgenic mice with a lox-P flanked exon 5 of the PTEN gene and Cre-dependent reporter gene tdTomato. PTEN-deleted CMN's identified by tdT expression and retrograde labeling with fluorogold (FG) were significantly enlarged four months following PTEN deletion, and continued to increase in size through the latest time intervals examined (12-15 months post-deletion). Sholl analyses of tdT-positive pyramidal neurons revealed increases in dendritic branches at 6 months following adult PTEN deletion, and greater increases at 12 months. 12 months after adult PTEN deletion, axons in the medullary pyramids were significantly larger and G-ratios were higher. Mice with PTEN deletion exhibited no overt neurological symptoms and no seizures. Assessment of motor function on the rotarod and cylinder test revealed slight impairment of coordination with unilateral deletion; however, mice with bilateral PTEN deletion in the motor cortex performed better than controls on the rotarod at 8 and 10 months post-deletion. Our findings demonstrate that robust neuronal growth can be induced in fully mature cortical neurons long after the developmental period has ended and that this continuous growth occurs without obvious functional impairments. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Association of BIM Deletion Polymorphism and BIM-γ RNA Expression in NSCLC with EGFR Mutation

    OpenAIRE

    ISOBE, KAZUTOSHI; KAKIMOTO, ATSUSHI; MIKAMI, TETSUO; KABURAKI, KYOHEI; KOBAYASHI, HIROSHI; YOSHIZAWA, TAKAHIRO; MAKINO, TAKASHI; OTSUKA, HAJIME; SANO, GO; SUGINO, KEISHI; SAKAMOTO, SUSUMU; TAKAI, YUJIRO; TOCHIGI, NAOBUMI; IYODA, AKIRA; HOMMA, SAKAE

    2016-01-01

    Aim: This pilot study assessed the association of BIM deletion polymorphism and BIM RNA isoform in patients with EGFR-positive non-small cell lung cancer (NSCLC). Patients and Methods: The study included 33 patients with EGFR-positive NSCLC treated with gefitinib. BIM deletion polymorphism and BIM RNA isoform (EL/L/S/γ) were determined by polymerase chain reaction (PCR). Results: BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM ...

  18. Analysis of spontaneous deletions and gene amplification in the lac region of Escherichia coli

    International Nuclear Information System (INIS)

    Albertini, A.M.; Hofer, M.; Calos, M.P.; Tlsty, T.D.; Miller, J.H.

    1983-01-01

    Spontaneous rearrangements, such as large deletions and duplications, have important implications for the structure of the genome. It is therefore of great interest to analyze these events at the molecular level. We have constructed derivatives of a lacI-Z fusion strain, which allow us to study deletions in a more systematic manner than was previously possible. These derivatives have been used to investigate how frequently larger deletions (> 700 bp) occur between short homologies on both recA and recA - strains and to determine the effect of the lengths of the short homologies and of the distance between homologies on the frequency of deletion formation. 38 references, 11 figures

  19. Genomic rearrangements by LINE-1 insertion-mediated deletion in the human and chimpanzee lineages.

    Science.gov (United States)

    Han, Kyudong; Sen, Shurjo K; Wang, Jianxin; Callinan, Pauline A; Lee, Jungnam; Cordaux, Richard; Liang, Ping; Batzer, Mark A

    2005-01-01

    Long INterspersed Elements (LINE-1s or L1s) are abundant non-LTR retrotransposons in mammalian genomes that are capable of insertional mutagenesis. They have been associated with target site deletions upon insertion in cell culture studies of retrotransposition. Here, we report 50 deletion events in the human and chimpanzee genomes directly linked to the insertion of L1 elements, resulting in the loss of approximately 18 kb of sequence from the human genome and approximately 15 kb from the chimpanzee genome. Our data suggest that during the primate radiation, L1 insertions may have deleted up to 7.5 Mb of target genomic sequences. While the results of our in vivo analysis differ from those of previous cell culture assays of L1 insertion-mediated deletions in terms of the size and rate of sequence deletion, evolutionary factors can reconcile the differences. We report a pattern of genomic deletion sizes similar to those created during the retrotransposition of Alu elements. Our study provides support for the existence of different mechanisms for small and large L1-mediated deletions, and we present a model for the correlation of L1 element size and the corresponding deletion size. In addition, we show that internal rearrangements can modify L1 structure during retrotransposition events associated with large deletions.

  20. Association between the CCR5 32-bp deletion allele and late onset of schizophrenia

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Berg; Timm, Sally; Wang, August G

    2006-01-01

    OBJECTIVE: The 32-bp deletion allele in chemokine receptor CCR5 has been associated with several immune-mediated diseases and might be implicated in schizophrenia as well. METHOD: The authors genotyped DNA samples from 268 schizophrenia patients and 323 healthy subjects. Age at first admission...... of the deletion allele in the latter subgroup of patients. CONCLUSIONS: These findings suggest that the CCR5 32-bp deletion allele is a susceptibility factor for schizophrenia with late onset. Alternatively, the CCR5 32-bp deletion allele may act as a modifier by delaying the onset of schizophrenia without...

  1. Induction of Mitochondrial DNA Deletion by Ionizing Radiation in Human Lung Fibroblast IMR-90 Cells

    Energy Technology Data Exchange (ETDEWEB)

    Eom, Hyeon Soo; Jung, U Hee; Park, Hae Ran; Jo, Sung Kee [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2009-06-15

    Mitochondrial DNA (mtDNA) deletion is a well-known marker for oxidative stress and aging and also contributes to their unfavorable effects in cultured cells and animal tissues. This study was conducted to investigate the effect of ionizing radiation (IR) on mtDNA deletion and the involvement of reactive oxygen species (ROS) in this process in human lung fibroblast (IMR-90) cells. Young IMR-90 cells at population doubling (PD) 39 were irradiated with {sup 137}Cs -rays and the intracellular ROS level was determined by 2',7'-dichlorofluorescein diacetate (DCFH-DA) and mtDNA common deletion (4977bp) was detected by nested PCR. Old cells at PD 55 and H{sub 2}O{sub 2}-treated young cells were compared as the positive control. IR increased the intracellular ROS level and mtDNA 4977 bp deletion in IMR-90 cells dose-dependently. The increases of ROS level and mtDNA deletion were also observed in old cells and H{sub 2}O{sub 2}-treated young cells. To confirm the increased ROS level is essential for mtDNA deletion in irradiated cells, the effects of N-acetylcysteine (NAC) on IRinduced ROS and mtDNA deletion were examined. 5 mM NAC significantly attenuated the IR-induced ROS increase and mtDNA deletion. These results suggest that IR induces the mtDNA deletion and this process is mediated by ROS in IMR-90 cells.

  2. Mosaic deletion of 20pter due to rescue by somatic recombination.

    Science.gov (United States)

    Martin, Megan M; Vanzo, Rena J; Sdano, Mallory R; Baxter, Adrianne L; South, Sarah T

    2016-01-01

    We report on a unique case of a mosaic 20pter-p13 deletion due to a somatic repair event identified by allele differentiating single nucleotide polymorphism (SNP) probes on chromosomal microarray. Small terminal deletions of 20p have been reported in a few individuals and appear to result in a variable phenotype. This patient was a 24-month-old female who presented with failure to thrive and speech delay. Chromosomal microarray analysis (CMA) performed on peripheral blood showed a 1.6 Mb deletion involving the terminus of 20p (20pter-20p13). This deletion appeared mosaic by CMA and this suspicion was confirmed by fluorescence in situ hybridization (FISH) analysis. Additionally, the deletion interval at 20p was directly adjacent to 15 Mb of mosaic copy-neutral loss of heterozygosity (LOH). The pattern of SNP probes was highly suggestive of a somatic repair event that resulted in rescue of the deleted region using the non-deleted homologue as a template. Structural mosaicism is rare and most often believed to be due to a postzygotic mechanism. This case demonstrates the additional utility of allele patterns to help distinguish mechanisms and in this case identified the possibility of either a post-zygotic repair of a germline deletion or a post-zygotic deletion with somatic recombination repair in a single step. © 2015 Wiley Periodicals, Inc.

  3. Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer.

    Science.gov (United States)

    Kluth, Martina; Runte, Frederic; Barow, Philipp; Omari, Jazan; Abdelaziz, Zaid M; Paustian, Lisa; Steurer, Stefan; Christina Tsourlakis, Maria; Fisch, Margit; Graefen, Markus; Tennstedt, Pierre; Huland, Hartwig; Michl, Uwe; Minner, Sarah; Sauter, Guido; Simon, Ronald; Adam, Meike; Schlomm, Thorsten

    2015-11-15

    The deletion of 16q23-q24 belongs to the most frequent chromosomal changes in prostate cancer, but the clinical consequences of this alteration have not been studied in detail. We performed fluorescence in situ hybridization analysis using a 16q23 probe in more than 7,400 prostate cancers with clinical follow-up data assembled in a tissue microarray format. Chromosome 16q deletion was found in 21% of cancers, and was linked to advanced tumor stage, high Gleason grade, accelerated cell proliferation, the presence of lymph node metastases (p Deletion was more frequent in ERG fusion-positive (27%) as compared to ERG fusion-negative cancers (16%, p deletions including phosphatase and tensin homolog (PTEN) (p deletion of 16q was linked to early biochemical recurrence independently from the ERG status (p deletion of 16q alone. Multivariate modeling revealed that the prognostic value of 16q/PTEN deletion patterns was independent from the established prognostic factors. In summary, the results of our study demonstrate that the deletion of 16q and PTEN cooperatively drives prostate cancer progression, and suggests that deletion analysis of 16q and PTEN could be of important clinical value particularly for preoperative risk assessment of the clinically most challenging group of low- and intermediated grade prostate cancers. © 2015 UICC.

  4. Syndrome of proximal interstitial deletion 4p15

    Energy Technology Data Exchange (ETDEWEB)

    Fryns, J.P. [Univ. of Leuven (Belgium)

    1995-09-11

    In this journal, Chitayat et al. reported on 2 boys and a girl with interstitial deletion in the short arm of chromosome 4, including p15.2p15.33. All 3 patients had a characteristic face distinct from that of Wolf-Hirschhorn syndrome and multiple minor congenital anomalies. One patient had a congenitally enlarged penis. The authors noted that all had normal growth, and all had moderate psychomotor retardation (patient 1, developmental age of 4-6 years at age 9 years; patient 2, mental age 6 years at age 25 years; and patient 3, global delay with hypotonia, difficulties in both gross and fine motor development, and persistent delay in language skills). 5 refs., 1 fig.

  5. Stella-Cre mice are highly efficient Cre deleters.

    Science.gov (United States)

    Liu, Hui; Wang, Wei; Chew, Su-Kit; Lee, Song-Choon; Li, Juan; Vassiliou, George S; Green, Tony; Futreal, P Andrew; Bradley, Allan; Zhang, Shujun; Liu, Pentao

    2011-08-01

    Cre-loxP recombination is widely used for genetic manipulation of the mouse genome. Here, we report generation and characterization of a new Cre line, Stella-Cre, where Cre expression cassette was targeted to the 3' UTR of the Stella locus. Stella is specifically expressed in preimplantation embryos and in the germline. Cre-loxP recombination efficiency in Stella-Cre mice was investigated at several genomic loci including Rosa26, Jak2, and Npm1. At all the loci examined, we observed 100% Cre-loxP recombination efficiency in the embryos and in the germline. Thus, Stella-Cre mice serve as a very efficient deleter line. Copyright © 2011 Wiley-Liss, Inc.

  6. A high-throughput method for the detection of homoeologous gene deletions in hexaploid wheat

    Directory of Open Access Journals (Sweden)

    Li Zhongyi

    2010-11-01

    Full Text Available Abstract Background Mutational inactivation of plant genes is an essential tool in gene function studies. Plants with inactivated or deleted genes may also be exploited for crop improvement if such mutations/deletions produce a desirable agronomical and/or quality phenotype. However, the use of mutational gene inactivation/deletion has been impeded in polyploid plant species by genetic redundancy, as polyploids contain multiple copies of the same genes (homoeologous genes encoded by each of the ancestral genomes. Similar to many other crop plants, bread wheat (Triticum aestivum L. is polyploid; specifically allohexaploid possessing three progenitor genomes designated as 'A', 'B', and 'D'. Recently modified TILLING protocols have been developed specifically for mutation detection in wheat. Whilst extremely powerful in detecting single nucleotide changes and small deletions, these methods are not suitable for detecting whole gene deletions. Therefore, high-throughput methods for screening of candidate homoeologous gene deletions are needed for application to wheat populations generated by the use of certain mutagenic agents (e.g. heavy ion irradiation that frequently generate whole-gene deletions. Results To facilitate the screening for specific homoeologous gene deletions in hexaploid wheat, we have developed a TaqMan qPCR-based method that allows high-throughput detection of deletions in homoeologous copies of any gene of interest, provided that sufficient polymorphism (as little as a single nucleotide difference amongst homoeologues exists for specific probe design. We used this method to identify deletions of individual TaPFT1 homoeologues, a wheat orthologue of the disease susceptibility and flowering regulatory gene PFT1 in Arabidopsis. This method was applied to wheat nullisomic-tetrasomic lines as well as other chromosomal deletion lines to locate the TaPFT1 gene to the long arm of chromosome 5. By screening of individual DNA samples from

  7. Deletion of 7q33-q35 in a Patient with Intellectual Disability and Dysmorphic Features: Further Characterization of 7q Interstitial Deletion Syndrome

    Directory of Open Access Journals (Sweden)

    Kristen Dilzell

    2015-01-01

    Full Text Available This case report concerns a 16-year-old girl with a 9.92 Mb, heterozygous interstitial chromosome deletion at 7q33-q35, identified using array comparative genomic hybridization. The patient has dysmorphic facial features, intellectual disability, recurrent infections, self-injurious behavior, obesity, and recent onset of hemihypertrophy. This patient has overlapping features with previously reported individuals who have similar deletions spanning the 7q32-q36 region. It has been difficult to describe an interstitial 7q deletion syndrome due to variations in the sizes and regions in the few patients reported in the literature. This case contributes to the further characterization of an interstitial distal 7q deletion syndrome.

  8. Genotype-phenotype correlation in 22q11.2 deletion syndrome

    Directory of Open Access Journals (Sweden)

    Michaelovsky Elena

    2012-12-01

    Full Text Available Abstract Background The 22q11.2 deletion syndrome (22q11.2DS is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion. Methods Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation. Results Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2% carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted. Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes. Conclusions MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms. Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

  9. Sex-specific aspects of endogenous retroviral insertion and deletion.

    Science.gov (United States)

    Gemmell, Patrick; Hein, Jotun; Katzourakis, Aris

    2013-11-07

    We wish to understand how sex and recombination affect endogenous retroviral insertion and deletion. While theory suggests that the risk of ectopic recombination will limit the accumulation of repetitive DNA in areas of high meiotic recombination, the experimental evidence so far has been inconsistent. Under the assumption of neutrality, we examine the genomes of eighteen species of animal in order to compute the ratio of solo-LTRs that derive from insertions occurring down the male germ line as opposed to the female one (male bias). We also extend the simple idea of comparing autosome to allosome in order to predict the ratio of full-length proviruses we would expect to see under conditions of recombination linked deletion or otherwise. Using our model, we predict the ratio of allosomal to autosomal full-length proviruses to lie between32 and 23 under increasing male bias in mammals and between 1 and 2 under increasing male bias in birds. In contrast to our expectations, we find that a pattern of male bias is not universal across species and that there is a frequent overabundance of full-length proviruses on the allosome beyond the ratios predicted by our model. We use our data as a whole to argue that full-length proviruses should be treated as deleterious mutations or as effectively neutral mutations whose persistence in a full-length state is linked to the rate of meiotic recombination and whose origin is not universally male biased. These conclusions suggest that retroviral insertions on the allosome may be more prolific and that it might be possible to identify mechanisms of replication that are enhanced in the female sex.

  10. Bad Clade Deletion Supertrees: A Fast and Accurate Supertree Algorithm.

    Science.gov (United States)

    Fleischauer, Markus; Böcker, Sebastian

    2017-09-01

    Supertree methods merge a set of overlapping phylogenetic trees into a supertree containing all taxa of the input trees. The challenge in supertree reconstruction is the way of dealing with conflicting information in the input trees. Many different algorithms for different objective functions have been suggested to resolve these conflicts. In particular, there exist methods based on encoding the source trees in a matrix, where the supertree is constructed applying a local search heuristic to optimize the respective objective function. We present a novel heuristic supertree algorithm called Bad Clade Deletion (BCD) supertrees. It uses minimum cuts to delete a locally minimal number of columns from such a matrix representation so that it is compatible. This is the complement problem to Matrix Representation with Compatibility (Maximum Split Fit). Our algorithm has guaranteed polynomial worst-case running time and performs swiftly in practice. Different from local search heuristics, it guarantees to return the directed perfect phylogeny for the input matrix, corresponding to the parent tree of the input trees, if one exists. Comparing supertrees to model trees for simulated data, BCD shows a better accuracy (F1 score) than the state-of-the-art algorithms SuperFine (up to 3%) and Matrix Representation with Parsimony (up to 7%); at the same time, BCD is up to 7 times faster than SuperFine, and up to 600 times faster than Matrix Representation with Parsimony. Finally, using the BCD supertree as a starting tree for a combined Maximum Likelihood analysis using RAxML, we reach significantly improved accuracy (1% higher F1 score) and running time (1.7-fold speedup). © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  11. Potential complications when developing gene deletion clones in Xylella fastidiosa.

    Science.gov (United States)

    Johnson, Kameka L; Cursino, Luciana; Athinuwat, Dusit; Burr, Thomas J; Mowery, Patricia

    2015-04-16

    The Gram-negative xylem-limited bacterium, Xylella fastidiosa, is an important plant pathogen that infects a number of high value crops. The Temecula 1 strain infects grapevines and induces Pierce's disease, which causes symptoms such as scorching on leaves, cluster collapse, and eventual plant death. In order to understand the pathogenesis of X. fastidiosa, researchers routinely perform gene deletion studies and select mutants via antibiotic markers. Site-directed pilJ mutant of X. fastidiosa were generated and selected on antibiotic media. Mutant cultures were assessed by PCR to determine if they were composed of purely transformant cells or included mixtures of non-transformants cells. Then pure pilJ mutant and wildtype cells were mixed in PD2 medium and following incubation and exposure to kanamycin were assessed by PCR for presence of mutant and wildtype populations. We have discovered that when creating clones of targeted mutants of X. fastidiosa Temecula 1 with selection on antibiotic plates, X. fastidiosa lacking the gene deletion often persist in association with targeted mutant cells. We believe this phenomenon is due to spontaneous antibiotic resistance and/or X. fastidiosa characteristically forming aggregates that can be comprised of transformed and non-transformed cells. A combined population was confirmed by PCR, which showed that targeted mutant clones were mixed with non-transformed cells. After repeated transfer and storage the non-transformed cells became the dominant clone present. We have discovered that special precautions are warranted when developing a targeted gene mutation in X. fastidiosa because colonies that arise following transformation and selection are often comprised of transformed and non-transformed cells. Following transfer and storage the cells can consist primarily of the non-transformed strain. As a result, careful monitoring of targeted mutant strains must be performed to avoid mixed populations and confounding results.

  12. [Chromosomal large fragment deletion induced by CRISPR/Cas9 gene editing system].

    Science.gov (United States)

    Cheng, L H; Liu, Y; Niu, T

    2017-05-14

    Objective: Using CRISPR-Cas9 gene editing technology to achieve a number of genes co-deletion on the same chromosome. Methods: CRISPR-Cas9 lentiviral plasmid that could induce deletion of Aloxe3-Alox12b-Alox8 cluster genes located on mouse 11B3 chromosome was constructed via molecular clone. HEK293T cells were transfected to package lentivirus of CRISPR or Cas9 cDNA, then mouse NIH3T3 cells were infected by lentivirus and genomic DNA of these cells was extracted. The deleted fragment was amplified by PCR, TA clone, Sanger sequencing and other techniques were used to confirm the deletion of Aloxe3-Alox12b-Alox8 cluster genes. Results: The CRISPR-Cas9 lentiviral plasmid, which could induce deletion of Aloxe3-Alox12b-Alox8 cluster genes, was successfully constructed. Deletion of target chromosome fragment (Aloxe3-Alox12b-Alox8 cluster genes) was verified by PCR. The deletion of Aloxe3-Alox12b-Alox8 cluster genes was affirmed by TA clone, Sanger sequencing, and the breakpoint junctions of the CRISPR-Cas9 system mediate cutting events were accurately recombined, insertion mutation did not occur between two cleavage sites at all. Conclusion: Large fragment deletion of Aloxe3-Alox12b-Alox8 cluster genes located on mouse chromosome 11B3 was successfully induced by CRISPR-Cas9 gene editing system.

  13. Deletion of amino acid residues 33-46 in growth hormone alters the ...

    African Journals Online (AJOL)

    To investigate the effect of deletion on the chemistry of the molecule, computational biology tools were employed. The mutant with the deletion of amino acid residues 33-46, was designed and the model was visualized on computer. The structure of 20k bGH was compared with bGH and dissected for hydrogen bonds and ...

  14. 31 CFR 363.144 - May I delete a pending transaction involving a certificate of indebtedness?

    Science.gov (United States)

    2010-07-01

    ... involving a certificate of indebtedness? 363.144 Section 363.144 Money and Finance: Treasury Regulations... DEBT REGULATIONS GOVERNING SECURITIES HELD IN TREASURYDIRECT Certificate of Indebtedness § 363.144 May I delete a pending transaction involving a certificate of indebtedness? (a) You may delete a pending...

  15. AZFc deletions do not affect the function of human spermatogonia in vitro

    NARCIS (Netherlands)

    Nickkholgh, B.; Korver, C. M.; van Daalen, S. K. M.; van Pelt, A. M. M.; Repping, S.

    2015-01-01

    Azoospermic factor c (AZFc) deletions are the underlying cause in 10% of azoo- or severe oligozoospermia. Through extensive molecular analysis the precise genetic content of the AZFc region and the origin of its deletion have been determined. However, little is known about the effect of AZFc

  16. Deletion of SNURF/SNRPN U1B and U1B* upstream exons in a ...

    Indian Academy of Sciences (India)

    Array-CGH analysis of the proband indicated a 15q11.2 deletion. The presence and the breakpoints of the deletion are underlined in red which correspond to approximately 13 kb (pos. 25,068,955–25,082,444) residing in the SNRNP gene as indicated by green line. MEO28-B2 (MRC, Holland) which is specific for Prader–.

  17. Rapid deletion plasmid construction methods for protoplast and Agrobacterium based fungal transformation systems

    Science.gov (United States)

    Increasing availability of genomic data and sophistication of analytical methodology in fungi has elevated the need for functional genomics tools in these organisms. Gene deletion is a critical tool for functional analysis. The targeted deletion of genes requires both a suitable method for the trans...

  18. De novo Xp terminal deletion in a triple X female with recurrent ...

    Indian Academy of Sciences (India)

    (MLS), a rare congenital, X-linked dominant syndrome is also most commonly caused by terminal deletions of Xp. (Vergult et al. 2013). In contrast with these reports, the patient in discussion was a true 47,XXX female without any mosaic cell line, but had an Xp terminal deletion in the extra copy of the X chromosome that had ...

  19. Pearson syndrome and the role of deletion dimers and duplications in the mtDNA

    NARCIS (Netherlands)

    Jacobs, L. J. A. M.; Jongbloed, R. J. E.; Wijburg, F. A.; de Klerk, J. B. C.; Geraedts, J. P. M.; Nijland, J. G.; Scholte, H. R.; de Coo, I. F. M.; Smeets, H. J. M.

    2004-01-01

    Pearson syndrome is an often fatal multisystem disease associated with mitochondrial DNA rearrangements. Here we report a patient with a novel mtDNA deletion of 3.4 kb ranging from nucleotides 6097 to 9541 in combination with deletion dimers. The mutation percentage in different tissues (blood,

  20. Risk of Psychiatric Disorders Among Individuals With the 22q11.2 Deletion or Duplication

    DEFF Research Database (Denmark)

    Hoeffding, Louise K; Trabjerg, Betina B; Olsen, Line

    2017-01-01

    .64-14.69) and childhood autism (IRR, 8.94; 95%CI, 3.21-19.23). Conclusions and relevance: Individuals with the 22q11.2 deletion or duplication have a significantly increased risk of developing psychiatric disorders. Survival analysis of persons carrying either the 22q11.2 deletion or duplication provides estimates...

  1. Delineating the psychiatric and behavioral phenotype of recurrent 2q13 deletions and duplications

    DEFF Research Database (Denmark)

    Wolfe, Kate; McQuillin, Andrew; Alesi, Viola

    2018-01-01

    ) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence...

  2. Neuroimaging Correlates of 22q11.2 Deletion Syndrome: Implications for Schizophrenia Research

    NARCIS (Netherlands)

    Boot, E.; van Amelsvoort, T. A. M. J.

    2012-01-01

    22q11.2 Deletion syndrome (22q11DS) is the most common known recurrent copy-number variant disorder. It is also the most common known genetic risk factor for schizophrenia. The greater homogeneity of subjects with schizophrenia in 22q11DS compared with schizophrenia in the wider non-deleted

  3. Characteristics of dystonia in the 18p deletion syndrome, including a new case

    NARCIS (Netherlands)

    Postma, Anna G.; Verschuuren - Bemelmans, Corien C.; Kok, Klaas; van Laar, Teus

    2009-01-01

    Objective of the present study was to evaluate the possible pathophysiology and clinical characteristics of dystonia in patients with the 18p deletion syndrome by describing a new case and reviewing the literature. Dystonia in patients with the 18p deletion syndrome seems to present heterogeneously

  4. Computational prediction of the tolerance to amino-acid deletion in green-fluorescent protein.

    Science.gov (United States)

    Jackson, Eleisha L; Spielman, Stephanie J; Wilke, Claus O

    2017-01-01

    Proteins evolve through two primary mechanisms: substitution, where mutations alter a protein's amino-acid sequence, and insertions and deletions (indels), where amino acids are either added to or removed from the sequence. Protein structure has been shown to influence the rate at which substitutions accumulate across sites in proteins, but whether structure similarly constrains the occurrence of indels has not been rigorously studied. Here, we investigate the extent to which structural properties known to covary with protein evolutionary rates might also predict protein tolerance to indels. Specifically, we analyze a publicly available dataset of single-amino-acid deletion mutations in enhanced green fluorescent protein (eGFP) to assess how well the functional effect of deletions can be predicted from protein structure. We find that weighted contact number (WCN), which measures how densely packed a residue is within the protein's three-dimensional structure, provides the best single predictor for whether eGFP will tolerate a given deletion. We additionally find that using protein design to explicitly model deletions results in improved predictions of functional status when combined with other structural predictors. Our work suggests that structure plays fundamental role in constraining deletions at sites in proteins, and further that similar biophysical constraints influence both substitutions and deletions. This study therefore provides a solid foundation for future work to examine how protein structure influences tolerance of more complex indel events, such as insertions or large deletions.

  5. The smt-0 mutation which abolishes mating-type switching in fission yeast is a deletion

    DEFF Research Database (Denmark)

    Styrkársdóttir, U; Egel, R; Nielsen, O

    1993-01-01

    Mating-type switching in the fission yeast, S. pombe, is initiated by a DNA double-strand break (DSB) between the mat1 cassette and the H1 homology box. The mat1-cis-acting mutant, smt-0, abolishes mating-type switching and is shown here to be a 263-bp deletion. This deletion starts in the middle...

  6. Deletion of /T, D/ and the Acquisition of Linguistic Variation by Second Language Learners of English

    Science.gov (United States)

    Edwards, Jette G. Hansen

    2011-01-01

    This study investigated second language (L2) learners' acquisition of English /t, d/ deletion patterns in word-final consonant clusters, (a) focusing on how constraints such as grammatical conditioning and phonological environment affect deletion of /t, d/ in L2 acquisition and (b) determining the extent to which these L2 learners had acquired…

  7. Multiple Patterns of FHIT Gene Homozygous Deletion in Egyptian Breast Cancer Patients

    International Nuclear Information System (INIS)

    Ismail, H.M.S.; Zakhary, N.I.; Medhat, A.M.; Karim, A.M.

    2011-01-01

    Fragile histidine triad (FHIT) gene encodes a putative tumour suppressor protein. Loss of Fhit protein in cancer is attributed to different genetic alterations that affect the FHIT gene structure. In this study, we investigated the pattern of homozygous deletion that target the FHIT gene exons 3 to 9 genomic structure in Egyptian breast cancer patients. We have found that 65% (40 out of 62) of the cases exhibited homozygous deletion in at least one FHIT exon. The incidence of homozygous deletion was not associated with patients clinico pathological parameters including patients age, tumour grade, tumour type, and lymph node involvement. Using correlation analysis, we have observed a strong correlation between homozygous deletions of exon 3 and exon 4 (P<0.0001). Deletions in exon 5 were positively correlated with deletions in exon 7 (P<0.0001), Exon 8 (P<0.027), and exon 9 (P=0.04). Additionally, a strong correlation was observed between exons 8 and exon 9 (P<0.0001).We conclude that FHIT gene exons are homozygously deleted at high frequency in Egyptian women population diagnosed with breast cancer. Three different patterns of homozygous deletion were observed in this population indicating different mechanisms of targeting FHIT gene genomic structure.

  8. 40 CFR 63.60 - Deletion of caprolactam from the list of hazardous air pollutants.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 9 2010-07-01 2010-07-01 false Deletion of caprolactam from the list of hazardous air pollutants. 63.60 Section 63.60 Protection of Environment ENVIRONMENTAL PROTECTION..., Source Category List § 63.60 Deletion of caprolactam from the list of hazardous air pollutants. The...

  9. Autism, ADHD, Mental Retardation and Behavior Problems in 100 Individuals with 22q11 Deletion Syndrome

    Science.gov (United States)

    Niklasson, Lena; Rasmussen, Peder; Oskarsdottir, Solveig; Gillberg, Christopher

    2009-01-01

    This study assessed the prevalence and type of associated neuropsychiatric problems in children and adults with 22q11 deletion syndrome. One-hundred consecutively referred individuals with 22q11 deletion syndrome were given in-depth neuropsychiatric assessments and questionnaires screens. Autism spectrum disorders (ASDs) and/or attention…

  10. Cardiac Defects and Results of Cardiac Surgery in 22q11.2 Deletion Syndrome

    Science.gov (United States)

    Carotti, Adriano; Digilio, Maria Cristina; Piacentini, Gerardo; Saffirio, Claudia; Di Donato, Roberto M.; Marino, Bruno

    2008-01-01

    Specific types and subtypes of cardiac defects have been described in children with 22q11.2 deletion syndrome as well as in other genetic syndromes. The conotruncal heart defects occurring in patients with 22q11.2 deletion syndrome include tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus, interrupted aortic…

  11. A new alpha(0)-thalassemia deletion found in a Dutch family (--(AW)).

    NARCIS (Netherlands)

    Phylipsen, M.; Vogelaar, I.P.; Schaap, R.A.; Arkesteijn, S.G.; Boxma, G.L.; Helden, W.C. van; Wildschut, I.C.; Bruin-Roest, A.C. de; Giordano, P.C.; Harteveld, C.L.

    2010-01-01

    Alpha-thalassemia is an inherited hemoglobin disorder characterized by a microcytic hypochromic anemia caused by a quantitative reduction of the alpha-globin chain. The majority of the alpha-thalassemias is caused by deletions in the alpha-globin gene cluster. A deletion in the alpha-globin gene

  12. Maladaptive Behavior Differences in Prader-Willi Syndrome Due to Paternal Deletion versus Maternal Uniparental Disomy.

    Science.gov (United States)

    Dykens, Elisabeth M.; King, Bryan H.; Cassidy, Suzanne B.

    1999-01-01

    This study compared maladaptive behavior in 23 people with Prader-Willi syndrome due to paternal deletion and in 23 age- and gender-matched subjects with maternal uniparental disomy. Controlling for IQs, the deletion cases showed significantly higher maladaptive ratings, more symptom-related distress, and more behavior problems. Findings suggest a…

  13. Deletion of a single-copy DAAM1 gene in congenital heart defect: a case report

    Directory of Open Access Journals (Sweden)

    Bao Bihui

    2012-08-01

    Full Text Available Abstract Background With an increasing incidence of congenital heart defects (CHDs in recent years, genotype-phenotype correlation and array-based methods have contributed to the genome-wide analysis and understanding of genetic variations in the CHD population. Here, we report a copy number deletion of chromosomal 14q23.1 in a female fetus with complex congenital heart defects. This is the first description of DAAM1 gene deletion associated with congenital heart anomalies. Case Presentation Compared with the control population, one CHD fetus showed a unique copy number deletion of 14q23.1, a region that harbored DAAM1 and KIAA0666 genes. Conclusions Results suggest that the copy number deletion on chromosome 14q23.1 may be critical for cardiogenesis. However, the exact relationship and mechanism of how DAAM1 and KIAA0666 deletion contributes to the onset of CHD is yet to be determined.

  14. Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation

    DEFF Research Database (Denmark)

    Lugtenberg, Dorien; Zangrande-Vieira, Luiz; Kirchhoff, Maria

    2010-01-01

    12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating...... that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P......-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation....

  15. FAMILIAL CASE OF CHROMOSOME 22q11.2 DELETION SYNDROME

    Directory of Open Access Journals (Sweden)

    I. A. Tuzankina

    2017-01-01

    Full Text Available The work represents a family which includes two siblings with chromosome 22q11.2 deletion syndrome. Their mother carries the same chromosome anomaly, but with apparently normal phenotype. Hence, this interesting case of 22q11.2 deletion syndrome exists in 2 generations of the same family. The aim of this study was analysis of phenotypic manifestations in the family members with 22q11.2 deletion syndrome. Clinical examination of the patients, their life story and pedigree and, along with routine clinical and biochemical analysis, and immune state testing, along with ultrasound imaging of thymus and thyroid glands, heart and abdominal cavity. We made conclusions that the phenotypic features associated with chromosome 22q11.2 deletion may be different for distinct family members. Further studies are required to determine length of deleted segment and the genes affected, as well as to establish the genotype-phenotype interactions and disease prognosis.

  16. Relatively low proportion of dystrophin gene deletions in Israeili Duchenne and Becker muscular dystrophy patients

    Energy Technology Data Exchange (ETDEWEB)

    Shomrat, R.; Gluck, E.; Legum, C.; Shiloh, Y. [Tel Aviv Univ. (Israel)

    1994-02-15

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55-65%). Seventy-eight percent of the deletions were confined to exons 44-52, half of these exons 44-45, and the remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes. 43 refs., 1 fig., 1 tab.

  17. Spontaneous and mutagen-induced deletions: mechanistic studies in Salmonella tester strain TA102

    International Nuclear Information System (INIS)

    Levin, D.E.; Marnett, L.J.; Ames, B.N.

    1984-01-01

    Salmonella tester strain TA102 carries the hisG428 ochre mutation on the multicopy plasmid pAQ1. DNA sequence analysis of 45 spontaneous revertants of hisG428 on the chromosome in the presence of pKM101 (strain TA103) indicates that hisG428 revertants fall into three major categories: (i) small, in-frame deletions (3 or 6 base pairs) that remove part or all of the ochre triplet; (ii) base substitution mutations at the ochre site; (iii) extragenic ochre suppressors. Deletion revertants are identified in a simple phenotypic screen by their resistance to the inhibitory histidine analog thiazolealanine, which feedback inhibits the wild-type hisG enzyme but not the enzyme resulting from the deletions. The effect of various genetic backgrounds on the generation of spontaneous deletion revertants was examined. The presence of a uvrB mutation or a recA mutation suppressed the generation of spontaneous deletion revertants to approximately 1/2.5. When hisG428 was in multiple copies on pAQ1, the frequency of spontaneous deletion revertants increased by 40-fold, which is the approximate copy number of pAQ1. Mutagenic agents that induce single-strand breaks in DNA (e.g., x-rays, bleomycin, and nalidixic acid) induced deletion revertants in TA102. These agents induced deletion revertants only in hisG428 on pAQ1 and only in the presence of pKM101. Deletion revertants were not induced by frameshift mutagens (i.e., ICR-191 and 9aminoacridine). These results indicate that different pathways exist for the generation of spontaneous and mutagen-induced deletion revertants of hisG428. 41 references, 2 figures, 3 tables

  18. APOBEC3 deletion polymorphism is associated with breast cancer risk among women of European ancestry.

    Science.gov (United States)

    Xuan, Dennis; Li, Guoliang; Cai, Qiuyin; Deming-Halverson, Sandra; Shrubsole, Martha J; Shu, Xiao-Ou; Kelley, Mark C; Zheng, Wei; Long, Jirong

    2013-10-01

    Copy number variations occur frequently in the genome and are a significant source of human genetic variation accounting for disease. Recently, we discovered a common deletion located in the APOBEC3A and APOBEC3B genes significantly associated with breast cancer in Chinese women. Investigating this locus in other populations would be an expedient way to evaluate the generalizability of the novel finding. We analyzed the APOBEC3 deletion in a large study of 3273 European-ancestry women (including 1671 breast cancer cases and 1602 controls) from the population-based Nashville Breast Health Study. All participants were genotyped using real-time qualitative PCR. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between the deletion polymorphism and breast cancer risk. The APOBEC3 deletion was observed in 12.4% of cases and 10.4% of controls. The deletion was significantly associated with breast cancer risk, with ORs and 95% CIs of 1.21 (1.02-1.43) associated with one-copy deletion and 2.29 (1.04-5.06) associated with two-copy deletion compared with women with no deletion (P for trend = 0.005). The positive association of the APOBEC3 deletion with breast cancer risk was similar for estrogen receptor-positive and estrogen receptor-negative breast cancer and was not modified by known breast cancer risk factors. Results from this study confirmed the association of the APOBEC3 deletion with breast cancer risk among women of European ancestry.

  19. Analysis of human HPRT- deletion mutants by the microarray-CGH (comparative genomic hybridization)

    International Nuclear Information System (INIS)

    Kodaira, M.; Sasaki, K.; Tagawa, H.; Omine, H.; Kushiro, J.; Takahashi, N.; Katayama, H.

    2003-01-01

    We are trying to evaluate genetic effects of radiation on human using mutation frequency as an indicator. For the efficient detection of mutations, it is important to understand the mechanism and the characteristics of radiation-induced mutations. We have started the analysis of hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutants induced by X-ray in order to clarify the deletion size and the mutation-distribution. We analyzed 39 human X-ray induced HPRT-deletion mutants by using the microarray-CGH. The array for this analysis contains 57 BAC clones covering as much as possible of the 4Mb of the 5' side and 10Mb of the 3' side of the HPRT gene based on the NCBI genome database. DNA from parent strain and each HPRT-mutant strain are labeled with Cy5 and Cy3 respectively, and were mixed and hybridized on the array. Fluorescent intensity ratio of the obtained spots was analyzed using software we developed to identify clones corresponding to the deletion region. The deletion in these strains ranged up to 3.5 Mb on the 5' side and 6 Mb on the 3' side of the HPRT gene. Deletions in 13 strains ended around BAC clones located at about 3 Mb on the 5' side. On the 3' side, deletions extended up to the specific clones located at 1.5 Mb in 11 strains. The mutations seem to be complex on the 3' end of deletion; some accompanied duplications with deletions and others could not be explained by one mutation event. We need to confirm these results, taking into account the experimental reproducibility and the accuracy of the published genetic map. The results of the research using the microarray-CGH help us to search the regions where deletions are easily induced and to identify the factors affecting the range of deletions

  20. Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples.

    Science.gov (United States)

    Maisenbacher, Melissa K; Merrion, Katrina; Pettersen, Barbara; Young, Michael; Paik, Kiyoung; Iyengar, Sushma; Kareht, Stephanie; Sigurjonsson, Styrmir; Demko, Zachary P; Martin, Kimberly A

    2017-01-01

    The 22q11.2 deletion syndrome is the most common microdeletion syndrome in livebirths, but data regarding its incidence in other populations is limited and also include ascertainment bias. This study was designed to determine the incidence of the 22q11.2 deletion in miscarriage samples sent for clinical molecular cytogenetic testing. Twenty-six thousand one hundred one fresh product of conception (POC) samples were sent to a CLIA- certified, CAP-accredited laboratory from April 2010--May 2016 for molecular cytogenetic miscarriage testing using a single-nucleotide polymorphism (SNP)-based microarray platform. A retrospective review determined the incidence of the 22q11.2 deletion in this sample set. Fetal results were obtained in 22,451 (86%) cases, of which, 15 (0.07%) had a microdeletion in the 22q11.2 region (incidence, 1/1497). Of those, 12 (80%) cases were found in samples that were normal at the resolution of traditional karyotyping (i.e., had no chromosome abnormalities above 10 Mb in size) and three (20%) cases had additional findings (Trisomy 15, Trisomy 16, XXY). Ten (67%) cases with a 22q11.2 deletion had the common ~3 Mb deletion; the remaining 5 cases had deletions ranging in size from 0.65 to 1.5 Mb. A majority (12/15) of cases had a deletion on the maternally inherited chromosome. No significant relationship between maternal age and presence of a fetal 22q11.2 deletion was observed. The observed incidence of 1/1497 for the 22q11.2 deletion in miscarriage samples is higher than the reported general population prevalence (1/4000-1/6000). Further research is needed to determine whether the 22q11.2 deletion is a causal factor for miscarriage.

  1. Diabetes and Neurodegeneration in Wolfram Syndrome

    Science.gov (United States)

    Rohayem, Julia; Ehlers, Christian; Wiedemann, Bärbel; Holl, Reinhard; Oexle, Konrad; Kordonouri, Olga; Salzano, Giuseppina; Meissner, Thomas; Burger, Walter; Schober, Edith; Huebner, Angela; Lee-Kirsch, Min Ae

    2011-01-01

    OBJECTIVE To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation. RESEARCH DESIGN AND METHODS The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. RESULTS WSD was diagnosed earlier than type 1 diabetes (5.4 ± 3.8 vs. 7.9 ± 4.2 years; P diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P 7.5% (P = 0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P = 0.028). CONCLUSIONS Endoplasmic reticulum stress–mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease. PMID:21602428

  2. Remote Wiping and Secure Deletion on Mobile Devices: A Review.

    Science.gov (United States)

    Leom, Ming Di; Choo, Kim-Kwang Raymond; Hunt, Ray

    2016-11-01

    Mobile devices have become ubiquitous in almost every sector of both private and commercial endeavors. As a result of such widespread use in everyday life, many users knowingly and unknowingly save significant amounts of personal and/or commercial data on these mobile devices. Thus, loss of mobile devices through accident or theft can expose users-and their businesses-to significant personal and corporate cost. To mitigate this data leakage issue, remote wiping features have been introduced to modern mobile devices. Given the destructive nature of such a feature, however, it may be subject to criminal exploitation (e.g., a criminal exploiting one or more vulnerabilities to issue a remote wiping command to the victim's device). To obtain a better understanding of remote wiping, we survey the literature, focusing on existing approaches to secure flash storage deletion and provide a critical analysis and comparison of a variety of published research in this area. In support of our analysis, we further provide prototype experimental results for three Android devices, thus providing both a theoretical and applied focus to this article as well as providing directions for further research. © 2016 American Academy of Forensic Sciences.

  3. Deletion of Pr130 Interrupts Cardiac Development in Zebrafish

    Directory of Open Access Journals (Sweden)

    Jie Yang

    2016-11-01

    Full Text Available Protein phosphatase 2 regulatory subunit B, alpha (PPP2R3A, a regulatory subunit of protein phosphatase 2A (PP2A, is a major serine/threonine phosphatase that regulates crucial function in development and growth. Previous research has implied that PPP2R3A was involved in heart failure, and PR130, the largest transcription of PPP2R3A, functioning in the calcium release of sarcoplasmic reticulum (SR, plays an important role in the excitation-contraction (EC coupling. To obtain a better understanding of PR130 functions in myocardium and cardiac development, two pr130-deletion zebrafish lines were generated using clustered regularly interspaced short palindromic repeats (CRISPR/CRISPR-associated proteins (Cas system. Pr130-knockout zebrafish exhibited cardiac looping defects and decreased cardiac function (decreased fractional area and fractional shortening. Hematoxylin and eosin (H&E staining demonstrated reduced cardiomyocytes. Subsequent transmission electron microscopy revealed that the bright and dark bands were narrowed and blurred, the Z- and M-lines were fogged, and the gaps between longitudinal myocardial fibers were increased. Additionally, increased apoptosis was observed in cardiomyocyte in pr130-knockout zebrafish compared to wild-type (WT. Taken together, our results suggest that pr130 is required for normal myocardium formation and efficient cardiac contractile function.

  4. Upper limb malformations in chromosome 22q11 deletions

    Energy Technology Data Exchange (ETDEWEB)

    Shalev, S.A.; Dar, H.; Barel, H.; Borochowitz, Z. [Bnai Zion Medical Center, Haifa (Israel)

    1996-03-29

    We read with interest the report of Cormier-Daire et al. in a recent issue of the journal, describing upper limb malformations in DiGeorge syndrome. We observed a family with this group of rare clinical expression of chromosome 22q11 deletions. The proposita was examined in our clinic when she was 4 years old. She was mildly mentally retarded. Clinical evaluation showed normal growth, long thin nose with squared tip, nasal speech, and abundant scalp hair and no cardiac anomalies. The girl was accompanied by her mother. Facial similarities were noted between the two. The mother reported to be treated with oral calcium due to hypoparathyroidism, diagnosed several years ago. Clinical evaluation showed wide flat face, short stature, mild mental retardation, slight hypertelorism, peculiar nose similar to her daughter`s, and nasal speech. No cardiac anomalies were found. Recently, a brother was born. Clinical examination documented large ventriculo-septal defect, retrognathia, narrow palpebral fissures, and long thin nose with squared tip. 1 ref.

  5. Clinical and molecuar characterization of Brazilian patients with growth hormone gene deletions

    Directory of Open Access Journals (Sweden)

    I.J.P. Arnhold

    1998-04-01

    Full Text Available Genomic DNA from 23 patients with isolated growth hormone (GH deficiency (12 males and 11 females: heights -4.9 ± 1.4 SDS was screened for GH gene deletions by restriction endonuclease analysis of polymerase chain reaction amplification products. Three unrelated patients had typical features of severe GH deficiency and deletions (6.7 kb in two and 7.6 kb in one of the GH gene. The two patients with 6.7-kb deletions developed growth-attenuating anti-GH antibodies whereas the patient with the 7.6-kb deletion continued to grow with GH replacement therapy. Our finding that 3/23 (~13% Brazilian subjects had GH gene deletions agrees with previous studies of severe isolated GH deficiency subjects in other populations. Two of three subjects (67% with deletions developed blocking antibodies despite administration of exogenous GH at low doses. Interestingly, only 1/10 of cases with affected relatives or parental consanguinity had GH-1 gene deletions

  6. FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Teshima, I.; Chadwick, D.; Chitayat, D. [Hospital for Sick Children and Univ. of Toronto, Ontario (Canada)

    1996-03-29

    We have evaluated fluorescence in situ hybridization (FISH) analysis for the clinical laboratory detection of the 15q11-q13 deletion seen in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) using probes for loci D15S11, SNRPN, D15S10, and GABRB3. In a series of 118 samples from patients referred for PWS or AS, 29 had deletions by FISH analysis. These included two brothers with a paternally transmitted deletion detectable with the probe for SNRPN only. G-banding analysis was less sensitive for deletion detection but useful in demonstrating other cytogenetic alterations in four cases. Methylation and CA-repeat analyses of 15q11-q13 were used to validate the FISH results. Clinical findings of patients with deletions were variable, ranging from newborns with hypotonia as the only presenting feature to children who were classically affected. We conclude that FISH analysis is a rapid and reliable method for detection of deletions within 15q11-q13 and whenever a deletion is found, FISH analysis of parental chromosomes should also be considered. 41 refs., 4 figs., 2 tabs.

  7. Association of BIM Deletion Polymorphism and BIM-γ RNA Expression in NSCLC with EGFR Mutation.

    Science.gov (United States)

    Isobe, Kazutoshi; Kakimoto, Atsushi; Mikami, Tetsuo; Kaburaki, Kyohei; Kobayashi, Hiroshi; Yoshizawa, Takahiro; Makino, Takashi; Otsuka, Hajime; Sano, G O; Sugino, Keishi; Sakamoto, Susumu; Takai, Yujiro; Tochigi, Naobumi; Iyoda, Akira; Homma, Sakae

    This pilot study assessed the association of BIM deletion polymorphism and BIM RNA isoform in patients with EGFR-positive non-small cell lung cancer (NSCLC). The study included 33 patients with EGFR-positive NSCLC treated with gefitinib. BIM deletion polymorphism and BIM RNA isoform (EL/L/S/γ) were determined by polymerase chain reaction (PCR). BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM deletion polymorphism inside tumors (p=0.038) and around tumors (p=0.0024). Relative BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM deletion polymorphism (p=0.0017). Patients with BIM-γ had significantly shorter progression-free survival than those without BIM-γ (median: 304 vs. 732 days; p=0.023). Expression of BIM-γ mRNA and BIM deletion polymorphism were strongly associated. BIM-γ overexpression may have a role in apoptosis related to EGFR-tyrosine kinase inhibitor. Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

  8. Microarray-based ultra-high resolution discovery of genomic deletion mutations

    Science.gov (United States)

    2014-01-01

    Background Oligonucleotide microarray-based comparative genomic hybridization (CGH) offers an attractive possible route for the rapid and cost-effective genome-wide discovery of deletion mutations. CGH typically involves comparison of the hybridization intensities of genomic DNA samples with microarray chip representations of entire genomes, and has widespread potential application in experimental research and medical diagnostics. However, the power to detect small deletions is low. Results Here we use a graduated series of Arabidopsis thaliana genomic deletion mutations (of sizes ranging from 4 bp to ~5 kb) to optimize CGH-based genomic deletion detection. We show that the power to detect smaller deletions (4, 28 and 104 bp) depends upon oligonucleotide density (essentially the number of genome-representative oligonucleotides on the microarray chip), and determine the oligonucleotide spacings necessary to guarantee detection of deletions of specified size. Conclusions Our findings will enhance a wide range of research and clinical applications, and in particular will aid in the discovery of genomic deletions in the absence of a priori knowledge of their existence. PMID:24655320

  9. Exploration of methods to localize DNA sequences missing from c-locus deletions

    International Nuclear Information System (INIS)

    Albritton, L.M.; Russell, L.B.; Montgomery, C.S.

    1987-01-01

    The authors have earlier characterized a large number of radiation-induced mutations at the c locus (on Chromosome 7) through genetic analysis, including extensive complementation tests. Based on this work, they have postulated that many of these mutations are deletions of various lengths, overlapping at c (the marker used in the mutation-rate experiments that generated the mutants). It was possible to apportion these deletions among 13 complementation groups and to fit them to a linear map of 8 functional units. Collectively, the deletions extend from a point between tp and c to one between sh-1 and Hbb, i.e., a genetic distance of from 6 to 10 cM, corresponding to at least 10 4 Kb of DNA. This year, the authors completed a pilot study designed to explore methods for finding DNA sequences that map to the region covered by the various c-deletions. The general plan was to probe DNA with clones derived from Chromosome-7-enriched libraries or with sequences known (or suspected) to reside in Chromosome 7. Three methods were explored for deriving the c-region-deficient DNA: (a) from mouse-hamster somatic-cell hydrids retaining a deleted mouse Chromosome 7, but no homologue; (b) from F 1 hybrids of M. musculus domesticus (carrying a c-locus deletion) by M. spretus; and (c) from F 1 hybrids of M. domesticus stocks carrying complementing deletions

  10. Growth hormone (GH-1) gene deletions in children with isolated growth hormone deficiency (IGHD).

    Science.gov (United States)

    Desai, Meena P; Mithbawkar, Shilpa M; Upadhye, Pradnya S; Shalia, Kavita K

    2012-07-01

    To detect growth hormone GH-1 gene deletions (6.7 kb, 7.6 kb, 7 kb) in familial/nonfamilial isolated growth hormone deficiency (IGHD) and note their clinical and investigative profile. Thirty (M16,F14) prepubertal IGHD patients aged 0.25 to 14 y, from 25 families were screened. Duration of growth failure, relevant history, clinical phenotype, and height SDS were recorded. Peak GH response to Clonidine (0.15 mg/m(2)), IGF-1, IGFBP-3 and pituitary/target gland hormones were studied. Genomic DNA of patients and family was analysed by PCR and DNA fragments were visualized on agarose gel electrophoresis. This series was divided into deletion +ve, Group I (n=12,40%) inclusive of six familial/six nonfamilial patients, and deletion -ve Group II (n=18,60%), 5 familial/13 nonfamilial cases; in total 11/30 were familial. Onset of growth failure was earlier in Group I (pGH hormones were normal and MRI showed hypoplastic adenohypophysis. 40% had GH-1 gene deletion (6.7 kb deletion in 83%, 7.6 kb and a compound heterozygote in 8% each). In this series of 30 IGHD patients, frequency of GH-1 gene deletions (12/30) was 40%, and 54% among familial patients, and 31% with height SDS>-4. 83% had 6.7 kb deletion. Height SDS>-4, clinical phenotype, peak GH<1 ng/ml and hypoglycemia characterised IGHD Type IA.

  11. Sequence characterisation of deletion breakpoints in the dystrophin gene by PCR

    Energy Technology Data Exchange (ETDEWEB)

    Abbs, S.; Sandhu, S.; Bobrow, M. [Guy`s Hospital, London (United Kingdom)

    1994-09-01

    Partial deletions of the dystrophin gene account for 65% of cases of Duchenne muscular dystrophy. A high proportion of these structural changes are generated by new mutational events, and lie predominantly within two `hotspot` regions, yet the underlying reasons for this are not known. We are characterizing and sequencing the regions surrounding deletion breakpoints in order to: (i) investigate the mechanisms of deletion mutation, and (ii) enable the design of PCR assays to specifically amplify mutant and normal sequences, allowing us to search for the presence of somatic mosaicism in appropriate family members. Using this approach we have been able to demonstrate the presence of somatic mosaicism in a maternal grandfather of a DMD-affected male, deleted for exons 49-50. Three deletions, namely of exons 48-49, 49-50, and 50, have been characterized using a PCR approach that avoids any cloning procedures. Breakpoints were initially localized to within regions of a few kilobases using Southern blot restriction analyses with exon-specific probes and PCR amplification of exonic and intronic loci. Sequencing was performed directly on PCR products: (i) mutant sequences were obtained from long-range or inverse-PCR across the deletion junction fragments, and (ii) normal sequences were obtained from the products of standard PCR, vectorette PCR, or inverse-PCR performed on YACs. Further characterization of intronic sequences will allow us to amplify and sequence across other deletion breakpoints and increase our knowledge of the mechanisms of mutation in the dystophin gene.

  12. Dual entanglement measures based on no local cloning and no local deleting

    International Nuclear Information System (INIS)

    Horodecki, Michal; Sen, Aditi; Sen, Ujjwal

    2004-01-01

    The impossibility of cloning and deleting of unknown states constitute important restrictions on processing of information in the quantum world. On the other hand, a known quantum state can always be cloned or deleted. However, if we restrict the class of allowed operations, there will arise restrictions on the ability of cloning and deleting machines. We have shown that cloning and deleting of known states is in general not possible by local operations. This impossibility hints at quantum correlation in the state. We propose dual measures of quantum correlation based on the dual restrictions of no local cloning and no local deleting. The measures are relative entropy distances of the desired states in a (generally impossible) perfect local cloning or local deleting process from the best approximate state that is actually obtained by imperfect local cloning or deleting machines. Just like the dual measures of entanglement cost and distillable entanglement, the proposed measures are based on important processes in quantum information. We discuss their properties. For the case of pure states, estimations of these two measures are also provided. Interestingly, the entanglement of cloning for a maximally entangled state of two two-level systems is not unity

  13. The role of mitochondrial DNA large deletion for the development of presbycusis in Fischer 344 rats.

    Science.gov (United States)

    Yin, Shankai; Yu, Zhiping; Sockalingam, Ravi; Bance, Manohar; Sun, Genlou; Wang, Jian

    2007-09-01

    Age-related hearing loss, or presbycusis, has been associated with large-scale mitochondrial DNA (mtDNA) deletion in previous studies. However, the role of this mtDNA damage in presbycusis is still not clear because the deletion in inner ears has not been measured quantitatively and analyzed in parallel with the time course of presbycusis. In the present study, the deletion was quantified using quantitative real-time PCR (qRT-PCR) in male Fischer 344 rats of different ages. It was found that the deletion increased quickly during young adulthood and reached over 60% at 6 months of age. However, a significant hearing loss was not seen until after 12 months of age. The results suggest that the existence of the deletion per se does not necessarily imply cochlear damage, but rather a critical level of the accumulated deletion seems to precede the hearing loss. The long delay may indicate the involvement of mechanisms other than mtDNA deletion in the development of presbycusis.

  14. Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy

    Directory of Open Access Journals (Sweden)

    Larsen Michael

    2011-04-01

    Full Text Available Abstract Background Autosomal dominant optic atrophy (ADOA, Kjer disease, MIM #165500 is the most common form of hereditary optic neuropathy. Mutations in OPA1 located at chromosome 3q28 are the predominant cause for ADOA explaining between 32 and 89% of cases. Although deletions of OPA1 were recently reported in ADOA, the frequency of OPA1 genomic rearrangements in Denmark, where ADOA has a high prevalence, is unknown. The aim of the study was to identify copy number variations in OPA1 in Danish ADOA patients. Methods Forty unrelated ADOA patients, selected from a group of 100 ADOA patients as being negative for OPA1 point mutations, were tested for genomic rearrangements in OPA1 by multiplex ligation probe amplification (MLPA. When only one probe was abnormal results were confirmed by additional manually added probes. Segregation analysis was performed in families with detected mutations when possible. Results Ten families had OPA1 deletions, including two with deletions of the entire coding region and eight with intragenic deletions. Segregation analysis was possible in five families, and showed that the deletions segregated with the disease. Conclusion Deletions in the OPA1 gene were found in 10 patients presenting with phenotypic autosomal dominant optic neuropathy. Genetic testing for deletions in OPA1 should be offered for patients with clinically diagnosed ADOA and no OPA1 mutations detected by DNA sequencing analysis.

  15. A novel 3q29 deletion associated with autism, intellectual disability, psychiatric disorders, and obesity.

    Science.gov (United States)

    Biamino, Elisa; Di Gregorio, Eleonora; Belligni, Elga Fabia; Keller, Roberto; Riberi, Evelise; Gandione, Marina; Calcia, Alessandro; Mancini, Cecilia; Giorgio, Elisa; Cavalieri, Simona; Pappi, Patrizia; Talarico, Flavia; Fea, Antonio M; De Rubeis, Silvia; Cirillo Silengo, Margherita; Ferrero, Giovanni Battista; Brusco, Alfredo

    2016-03-01

    Copy number variation (CNV) has been associated with a variety of neuropsychiatric disorders, including intellectual disability/developmental delay (ID/DD), autism spectrum disorder (ASD), and schizophrenia (SCZ). Often, individuals carrying the same pathogenic CNV display high clinical variability. By array-CGH analysis, we identified a novel familial 3q29 deletion (1.36 Mb), centromeric to the 3q29 deletion region, which manifests with variable expressivity. The deletion was identified in a 3-year-old girl diagnosed with ID/DD and autism and segregated in six family members, all affected by severe psychiatric disorders including schizophrenia, major depression, anxiety disorder, and personality disorder. All individuals carrying the deletion were overweight or obese, and anomalies compatible with optic atrophy were observed in three out of four cases examined. Amongst the 10 genes encompassed by the deletion, the haploinsufficiency of Optic Atrophy 1 (OPA1), associated with autosomal dominant optic atrophy, is likely responsible for the ophthalmological anomalies. We hypothesize that the haploinsufficiency of ATPase type 13A4 (ATP13A4) and/or Hairy/Enhancer of Split Drosophila homolog 1 (HES1) contribute to the neuropsychiatric phenotype, while HES1 deletion might underlie the overweight/obesity. In conclusion, we propose a novel contiguous gene syndrome due to a proximal 3q29 deletion variably associated with autism, ID/DD, psychiatric traits and overweight/obesity. © 2015 Wiley Periodicals, Inc.

  16. Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome.

    Science.gov (United States)

    Vieira, Gustavo H; Rodriguez, Jayson D; Carmona-Mora, Paulina; Cao, Lei; Gamba, Bruno F; Carvalho, Daniel R; de Rezende Duarte, Andréa; Santos, Suely R; de Souza, Deise H; DuPont, Barbara R; Walz, Katherina; Moretti-Ferreira, Danilo; Srivastava, Anand K

    2012-02-01

    Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ~139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS.

  17. Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment

    Directory of Open Access Journals (Sweden)

    Ritch Robert

    2004-06-01

    Full Text Available Abstract Background Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. Methods We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. Results Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1 probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. Conclusions Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss.

  18. Selection of Mycoplasma hominis PG21 deletion mutants by cultivation in the presence of monoclonal antibody 552

    DEFF Research Database (Denmark)

    Jensen, L T; Ladefoged, S; Birkelund, S

    1995-01-01

    characterized. The mutants showed deletions of a various number of repeats. The deletions were accompanied by a decrease in size of the proteins. With increasing size of deletions, agglutination and growth inhibition by MAb 552 became less pronounced. Spontaneous aggregation of the mutant M. hominis cells...

  19. Construction and characterization of a glycoprotein E deletion mutant of bovine herpesvirus type 1.2 strain isolated in Brazil

    NARCIS (Netherlands)

    Franco, A.C.; Rijsewijk, F.A.M.; Flores, E.F.; Weiblen, R.; Roehe, P.M.

    2002-01-01

    This paper describes the construction and characterization of a Brazilian strain of bovine herpesvirus type 1.2a (BoHV-1.2a) with a deletion of the glycoprotein E (gE) gene. The deletion was introduced by co-transfection of a deletion fragment containing the 5´and 3´gE flanking regions and genomic

  20. Correlation between chromosome 9p21 locus deletion and prognosis in clinically localized prostate cancer.

    Science.gov (United States)

    Barros, Érika Aparecida Felix de; Pontes-Junior, José; Reis, Sabrina Thalita; Lima, Amanda Eunice Ramos; Souza, Isida C; Salgueiro, Jose Lucas; Fontes, Douglas; Dellê, Humberto; Coelho, Rafael Ferreira; Viana, Nayara Izabel; Leite, Kátia Ramos Moreira; Nahas, William C; Srougi, Miguel

    2017-05-04

    Some studies have reported that deletions at chromosome arm 9p occur frequently and represent a critical step in carcinogenesis of some neoplasms. Our aim was to evaluate the deletion of locus 9p21 and chromosomes 3, 7 and 17 in localized prostate cancer (PC) and correlate these alterations with prognostic factors and biochemical recurrence after surgery. We retrospectively evaluated surgical specimens from 111 patients with localized PC who underwent radical prostatectomy. Biochemical recurrence was defined as a prostate-specific antigen (PSA) >0.2 ng/mL and the mean postoperative follow-up was 123 months. The deletions were evaluated using fluorescence in situ hybridization with centromeric and locus-specific probes in a tissue microarray containing 2 samples from each patient. We correlated the occurrence of any deletion with pathological stage, Gleason score, ISUP grade group, PSA and biochemical recurrence. We observed a loss of any probe in only 8 patients (7.2%). The most common deletion was the loss of locus 9p21, which occurred in 6.4% of cases. Deletions of chromosomes 3, 7 and 17 were observed in 2.3%, 1.2% and 1.8% patients, respectively. There was no correlation between chromosome loss and Gleason score, ISUP, PSA or stage. Biochemical recurrence occurred in 83% cases involving 9p21 deletions. Loss of 9p21 locus was significantly associated with time to recurrence (p = 0.038). We found low rates of deletion in chromosomes 3, 7 and 17 and 9p21 locus. We observed that 9p21 locus deletion was associated with worse prognosis in localized PC treated by radical prostatectomy.

  1. Variety of prenatally diagnosed congenital heart disease in 22q11.2 deletion syndrome

    Science.gov (United States)

    Lee, Mi-Young; Baek, Ju Won; Cho, Jae-Hyun; Shim, Jae-Yoon; Lee, Pil-Ryang; Kim, Ahm

    2014-01-01

    Objective To analyze the spectrum of prenatally diagnosed congenital heart disease in a Korean population with 22q11.2 deletion syndrome, and to provide guidelines for screening 22q11.2 deletion prenatally. Methods This retrospective study evaluated 1,137 consecutive fetuses that had prenatal genetic testing for 22q11.2 deletion because of suspected congenital heart disease between September 2002 and December 2012, at Asan Medical Center, Seoul, Korea. Results Main cardiovascular diseases in the 53 fetuses with confirmed 22q11.2 deletions were tetralogy of Fallot (n = 24, 45%), interrupted aortic arch (n = 10, 19%), ventricular septal defect (n = 5, 9%), double outlet right ventricle (n = 4, 8%), and coarctation of the aorta (n = 4, 8%). Other cardiac defects were rarely associated with 22q11.2 deletion. One fetus had persistent truncus arteriosus, one had aortic stenosis, and one had hypoplastic right heart syndrome. Two fetuses had normal intracardiac anatomy with an isolated right aortic arch, and one had an isolated bilateral superior vena cava. Conclusion A variety of congenital heart diseases were seen during the prenatal period. Conotruncal cardiac defects except transposition of great arteries were strongly associated with 22q11.2 deletion. When such anomalies are diagnosed by fetal echocardiography, genetic testing for 22q11.2 deletion should be offered. Even if less frequent deletion-related cardiac defects are detected, other related anomalies, such as thymic hypoplasia or aplasia, should be evaluated to rule out a 22q11.2 deletion. PMID:24596813

  2. Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: Evaluation of 235 patients

    Energy Technology Data Exchange (ETDEWEB)

    Lowery, M.C.; Brothman, L.J.; Leonard, C.O. [Univ. of Utah Health Sciences Center, Salt Lake City, UT (United States)] [and others

    1995-07-01

    Williams syndrome (WS) is generally characterized by mental deficiency, gregarious personality, dysmorphic facies, supravalvular aortic stenosis, and idiopathic infantile hypercalcemia. Patients with WS show allelic loss of elastin (ELN), exhibiting a submicroscopic deletion, at 7q11.23, detectable by FISH. Hemizygosity is likely the cause of vascular abnormalities in WS patients. A series of 235 patients was studied, and molecular cytogenetic deletions were seen in 96% of patients with classic WS. Patients included 195 solicited through the Williams Syndrome Association (WSA), plus 40 clinical cytogenetics cases referred by primary-care physicians. Photographs and medical records of most WSA subjects were reviewed, and patients were identified as {open_quotes}classic{open_quotes} (n = 114) or{open_quotes}uncertain{close_quotes} (n = 39). An additional 42 WSA patients were evaluated without clinical information. FISH was performed with biotinylated ELN cosmids on metaphase cells from immortalized lymphoblastoid lines from WSA patients and after high-resolution banding analysis on clinical referral patients. An alpha-satellite probe for chromosome 7 was included in hybridizations, as an internal control. Ninety-six percent of the patients with classic WS showed a deletion in one ELN allele; four of these did not show a deletion. Of the uncertain WS patients, only 3 of 39 showed a deletion. Of the 42 who were not classified phenotypically, because of lack of clinical information, 25 patients (60%) showed a deletion. Thirty-eight percent (15/40) of clinical cytogenetics cases showed an ELN deletion and no cytogenetic deletion by banded analysis. These results support the usefulness of FISH for the detection of elastin deletions as an initial diagnostic assay for WS. 14 refs., 2 figs., 4 tabs.

  3. Do mtDNA Deletions Play a Role in the Development of Nasal Polyposis?

    Directory of Open Access Journals (Sweden)

    Arzu Tatar

    2014-04-01

    Full Text Available Objective:Nasal polyposis (NP is an inflammatory disease of the nasal mucosa and paranasal sinuses. Mitochondria are the cellular organelles which produce cellular energy by Oxidative Phosphorylation (OXPHOS, and they have own inheritance material, mtDNA. mtDNA is affected by reactive oxygen samples (ROS which are produced by both OXPHOS and the inflammatory process. The aim of this study was to investigate the 4977 bp and 7400 bp deletions of mtDNA in nasal polyposis tissue, and to indicate the possible association of mtDNA deletions with NP. Methods:Thirty-three patients, aged 15 to 65 years, with nasal polyposis were selected to be assessed for mitochondrial DNA deletions. The patients with possible mtDNA mutations due to mitochondrial disease, being treated with radiotherapy, of advanced age, with a familiar history, aspirin hypersensitivity, or a history of asthma, were excluded. Polyp excision surgery was applied to the treatment of the NP, and after histopathological diagnosis 1x1 cm of polyp tissue samples were used to isolate mtDNA. The 4977 bp and 7400 bp deletion regions, and two control regions of mtDNA were assessed by using four pairs of primers. DNA extractions from the NP tissues and peripheral blood samples of the patients were made, and then Polymerase Chain Reactions (PCR were made. PCR products were separated in 2% agarose gel.Results:No patient had either the 4977 bp deletion or the 7400 bp deletion in their NP tissue, and neither were these deletions evident in their peripheral blood. Two control sequences, one of them from a non-deleted region, and the other from a possible deletion region, were detected in the NP tissues and peripheral blood of all the patients.Conclusions:We had anticipated that some mtDNA deletion might have occurred in NP tissue due to the increased ROS levels caused by chronic inflammation, but we did not detect any deletion. Probably, the duration of inflammation in NP is insufficient to form mt

  4. 20q13.2-q13.33 deletion syndrome: A case report.

    Science.gov (United States)

    Butler, Merlin G; Usrey, Kelly M; Roberts, Jennifer L; Manzardo, Ann M; Schroeder, Stephen R

    2013-01-01

    We report a 32-month-old female of Peruvian ethnicity identified with a rare 20q13.2-q13.33 deletion using microarray analysis. She presented with intellectual disability, absent speech, hypotonia, pre- and post-natal growth retardation and an abnormal face with a unilateral cleft lip. Clinical features and genetic findings with the loss of 30 genes, including GNAS, MC3R, CDH4 and TFAP2C , are described in relationship to the very few cases of 20q13 deletion reported in the literature. Deletion of this region may play an important role in neurodevelopment and function and in causing specific craniofacial features.

  5. ErasuCrypto: A Light-weight Secure Data Deletion Scheme for Solid State Drives

    Directory of Open Access Journals (Sweden)

    Liu Chen

    2017-01-01

    Full Text Available Securely deleting invalid data from secondary storage is critical to protect users’ data privacy against unauthorized accesses. However, secure deletion is very costly for solid state drives (SSDs, which unlike hard disks do not support in-place update. When applied to SSDs, both erasure-based and cryptography-based secure deletion methods inevitably incur large amount of valid data migrations and/or block erasures, which not only introduce extra latency and energy consumption, but also harm SSD lifetime.

  6. A novel large deletion of the ICR1 region including H19 and putative enhancer elements.

    Science.gov (United States)

    Fryssira, Helen; Amenta, Stella; Kanber, Deniz; Sofocleous, Christalena; Lykopoulou, Evangelia; Kanaka-Gantenbein, Christina; Cerrato, Flavia; Lüdecke, Hermann-Josef; Bens, Susanne; Riccio, Andrea; Buiting, Karin

    2015-05-06

    Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the IGF2/H19 locus resulting in biallelic expression of IGF2 and biallelic silencing of H19 account for approximately 10% of patients with BWS. The majority of these patients have epimutations of the ICR1 without detectable DNA sequence changes. Only a few patients were found to have deletions. Most of these deletions are small affecting different parts of the ICR1 differentially methylated region (ICR1-DMR) removing target sequences for CTCF. Only a very few deletions reported so far include the H19 gene in addition to the CTCF binding sites. None of these deletions include IGF2. A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR, H19, two adjacent non-imprinted genes and two of three predicted enhancer elements downstream to H19. Methylation analysis by deep bisulfite next generation sequencing revealed hypermethylation of the maternal allele at the IGF2 locus in both, mother and child, although IGF2 is not affected by the deletion. We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the IGF2 promoters. The aberrant methylation (hypermethylation) of the maternal IGF2

  7. 22q11.2 deletion (DiGeorge syndrome: a mother’s open letter

    Directory of Open Access Journals (Sweden)

    Antonio Baldini

    2011-07-01

    Full Text Available Dear E.G., this is an open letter on 22q11.2 deletion syndrome (DiGeorge syndrome. You are the mother of a beautiful 3 year old child. And you are one of the most active members of Aidel22, the Italian Association of 22q deletion syndrome patients and families. We would like to hear your story and learn from you. But before that, we asked some scholars in the field to help us understand what 22q11.2 deletion syndrome is.

  8. Thrombocytopenia and Postpartum Hemorrhage in a Woman with Chromosome 22q11.2 Deletion Syndrome

    Directory of Open Access Journals (Sweden)

    Sarah L. Pachtman

    2016-01-01

    Full Text Available Chromosome 22q11.2 deletion syndrome, also known as DiGeorge or velocardiofacial syndrome, is associated with a wide spectrum of phenotypic features. It is known to be associated with severe macrothrombocytopenia. Postpartum hemorrhage is a leading cause of maternal morbidity and mortality globally. Chromosome 22q11.2 deletion syndrome is rare cause of thrombocytopenia that can be a significant risk factor for life-threatening postpartum hemorrhage. We report a case of postpartum hemorrhage in a woman with 22q11.2 deletion syndrome causing severe macrothrombocytopenia.

  9. Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome

    OpenAIRE

    Bassett, Anne S.; Marshall, Christian R.; Lionel, Anath C.; Chow, Eva W.C.; Scherer, Stephen W.

    2008-01-01

    22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with congenital and late-onset features. Testing for the genomic content of copy number variations (CNVs) may help elucidate the 22q11.2 deletion mechanism and the variable clinical expression of the syndrome including the high (25%) risk for schizophrenia. We used genome-wide microarrays to assess CNV content and the parental origin of 22q11.2 deletions in a cohort of 100 adults with 22q11.2DS (44 with schizophrenia) an...

  10. [Diagnosis of 22q11.2 deletion syndrome in the context of newly developed psychosis].

    Science.gov (United States)

    Kaltenboeck, Alexander; Friedrich, Fabian; Hinterbuchinger, Barbara; Litvan, Zsuzsa; Mossaheb, Nilufar

    2016-12-01

    22q11.2 deletion syndrome (clinically also known as velocardiofacial or DiGeorge syndrome) is the most common human microdeletion syndrome and can be associated with a multitude of clinical features. In this article we report the case of a 22-year-old patient from Austria who was diagnosed with previously unknown 22q11.2 deletion syndrome in the context of newly developed psychosis. Using this case as an example, we then discuss the implications of 22q11.2 deletion syndrome for clinical psychiatric practice.

  11. Axenfeld-Rieger ocular anomaly and retinoblastoma caused by constitutional chromosome 13q deletion.

    Science.gov (United States)

    Roche, Ana; Mora, Jaume; Perez, Maria Del Mar; Gean, Esther; Perez, Belen; O'Callaghan, Mar; Catala, Jaume; De Torres, Carmen; Cruz, Ofelia; Prat, Joan; Parareda, Andreu

    2010-03-01

    Axenfeld-Rieger (AR) ocular anomaly might be due to deletions of different chromosomes. No association between AR, mental retardation, and retinoblastoma has been described. We report a 2-month-old female with general development delay and dysmorphic features. AR anomaly was detected, and a retinoblastoma (RB) was diagnosed in a very early stage. De novo 13q deletion was identified. Systemic chemotherapy, focal cryotherapy, transpupillary thermotherapy, brachytherapy, and intra-arterial chemotherapy were needed to control the RB. This is the first report of an association of AR, 13q deletion, and retinoblastoma, to be disclosed in patients born with such ocular and dysmorphic features. Copyright 2009 Wiley-Liss, Inc.

  12. Occurrence of two different intragenic deletions in two male relatives affected with Duchenne muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Mostacciuolo, M.L.; Miorin, M.; Vitiello, L.; Rampazzo, A.; Fanin, M.; Angelini, C.; Danieli, G.A. [Univ. of Padua (Italy)

    1994-03-01

    The occurrence of 2 different intragenic deletions (exons 10-44 and exon 45, respectively) is reported in 2 male relatives affected with Duchenne muscular dystrophy, both showing the same haplotype for DNA markers not included in the deleted segment. The 2 different deletions seem to have occurred independently in the same X chromosome. This finding, together with other reports, suggests possibly an increased predisposition to mutations within the DMD locus in some families. Therefore, when dealing with prenatal diagnosis, the investigation on fetal DNA cannot be restricted only to the region in which a mutation was previously identified in the family. 14 refs., 1 fig.

  13. A Case of Concurrent Miller-Dieker Syndrome (17p13.3 Deletion) and 22q11.2 Deletion Syndrome.

    Science.gov (United States)

    Atwal, Paldeep S; Macmurdo, C

    2015-12-01

    Features of Miller-Dieker syndrome (MDS, 17p13.3 deletion syndrome, LIS1-associated lissencephaly) include classic lissencephaly, microcephaly, cardiac malformations, growth restriction, and characteristic facial changes. Individuals with 22q11.2 deletion syndrome (DiGeorge syndrome or velocardiofacial syndrome) are known to have congenital cardiac malformations (in particular conotruncal defects), palatal abnormalities (especially velopharyngeal insufficiency), hypocalcemia, immune deficiency, learning disabilities, and characteristic facial features. This case report describes phenotypic characteristics of a patient with extremely rare instance of having both MDS and 22q11.2 deletion syndrome that is unique in the medical literature. Prognosis in this concurrent phenotype is poor with our patient suffering from several malformations seen in both conditions and expiring in the neonatal period.

  14. Mapping the end points of large deletions affecting the hprt locus in human peripheral blood cells and cell lines

    International Nuclear Information System (INIS)

    Nelson, S.L.; Grosovsky, A.J.; Jones, I.M.; Burkhart-Schultz, K.; Fuscoe, J.C.

    1995-01-01

    We have examined the extent of of HPRT - total gene deletions in three mutant collections: spontaneous and X-ray-induced deletions in TK6 human B lymphoblasts, and HPRT - deletions arising in vivo in T cells. A set of 13 Xq26 STS markers surrounding hprt and spanning approximately 3.3 Mb was used. Each marker used was observed to be missing in at least one of the hprt deletion mutants analyzed. The largest deletion observed encompassed at least 3 Mb. Nine deletions extended outside of the mapped region in the centromeric direction (>1.7 Mb). In contrast, only two telomeric deletions extended to marker 342R (1.26 Mb), and both exhibited slowed or limited cell growth. These data suggest the existence of a gene, within the vicinity of 342R, which establishes the telomeric limit of recoverable deletions. Most (25/41) X-ray-induced total gene deletion mutants exhibited marker loss, but only 1/8 of the spontaneous deletions encompassed any Xq26 markers (P = 0.0187). Furthermore, nearly half (3/8) of the spontaneous 3' total deletion breakpoints were within 14 kb of the hprt coding sequence. In contrast, 40/41 X-ray-induced HPRT - total deletions extended beyond this point (P = 0.011). Although the overall representation of total gene deletions in the in vivo spectrum is low, 4/5 encompass Xq26 markers flanking hprt. This pattern differs significantly from spontaneous HPRT - large deletions occurring in vitro (P = 0.032) but resembles the spectrum of X-ray-induced deletions. 24 refs., 6 figs., 1 tab

  15. The prevalence of chromosomal deletions relating to developmental delay and/or intellectual disability in human euploid blastocysts.

    Science.gov (United States)

    He, Wenyin; Sun, Xiaofang; Liu, Lian; Li, Man; Jin, Hua; Wang, Wei-Hua

    2014-01-01

    Chromosomal anomalies in human embryos produced by in vitro fertilization are very common, which include numerical (aneuploidy) and structural (deletion, duplication or others) anomalies. Our previous study indicated that chromosomal deletion(s) is the most common structural anomaly accounting for approximately 8% of euploid blastocysts. It is still unknown if these deletions in human euploid blastocysts have clinical significance. In this study, we analyzed 15 previously diagnosed euploid blastocysts that had chromosomal deletion(s) using Agilent oligonucleotide DNA microarray platform and localized the gene location in each deletion. Then, we used OMIM gene map and phenotype database to investigate if these deletions are related with some important genes that cause genetic diseases, especially developmental delay or intellectual disability. As results, we found that the detectable chromosomal deletion size with Agilent microarray is above 2.38 Mb, while the deletions observed in human blastocysts are between 11.6 to 103 Mb. With OMIM gene map and phenotype database information, we found that deletions can result in loss of 81-464 genes. Out of these genes, 34-149 genes are related with known genetic problems. Furthermore, we found that 5 out of 15 samples lost genes in the deleted region, which were related to developmental delay and/or intellectual disability. In conclusion, our data indicates that all human euploid blastocysts with chromosomal deletion(s) are abnormal and transfer of these embryos may cause birth defects and/or developmental and intellectual disabilities. Therefore, the embryos with chromosomal deletion revealed by DNA microarray should not be transferred to the patients, or further gene map and/or phenotype seeking is necessary before making a final decision.

  16. Discrimination of Deletion and Duplication Subtypes of the Deleted in Azoospermia Gene Family in the Context of Frequent Interloci Gene Conversion

    Science.gov (United States)

    Vaszkó, Tibor; Papp, János; Krausz, Csilla; Casamonti, Elena; Géczi, Lajos; Olah, Edith

    2016-01-01

    Due to its palindromic setup, AZFc (Azoospermia Factor c) region of chromosome Y is one of the most unstable regions of the human genome. It contains eight gene families expressed mainly in the testes. Several types of rearrangement resulting in changes in the cumulative copy number of the gene families were reported to be associated with diseases such as male infertility and testicular germ cell tumors. The best studied AZFc rearrangement is gr/gr deletion. Its carriers show widespread phenotypic variation from azoospermia to normospermia. This phenomenon was initially attributed to different gr/gr subtypes that would eliminate distinct members of the affected gene families. However, studies conducted to confirm this hypothesis have brought controversial results, perhaps, in part, due to the shortcomings of the utilized subtyping methodology. This proof-of-concept paper is meant to introduce here a novel method aimed at subtyping AZFc rearrangements. It is able to differentiate the partial deletion and partial duplication subtypes of the Deleted in Azoospermia (DAZ) gene family. The keystone of the method is the determination of the copy number of the gene family member-specific variant(s) in a series of sequence family variant (SFV) positions. Most importantly, we present a novel approach for the correct interpretation of the variant copy number data to determine the copy number of the individual DAZ family members in the context of frequent interloci gene conversion.Besides DAZ1/DAZ2 and DAZ3/DAZ4 deletions, not yet described rearrangements such as DAZ2/DAZ4 deletion and three duplication subtypes were also found by the utilization of the novel approach. A striking feature is the extremely high concordance among the individual data pointing to a certain type of rearrangement. In addition to being able to identify DAZ deletion subtypes more reliably than the methods used previously, this approach is the first that can discriminate DAZ duplication subtypes as well

  17. Developmental trajectories in 22q11.2 deletion.

    Science.gov (United States)

    Swillen, Ann; McDonald-McGinn, Donna

    2015-06-01

    Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, is the most common microdeletion syndrome affecting 1 in 2,000-4,000 live births and involving haploinsufficiency of ∼50 genes resulting in a multisystem disorder. Phenotypic expression is highly variable and ranges from severe life-threatening conditions to only a few associated features. Most common medical problems include: congenital heart disease, in particular conotruncal anomalies; palatal abnormalities, most frequently velopharyngeal incompetence (VPI); immunodeficiency; hypocalcemia due to hypoparathyroidism; genitourinary anomalies; severe feeding/gastrointestinal differences; and subtle dysmorphic facial features. The neurocognitive profile is also highly variable, both between individuals and during the course of development. From infancy onward, motor delays (often with hypotonia) and speech/language deficits are commonly observed. During the preschool and primary school ages, learning difficulties are very common. The majority of patients with 22q11.2DS have an intellectual level that falls in the borderline range (IQ 70-84), and about one-third have mild to moderate intellectual disability. More severe levels of intellectual disability are uncommon in children and adolescents but are more frequent in adults. Individuals with 22q11.2DS are at an increased risk for developing several psychiatric disorders including attention deficit with hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety and mood disorders, and psychotic disorders and schizophrenia. In this review, we will focus on the developmental phenotypic transitions regarding cognitive development in 22q11.2DS from early preschool to adulthood, and on the changing behavioral/psychiatric phenotype across age, on a background of frequently complex medical conditions. © 2015 Wiley Periodicals, Inc.

  18. Growth hormone deficiency in 18q deletion syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Ghidoni, P.D.; Cody, J.; Danney, J. [Univ. of Texas Health Science Center, San Antonio, TX (United States)] [and others

    1994-09-01

    The 18q- syndrome is one of the most common chromosomal deletion syndromes. Clinical characteristics are variable but may include: hypotonia, cleft palate, mental retardation and hearing impairment. Growth failure (GF) (<3% weight/height) is present in 80% of affected individuals. We evaluated growth hormone (GH) sufficiency in 15 patients with 18q- syndrome. Of these 15 patients, 10 have growth failure (<3% weight/height); of the remaining 5, 3 had normal growth parameters and 2 had growth along the 5%. Twelve patients failed to produce adequate GH following standard stimulation testing. Of these 12 patients with inadequate GH production, 2 had normal growth (above 3%). Of the 15, only 1 has normal GH production and normal growth parameters. Bone age was obtained on 1 patient with both GH deficiency and GF, and revealed significant delays. GH levels in response to GH releasing factor were normal in 3 out of 4 patients. MRI studies of GH-deficient patients indicated normal midline structures. Myelination in the few studied GH-deficient patients appeared delayed. The gene for myelin basic protein (MBP) is known to be located on the terminal portion of the long arm of chromosome 18. Neither the gene for GH, GH releasing factor nor GH releasing factor receptor is on chromosome 18. These genes are located on chromosomes 17, chromosome 20 and chromosome 7, respectively. Findings to date suggest that GH deficiency is common in individuals with 18q- syndrome. The etiology of this finding is unknown. We postulate that a gene(s) on chromosome 18q is involved in GH expression.

  19. Clonal Expansion of Mitochondrial DNA Deletions in Multiple Sclerosis

    Science.gov (United States)

    Campbell, Graham R; Kraytsberg, Yevgenya; Krishnan, Kim J; Ohno, Nobuhiko; Ziabreva, Iryna; Reeve, Amy; Newcombe, Jia; Reynolds, Richard; Lassmann, Hans; Khrapko, Konstantin; Turnbull, Doug M; Mahad, Don J

    2013-01-01

    Objective Mitochondrial DNA deletions (Δ-mtDNA) are implicated in the pathogenesis of multiple sclerosis (MS), Parkinson’s disease (PD), Alzheimer’s disease (AD) and ageing. Given the diffuse nature of inflammation in MS, aim of this study was to determine whether Δ-mtDNA caused respiratory deficient cells in excess of age within choroid plexus (CP) and ongoing mutagenesis or clonal expansion accounted for the respiratory deficiency in MS. Methods Respiratory chain complex IV and complex II activity was determined sequentially using histochemistry. Δ-mtDNA were characterized using real time PCR, long range PCR, sequencing and single molecule PCR. Sources of reactive oxygen and nitrogen species (RONS) were explored using immunohistochemistry. Results Respiratory deficient cells (lacking complex IV and with intact complex II activity) within CP epithelium were in excess of age in MS, PD and AD. Subunit-I of complex IV was lacking to a greater extent in MS than controls. Percentage of respiratory deficient cells harboring >50% heteroplasmy level of Δ-mtDNA was significantly greater in MS than PD, AD and controls. Long range PCR and sequencing confirmed Δ-mtDNA. Single molecule PCR identified clonally expanded Δ-mtDNA in MS, despite an increase in sources of RONS. Interpretation Our findings establish clonal expansion of Δ-mtDNA causing respiratory deficiency in MS and the extraparenchymal intracranial location indicated the potential to involve multiple cell types. Understanding factors that influence clonal expansion of Δ-mtDNA, a molecular link between inflammation and delayed cellular energy failure, may identify potential therapeutic targets for progressive forms of MS as well as other neurodegenerative disorders. PMID:22688405

  20. Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Mullighan, Charles G.; Su, Xiaoping; Zhang, Jinghui; Radtke, Ina; Phillips, Letha A.A.; Miller, Christopher B.; Ma, Jing; Liu, Wei; Cheng, Cheng; Schulman, Brenda A.; Harvey, Richard C.; Chen, I-Ming; Clifford, Robert J.; Carroll, William L.; Reaman, Gregory; Bowman, W. Paul; Devidas, Meenakshi; Gerhard, Daniela S.; Yang, Wenjian; Relling, Mary V.; Shurtleff, Sheila A.; Campana, Dario; Borowitz, Michael J.; Pui, Ching-Hon; Smith, Malcolm; Hunger, Stephen P.; Willman, Cheryl L.; Downing, James R.

    2009-01-01

    Background Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. Methods We studied a cohort of 221 children with high-risk B-cell–progenitor ALL with the use of single-nucleotide–polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1–positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell–progenitor ALL. Results More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell–lineage genes, and it was similar to the signature of BCR-ABL1–positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. Conclusions Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell–progenitor ALL. PMID:19129520

  1. 22q11.2 deletion syndrome in diverse populations.

    Science.gov (United States)

    Kruszka, Paul; Addissie, Yonit A; McGinn, Daniel E; Porras, Antonio R; Biggs, Elijah; Share, Matthew; Crowley, T Blaine; Chung, Brian H Y; Mok, Gary T K; Mak, Christopher C Y; Muthukumarasamy, Premala; Thong, Meow-Keong; Sirisena, Nirmala D; Dissanayake, Vajira H W; Paththinige, C Sampath; Prabodha, L B Lahiru; Mishra, Rupesh; Shotelersuk, Vorasuk; Ekure, Ekanem Nsikak; Sokunbi, Ogochukwu Jidechukwu; Kalu, Nnenna; Ferreira, Carlos R; Duncan, Jordann-Mishael; Patil, Siddaramappa Jagdish; Jones, Kelly L; Kaplan, Julie D; Abdul-Rahman, Omar A; Uwineza, Annette; Mutesa, Leon; Moresco, Angélica; Obregon, María Gabriela; Richieri-Costa, Antonio; Gil-da-Silva-Lopes, Vera L; Adeyemo, Adebowale A; Summar, Marshall; Zackai, Elaine H; McDonald-McGinn, Donna M; Linguraru, Marius George; Muenke, Maximilian

    2017-04-01

    22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world. © 2017 Wiley Periodicals, Inc.

  2. Developmental Trajectories in 22q11.2 Deletion

    Science.gov (United States)

    Swillen, Ann; McDonald-McGinn, Donna M.

    2016-01-01

    Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, is the most common microdeletion syndrome affecting 1 in 2,000–4,000 live births and involving haploinsufficiency of ∼50 genes resulting in a multisystem disorder. Phenotypic expression is highly variable and ranges from severe life-threatening conditions to only a few associated features. Most common medical problems include: congenital heart disease, in particular conotruncal anomalies; palatal abnormalities, most frequently velopharyngeal incompetence (VPI); immunodeficiency; hypocalcemia due to hypoparathyroidism; genitourinary anomalies; severe feeding/gastrointestinal differences; and subtle dysmorphic facial features. The neurocognitive profile is also highly variable, both between individuals and during the course of development. From infancy onward, motor delays (often with hypotonia) and speech/language deficits are commonly observed. During the preschool and primary school ages, learning difficulties are very common. The majority of patients with 22q11.2DS have an intellectual level that falls in the borderline range (IQ 70–84), and about one-third have mild to moderate intellectual disability. More severe levels of intellectual disability are uncommon in children and adolescents but are more frequent in adults. Individuals with 22q11.2DS are at an increased risk for developing several psychiatric disorders including attention deficit with hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety and mood disorders, and psychotic disorders and schizophrenia. In this review, we will focus on the developmental phenotypic transitions regarding cognitive development in 22q11.2DS from early preschool to adulthood, and on the changing behavioral/psychiatric phenotype across age, on a background of frequently complex medical conditions. PMID:25989227

  3. Quantification of the mitochondrial DNA common deletion in presbycusis.

    Science.gov (United States)

    Markaryan, Adam; Nelson, Erik G; Hinojosa, Raul

    2009-06-01

    This study was conducted to evaluate the association between the mitochondrial DNA (mtDNA) common deletion (CD) level in cochlear tissue and the severity of hearing loss in individuals with presbycusis. Nineteen individuals with presbycusis, ranging from 60 to 87 years of age, who met strict audiometric criteria were compared with four age frequency-matched normal hearing controls ranging from 51 to 76 years of age. Five additional normal hearing individuals, ranging from 9 to 50 years of age, were also studied. A duplex real time polymerase chain reaction assay was used to quantify the mtDNA in archival cochlear tissue samples. Linear regression models were used for comparison of the CD level between groups. The presbycusis group had a mean CD level of 32% with a standard deviation of 14%, and the normal hearing age matched control group had a mean CD level of 12% with a standard deviation of 2%. This difference in CD levels reached statistical significance (P = .011) and remained significant after adjusting for any differences in age between the two groups (age-adjusted P = .007). Furthermore, there was evidence for a significant association between the CD level and the severity of hearing loss based on audiometric thresholds at 8 kHz (r = 0.44, P = .034; age-adjusted partial correlation = 0.55, P = .007). For the first time, to our knowledge, these results demonstrate a relationship between quantitatively measured levels of the CD in human cochlear tissue and the severity of hearing loss in individuals with presbycusis. Laryngoscope, 2009.

  4. How to diagnose the 22q11.2 deletion syndrome in patients with schizophrenia: a case report

    OpenAIRE

    Ohi, Kazutaka; Hashimoto, Ryota; Yamamori, Hidenaga; Yasuda, Yuka; Fujimoto, Michiko; Nakatani, Noriko; Kamino, Kouzin; Takeda, Masatoshi

    2013-01-01

    The 22q11.2 deletion syndrome is caused by a microdeletion of chromosome 22. One third of all patients with 22q11.2 deletion develop schizophrenia-like symptoms. In general, the prevalence of 22q11.2 deletion in patients with schizophrenia is 1%?2%. The 22q11.2 deletion is one of the major known genetic risk factors for schizophrenia. However, clinical differences in the phenotypes between patients with schizophrenia who are 22q11.2 deletion carriers and those who are not are still unknown. T...

  5. A catalog of hemizygous variation in 127 22q11 deletion patients.

    Science.gov (United States)

    Hestand, Matthew S; Nowakowska, Beata A; Vergaelen, Elfi; Van Houdt, Jeroen; Dehaspe, Luc; Suhl, Joshua A; Del-Favero, Jurgen; Mortier, Geert; Zackai, Elaine; Swillen, Ann; Devriendt, Koenraad; Gur, Raquel E; McDonald-McGinn, Donna M; Warren, Stephen T; Emanuel, Beverly S; Vermeesch, Joris R

    2016-01-01

    The 22q11.2 deletion syndrome is the most common microdeletion disorder, with wide phenotypic variability. To investigate variation within the non-deleted allele we performed targeted resequencing of the 22q11.2 region for 127 patients, identifying multiple deletion sizes, including two deletions with atypical breakpoints. We cataloged ~12,000 hemizygous variant positions, of which 84% were previously annotated. Within the coding regions 95 non-synonymous variants, three stop gains, and two frameshift insertions were identified, some of which we speculate could contribute to atypical phenotypes. We also catalog tolerability of 22q11 gene mutations based on related autosomal recessive disorders in man, embryonic lethality in mice, cross-species conservation and observations that some genes harbor more or less variants than expected. This extensive catalog of hemizygous variants will serve as a blueprint for future experiments to correlate 22q11DS variation with phenotype.

  6. Novel Vascular Malformation in an Affected Newborn with Deletion Del(4(q31.3

    Directory of Open Access Journals (Sweden)

    Norma Elena de León Ojeda

    2012-01-01

    Full Text Available We report on a newborn male patient with a terminal deletion in the long arm of the chromosome 4 with a congenital heart defect unreported before in association with this syndrome. The patient had multiple congenital anomalies including a pointed duplicated fingernail, low set posteriorly rotated ears, large anterior fontanel, micrognathia, glabellar capillary vascular malformation, and Interrupted Aortic Arch type C. The patient died due to multiple congenital malformations; a peripheral chromosome analysis showed 46, XY, del(4(q31.3 de novo. The only reported case with the same deletion was a male newborn that exhibited the pattern of minor anomalies of deletion 4q31 syndrome. The parents were cytogenetically normal. We compare clinical signs to other cases with a deletion in long arm of chromosome 4.

  7. Neonatal hyperinsulinemic hypoglycemia in a patient with 9p deletion syndrome

    DEFF Research Database (Denmark)

    Bayat, Allan; Kirchhoff, Maria; Madsen, Camilla Gøbel

    2018-01-01

    We report the clinical and neuroradiological findings in a young boy harboring the 9p deletion syndrome including the novel findings of thalamic infarction and germinal matrix haemorrhage and neonatal hyperinsulinemic hypoglycemia. Both the hypoglycemic events and the ventriculomegaly found...

  8. Retention or deletion of personality disorder diagnoses for DSM-5: an expert consensus approach.

    Science.gov (United States)

    Mullins-Sweatt, Stephanie N; Bernstein, David P; Widiger, Thomas A

    2012-10-01

    One of the official proposals for the fifth edition of the American Psychiatric Association's (APA) diagnostic manual (DSM-5) is to delete half of the existing personality disorders (i.e., dependent, histrionic, narcissistic, paranoid, and schizoid). Within the APA guidelines for DSM-5 decisions, it is stated that there should be expert consensus agreement for the deletion of a diagnostic category. Additionally, categories to be deleted should have low clinical utility and/or minimal evidence for validity. The current study surveyed members of two personality disorder associations (n = 146) with respect to the utility, validity, and status of each DSM-IV-TR personality disorder diagnosis. Findings indicated that the proposal to delete five of the personality disorders lacks consensus support within the personality disorder community.

  9. Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene

    Directory of Open Access Journals (Sweden)

    Colovati Mileny ES

    2012-01-01

    Full Text Available Abstract Background The majority of Marfan syndrome (MFS cases is caused by mutations in the fibrillin-1 gene (FBN1, mapped to chromosome 15q21.1. Only few reports on deletions including the whole FBN1 gene, detected by molecular cytogenetic techniques, were found in literature. Results We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15. Discussion This is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to FBN1 gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement.

  10. Myopathology and a mitochondrial DNA deletion in the Pearson marrow and pancreas syndrome.

    Science.gov (United States)

    de Vries, D D; Buzing, C J; Ruitenbeek, W; van der Wouw, M P; Sperl, W; Sengers, R C; Trijbels, J M; van Oost, B A

    1992-01-01

    A patient with the Pearson marrow and pancreas syndrome is presented. She showed an anaemia with neutropenia and thrombopenia, failure to thrive, diarrhoea, disturbed glucose homeostasis and lactic acidosis. An exocrine pancreatic insufficiency was lacking. The disease followed a fatal course. Biochemical investigations of skeletal muscle revealed a disturbed mitochondrial energy metabolism, while many ultrastructural abnormal features were observed in the muscle tissue. Molecular genetic studies showed a de novo deletion in the mitochondrial DNA (mtDNA), different in size from the already published deletions and flanked by two 4 bp direct repeats, interspaced by 4-5 non-repeated nucleotides. mtDNA from 12 other tissues showed the same deletion in different percentages. No obvious relation between these percentages and tissue dysfunction was found. In spite of an open reading frame of 74 codons, only little transcription product of the genomic region resulting from the deletion was found.

  11. 77 FR 26279 - Scheduled Change and Deletion of Agenda Item From April 27, 2012, Open Meeting

    Science.gov (United States)

    2012-05-03

    ... From the Federal Register Online via the Government Publishing Office FEDERAL COMMUNICATIONS COMMISSION Scheduled Change and Deletion of Agenda Item From April 27, 2012, Open Meeting Date: April 25... of Managing Director. BILLING CODE 6712-01-P ...

  12. A method for the analysis of 32 X chromosome insertion deletion polymorphisms in a single PCR

    DEFF Research Database (Denmark)

    Pereira, Rui; Pereira, Vania; Gomes, Iva

    2012-01-01

    Studies of human genetic variation predominantly use short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) but Insertion deletion polymorphisms (Indels) are being increasingly explored. They combine desirable characteristics of other genetic markers, especially the possibility...

  13. Association between the CCR5 32-bp deletion allele and late onset of schizophrenia

    DEFF Research Database (Denmark)

    Rasmussen, H.B.; Timm, S.; Wang, A.G.

    2006-01-01

    OBJECTIVE: The 32-bp deletion allele in chemokine receptor CCR5 has been associated with several immune-mediated diseases and might be implicated in schizophrenia as well. METHOD: The authors genotyped DNA samples from 268 schizophrenia patients and 323 healthy subjects. Age at first admission...... to a psychiatric hospital department served as a measure of disease onset. RESULTS: Patients and comparison subjects differed marginally in their genotype distribution, with a slightly higher frequency of the deletion allele seen in the patients. The authors found the deletion allele to be associated with higher......-onset schizophrenia) and healthy subjects differed significantly. This was reflected in an increased frequency of the deletion allele in the patient subgroup. Patients with ages at first admission below and above 40 years significantly differed in distribution of genotypes and alleles, with an overrepresentation...

  14. Identifying and calling insertions, deletions, and single-base mutations efficiently from sequence data

    Science.gov (United States)

    Whole genome sequencing studies can directly identify causative mutations for subsequent use in genomic evaluations, but sequence variant identification is a lengthy and sometimes inaccurate process. The speed and accuracy of identifying small insertions and deletions of sequence, collectively terme...

  15. Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation

    DEFF Research Database (Denmark)

    Lugtenberg, Dorien; Zangrande-Vieira, Luiz; Kirchhoff, Maria

    2010-01-01

    ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected...... 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating...... that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P...

  16. Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels.

    Science.gov (United States)

    Boettger, Linda M; Salem, Rany M; Handsaker, Robert E; Peloso, Gina M; Kathiresan, Sekar; Hirschhorn, Joel N; McCarroll, Steven A

    2016-04-01

    One of the first protein polymorphisms identified in humans involves the abundant blood protein haptoglobin. Two exons of the HP gene (encoding haptoglobin) exhibit copy number variation that affects HP protein structure and multimerization. The evolutionary origins and medical relevance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from many recurring deletions, more specifically, reversions of an ancient hominin-specific duplication of these exons. Although this polymorphism has been largely invisible to genome-wide genetic studies thus far, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We further show that these deletions, and a SNP that affects HP expression, appear to drive the strong association of cholesterol levels with SNPs near HP. Recurring exonic deletions in HP likely enhance human health by lowering cholesterol levels in the blood.

  17. Absence of the 9-bp deletion of mitochondrial DNA in pre-Hispanic inhabitants of Argentina.

    Science.gov (United States)

    Demarchi, D A; Panzetta-Dutari, G M; Colantonio, S E; Marcellino, A J

    2001-08-01

    We investigated the incidence of the Region V mitochondrial DNA 9-base-pair (bp) deletion from human remains recovered from several archaeological sites and contexts throughout Argentina. Of the 34 samples analyzed, 24 yielded DNA extractions that gave clear amplification results. All of the individuals carried two repeats of the 9 bp, one of which has been shown to be deleted in some individuals of Asian origin and defines mitochondrial lineage B. Although most of the modern Amerindian groups in the region exhibit the deletion in high frequencies, the absence of the 9-bp deletion among ancient populations of South America seems to be the rule rather than the exception, as was reported by several studies involving extinct populations. The evidence gathered until now suggests that the earliest settlers of this region of South America did not carry mitochondrial lineage B.

  18. Deletion analysis of susy-sl promoter for the identification of optimal promoter sequence

    International Nuclear Information System (INIS)

    Bacha, S.; Khatoon, A.; Asif, M.; Bshir, A.

    2015-01-01

    The promoter region of sucrose synthase (susy-Sl) was identified and isolated from tomato. The 5? deletion analysis was carried out for the identification of minimum optimal promoter. Transgenic lines of Arabidopsis thaliana were developed by floral dip method incorporating various promoter deletion cassettes controlling GUS reporter gene. GUS assay of transgenic tissues indicated that full length susy-Sl promoter and its deletion mutants were constitutively expressed in vegetative and floral tissues of A. thaliana. The expression was observed in roots, shoots and flowers of A. thaliana. Analysis of 5? deletion series of susy-Sl promoter showed that a minimum of 679 bp fragment of the promoter was sufficient to drive expression of GUS reporter gene in the major tissues of transgenic A. thaliana. (author)

  19. A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype.

    Science.gov (United States)

    Elli, Francesca M; Ghirardello, Stefano; Giavoli, Claudia; Gangi, Silvana; Dioni, Laura; Crippa, Milena; Finelli, Palma; Bergamaschi, Silvia; Mosca, Fabio; Spada, Anna; Beck-Peccoz, Paolo

    2012-11-01

    Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus (DI), insulin-dependent diabetes mellitus (DM), optic atrophy (OA) and deafness caused by mutations in WFS1 gene (4p16.1), which encodes an endoplasmic reticulum protein, called Wolframin. We describe the case of an infant who presented hypernatremia and severe hypoplasia of the left eyeball with alteration of visual evoked potentials. Persistent hypernatremia, iposmolar polyuria and high plasma osmolality suggested DI, confirmed by a normal urine concentration after vasopressin test. Treatment with vasopressin allowed a normalization of sodium levels and urine output. Brain magnetic resonance imaging showed absence of the neurohypophysis hyperintense signal, normal adenohypophysis and optic tracts hypoplasia. The concomitant presence of DI and OA, even in the absence of DM and deafness, prompted the suspicion of WS and complete genetic analysis was performed. Genomic DNA sequencing of WFS1 showed no inactivating mutations described to date, but suggested a structural mutation as markers genotyping revealed a segmental paternal heterodisomy involving the upstream regulatory region (promoter and 5'UTR). cDNA sequencing revealed the coexistence of the wild-type transcript and two splice variants; one variant, probably benign, is known in literature and the other one causes the loss of exon 2, containing the translation initiation site. Western blot confirmed a marked protein reduction. During the clinical follow-up child's condition remained stable and glucose metabolism is still in the standard. In conclusion, the phenotype associated with this structural rearrangement, which substantially reduces the synthesis of Wolframin, confirms a tissue-specific pattern of expression of WFS1, suggests the presence of a different protein dosage sensitivity in different tissues and could be causative of DI and OA in our patient. The "incomplete" phenotype here described, usually

  20. Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow-pancreas syndrome.

    Science.gov (United States)

    van den Ouweland, J M; de Klerk, J B; van de Corput, M P; Dirks, R W; Raap, A K; Scholte, H R; Huijmans, J G; Hart, L M; Bruining, G J; Maassen, J A

    2000-03-01

    We have recently diagnosed a patient with anaemia, severe tubulopathy, and diabetes mellitus. As the clinical characteristics resembled Pearson marrow-pancreas syndrome, despite the absence of malfunctioning of the exocrine pancreas in this patient, we have performed DNA analysis to seek for deletions in mtDNA. DNA analysis showed a novel heteroplasmic deletion in mtDNA of 8034bp in length, with high proportions of deleted mtDNA in leukocytes, liver, kidney, and muscle. No deletion could be detected in mtDNA of leukocytes from her mother and young brother, indicating the sporadic occurrence of this deletion. During culture, skin fibroblasts exhibited a rapid decrease of heteroplasmy indicating a selection against the deletion in proliferating cells. We estimate that per cell division heteroplasmy levels decrease by 0.8%. By techniques of fluorescent in situ hybridisation (FISH) and mitochondria-mediated transformation of rho(o) cells we could show inter- as well as intracellular variation in the distribution of deleted mtDNA in a cell population of cultured skin fibroblasts. Furthermore, we studied the mitochondrial translation capacity in cybrid cells containing various proportions of deleted mtDNA. This result revealed a sharp threshold, around 80%, in the proportion of deleted mtDNA, above which there was strong depression of overall mitochondrial translation, and below which there was complementation of the deleted mtDNA by the wild-type DNA. Moreover, catastrophic loss of mtDNA occurred in cybrid cells containing 80% deleted mtDNA.

  1. Enhancement of astaxanthin production in Xanthophyllomyces dendrorhous by efficient method for the complete deletion of genes.

    Science.gov (United States)

    Yamamoto, Keisuke; Hara, Kiyotaka Y; Morita, Toshihiko; Nishimura, Akira; Sasaki, Daisuke; Ishii, Jun; Ogino, Chiaki; Kizaki, Noriyuki; Kondo, Akihiko

    2016-09-13

    Red yeast, Xanthophyllomyces dendrorhous is the only yeast known to produce astaxanthin, an anti-oxidant isoprenoid (carotenoid) widely used in the aquaculture, food, pharmaceutical and cosmetic industries. The potential of this microorganism as a platform cell factory for isoprenoid production has been recognized because of high flux through its native terpene pathway. Recently, we developed a multiple gene expression system in X. dendrorhous and enhanced the mevalonate synthetic pathway to increase astaxanthin production. In contrast, the mevalonate synthetic pathway is suppressed by ergosterol through feedback inhibition. Therefore, releasing the mevalonate synthetic pathway from this inhibition through the deletion of genes involved in ergosterol synthesis is a promising strategy to improve isoprenoid production. An efficient method for deleting diploid genes in X. dendrorhous, however, has not yet been developed. Xanthophyllomyces dendrorhous was cultivated under gradually increasing concentrations of antibiotics following the introduction of antibiotic resistant genes to be replaced with target genes. Using this method, double CYP61 genes encoding C-22 sterol desaturases relating to ergosterol biosynthesis were deleted sequentially. This double CYP61 deleted strain showed decreased ergosterol biosynthesis compared with the parental strain and single CYP61 disrupted strain. Additionally, this double deletion of CYP61 genes showed increased astaxanthin production compared with the parental strain and the single CYP61 knockout strain. Finally, astaxanthin production was enhanced by 1.4-fold compared with the parental strain, although astaxanthin production was not affected in the single CYP61 knockout strain. In this study, we developed a system to completely delete target diploid genes in X. dendrorhous. Using this method, we deleted diploid CYP61 genes involved in the synthesis of ergosterol that inhibits the pathway for mevalonate, which is a common

  2. Deleting Items and Disturbing Mesh Theorems for Riemann Definite Integral and Their Applications

    OpenAIRE

    Liu, Jingwei; Liu, Yi

    2017-01-01

    Based on the definition of Riemann definite integral,deleting items and disturbing mesh theorems on Riemann sums are given. After deleting some items or disturbing the mesh of partition, the limit of Riemann sums still converges to Riemann definite integral under specific conditions. These theorems can deal with a class of complicate limitation of sum and product of series of a function, and demonstrate that the geometric intuition of Riemann definite integral is more profound than ordinary t...

  3. Prevalence and Nature of Hearing Loss in 22q11.2 Deletion Syndrome

    Science.gov (United States)

    Van Eynde, Charlotte; Swillen, Ann; Lambeens, Elien; Verhaert, Nicolas; Desloovere, Christian; Luts, Heleen; Vander Poorten, Vincent; Devriendt, Koenraad; Hens, Greet

    2016-01-01

    Purpose: The purpose of this study was to clarify the prevalence, type, severity, and age-dependency of hearing loss in 22q11.2 deletion syndrome. Method: Extensive audiological measurements were conducted in 40 persons with proven 22q11.2 deletion (aged 6-36 years). Besides air and bone conduction thresholds in the frequency range between 0.125…

  4. Nasal dimple as part of the 22q11.2 deletion syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Gripp, K.W.; Reed, L.A. [Children`s Hospital of Philadelphia, PA (United States); Emanuel, B.S. [Children`s Hospital of Philadelphia, PA (United States)]|[Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)] [and others

    1997-03-31

    The phenotype of the 22q11.2 microdeletion syndrome is quite variable. We describe 2 patients with a 22q11.2 deletion and a dimpled nasal tip, which, we suggest can be the extreme of the broad or bulbous nose commonly found in the 22q11.2 deletion syndrome, and should not be confused with the more severe nasal abnormalities seen in frontonasal dysplasia. 11 refs., 2 figs.

  5. Candidate Genes and the Behavioral Phenotype in 22q11.2 Deletion Syndrome

    Science.gov (United States)

    Prasad, Sarah E.; Howley, Sarah; Murphy, Kieran C.

    2008-01-01

    There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk…

  6. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11.

    OpenAIRE

    Burn, J; Takao, A; Wilson, D; Cross, I; Momma, K; Wadey, R; Scambler, P; Goodship, J

    1993-01-01

    The conotruncal anomaly face syndrome was described in a Japanese publication in 1976 and comprises dysmorphic facial appearance and outflow tract defects of the heart. The authors subsequently noted similarities to Shprintzen syndrome and DiGeorge syndrome. Chromosome analysis in five cases did not show a deletion at high resolution, but fluorescent in situ hybridisation using probe DO832 showed a deletion within chromosome 22q11 in all cases.

  7. Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

    DEFF Research Database (Denmark)

    Møller, Rikke S; Weber, Yvonne G; Klitten, Laura L

    2013-01-01

    Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been ...... associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs)....

  8. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients

    Energy Technology Data Exchange (ETDEWEB)

    Juyal, R.C.; Figuera, L.E.; Hauge, X. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1996-05-01

    Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (1) FISH analysis, (2) PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (3) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS. 49 refs.

  9. Xp22. 3 deletions in isolated familial Kallmann's syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Hardelin, J.P.; Levilliers, J.; Legouis, R.; Petit, C. (Institut Pasteur, Paris (France)); Young, J.; Pholsena, M.; Schaison, G. (Centre Hospitalier de Bicetre, Le Kremlin-Bicetre (France)); Kirk, J.; Bouloux, P. (Royal Free Hospital, London (United Kingdom))

    1993-04-01

    Several familial cases of Kallmann's syndrome (KS) have been reported, among which the X-chromosome-linked mode of inheritance is the most frequent. The gene responsible for the X-linked KS has been localized to the terminal part of the X-chromosome short arm (Xp22.3 region), immediately proximal to the steroid sulfatase gene responsible for X-linked ichthyosis. Large deletions of this region have been previously shown in patients affected with both X-linked ichthyosis and KS. The authors report here the search for Xp22.3 deletions in 20 unrelated males affected with isolated X-linked KS. Only 2 deletions were found using Southern blot analysis, indicating that large deletions are uncommon in patients affected with KS alone. Both deletions were shown to include the entire KAL gene responsible for X-linked KS. The patients carrying these deletions exhibit additional clinical anomalies, which are discussed: unilateral renal aplasia, unilateral absence of vas deferens, mirror movements, and sensory neural hearing loss. 47 refs., 2 figs., 1 tab.

  10. Unambiguous molecular detections with multiple genetic approach for the complicated chromosome 22q11 deletion syndrome

    Directory of Open Access Journals (Sweden)

    Lin Lung-Huang

    2009-02-01

    Full Text Available Abstract Background Chromosome 22q11 deletion syndrome (22q11DS causes a developmental disorder during the embryonic stage, usually because of hemizygous deletions. The clinical pictures of patients with 22q11DS vary because of polymorphisms: on average, approximately 93% of affected individuals have a de novo deletion of 22q11, and the rest have inherited the same deletion from a parent. Methods using multiple genetic markers are thus important for the accurate detection of these microdeletions. Methods We studied 12 babies suspected to carry 22q11DS and 18 age-matched healthy controls from unrelated Taiwanese families. We determined genomic variance using microarray-based comparative genomic hybridization (array-CGH, quantitative real-time polymerase chain reaction (qPCR and multiplex ligation-dependent probe amplification (MLPA. Results Changes in genomic copy number were significantly associated with clinical manifestations for the classical criteria of 22q11DS using MPLA and qPCR (p Conclusion Both MLPA and qPCR could produce a clearly defined range of deleted genomic DNA, whereas there must be a deleted genome that is not distinguishable using MLPA. These data demonstrate that such multiple genetic approaches are necessary for the unambiguous molecular detection of these types of complicated genomic syndromes.

  11. Haploid deletion strains of Saccharomyces cerevisiae that determine survival during space flight

    Science.gov (United States)

    Johanson, Kelly; Allen, Patricia L.; Gonzalez-Villalobos, Romer A.; Nesbit, Jacqueline; Nickerson, Cheryl A.; Höner zu Bentrup, Kerstin; Wilson, James W.; Ramamurthy, Rajee; D'Elia, Riccardo; Muse, Kenneth E.; Hammond, Jeffrey; Freeman, Jake; Stodieck, Louis S.; Hammond, Timothy G.

    2007-02-01

    This study identifies genes that determine survival during a space flight, using the model eukaryotic organism, Saccharomyces cerevisiae. Select strains of a haploid yeast deletion series grew during storage in distilled water in space, but not in ground based static or clinorotation controls. The survival advantages in space in distilled water include a 133-fold advantage for the deletion of PEX19, a chaperone and import receptor for newly- synthesized class I peroxisomal membrane proteins, to 77-40 fold for deletion strains lacking elements of aerobic respiration, isocitrate metabolism, and mitochondrial electron transport. Following automated addition of rich growth media, the space flight was associated with a marked survival advantage of strains with deletions in catalytically active genes including hydrolases, oxidoreductases and transferases. When compared to static controls, space flight was associated with a marked survival disadvantage of deletion strains lacking transporter, antioxidant and catalytic activity. This study identifies yeast deletion strains with a survival advantage during storage in distilled water and space flight, and amplifies our understanding of the genes critical for survival in space.

  12. Skin fibroblasts from a D-deletion type retinoblastoma patient are abnormally X-ray sensitive

    International Nuclear Information System (INIS)

    Weichselbaum, R.R.; Nove, J.; Little, J.B.

    1977-01-01

    Retinoblastoma is a rare malignant eye tumour that appears either spontaneously or in genetically predisposed persons. The latter group is composed of persons who inherit the tumour with a dominant mode of transmission (the familial type) and those who have a deletion in the long arm of chromosome 13 referred to as the D-deletion type. When this deletion is present it is observed in many somatic cells and is often associated with structural defects. Survivors of the genetic forms of retinoblastoma have an increased risk of the development of cancers at other sites. A single genetic locus is unlikely to predispose many somatic cells to tumour formation unless a fundamental molecular defect, possibly related to DNA repair, is present. In order to investigate this hypothesis a study was made of the in vitro X-ray sensitivity of skin fibroblasts derived from three retinoblastoma patients, comprising a pair of twins with the familial type accompanied by no gross chromosome abnormalities, and a patient with the D-deletion type. It was found that fibroblasts derived from the D-deletion patient were significantly more radiosensitive than those from the other two patients. X-ray survival curves are shown. It is concluded that skin fibroblasts derived from a patient with the D-deletion variant of retinoblastoma are abnormally radiosensitive. Future investigations may indicate a specific defect in molecular repair of DNA that will explain the predisposition of these patients to the development of other tumours. (U.K.)

  13. Mitochondrial common deletion is elevated in blood of breast cancer patients mediated by oxidative stress.

    Science.gov (United States)

    Nie, Hezhongrong; Chen, Guorong; He, Jing; Zhang, Fengjiao; Li, Ming; Wang, Qiufeng; Zhou, Huaibin; Lyu, Jianxin; Bai, Yidong

    2016-01-01

    The 4977 bp common deletion is one of the most frequently observed mitochondrial DNA (mtDNA) mutations in human tissues and has been implicated in various human cancer types. It is generally believed that continuous generation of intracellular reactive oxygen species (ROS) during oxidative phosphorylation (OXPHOS) is a major underlying mechanism for generation of such mtDNA deletions while antioxidant systems, including Manganese superoxide dismutase (MnSOD), mitigating the deleterious effects of ROS. However, the clinical significance of this common deletion remains to be explored. A comprehensive investigation on occurrence and accumulation of the common deletion and mtDNA copy number was carried out in breast carcinoma (BC) patients, benign breast disease (BBD) patients and age-matched healthy donors in our study. Meanwhile, the representative oxidative (ROS production, mtDNA and lipid oxidative damage) and anti-oxidative features (MnSOD expression level and variation) in blood samples from these groups were also analyzed. We found that the mtDNA common deletion is much more likely to be detected in BC patients at relatively high levels while the mtDNA content is lower. This alteration has been associated with a higher MnSOD level and higher oxidative damages in both BC and BBD patients. Our results indicate that the mtDNA common deletion in blood may serve a biomarker for the breast cancer. Copyright © 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  14. Molecular evidence for the induction of large interstitial deletions on mouse chromosome 8 by ionizing radiation

    International Nuclear Information System (INIS)

    Turker, Mitchell S.; Pieretti, Maura; Kumar, Sudha

    1997-01-01

    The P19H22 mouse embryonal carcinoma cell line is characterized by a hemizygous deficiency for the chromosome 8 encoded aprt (adenine phosphoribosyltransferase) gene and heterozygosity for many chromosome 8 loci. We have previously demonstrated that this cell line is suitable for mutational studies because it is permissive of events ranging in size from base-pair substitutions at the aprt locus to apparent loss of chromosome 8. Large mutational events, defined by loss of the remaining aprt allele, were found to predominate in spontaneous mutants and those induced by ionizing radiation. In this study we have used a PCR based assay to screen for loss of heterozygosity at microsatellite loci both proximal and distal to aprt in 137 Cs-induced and spontaneous aprt mutants. This approach allowed us to distinguish apparent interstitial deletional events from apparent recombinational events. Significantly, 32.5% (26 of 80) of the mutational events induced by 137 Cs appeared to be interstitial deletions as compared with 7.7% (6 of 78) in the spontaneous group. This difference was statistically significant (p 137 Cs caused a significant number of deletion mutations. Most 137 Cs-induced interstitial deletions were larger than 6 cM, whereas none of the spontaneous deletions were larger than 6 cM. These results provide further support for the notion that ionizing radiation induces deletion mutations and validate the use of the P19H22 cell line for the study of events induced by ionizing radiation

  15. PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1994-01-01

    From 1971--1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ-rays or JANUS fission-spectrum neutrons. Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice were analyzed for mRb deletions. In all normal mouse tissues studies all six mRb exon fragments were present on Southern blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, 1 of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  16. DiGeorge anomaly in the absence of chromosome 22q11.2 deletion.

    Science.gov (United States)

    Rope, Alan F; Cragun, Deborah L; Saal, Howard M; Hopkin, Robert J

    2009-10-01

    To test the hypothesis that the prevalence of deletion 22q11.2 among individuals who meet criteria for DiGeorge anomaly (DGA) is lower than the 90% commonly cited. Participants were identified through retrospective chart reviews on all patients who underwent testing for deletion 22q11.2 and all patients with a diagnosis of "DiGeorge" or any of the major criteria associated with DGA at a large pediatric hospital over a period of 6 years. DGA was confirmed in 64 individuals, based on the presence of at least 2 of the following features: (1) cellular immune deficiency and/or absence of part or all of the thymus; (2) hypocalcemia and/or parathyroid deficiency; (3) congenital heart disease. Of the 64 individuals with DGA, 29 (45%) did not have a chromosome 22q11.2 deletion. Among this deletion-negative subset, diabetic embryopathy and other chromosome abnormalities were the most commonly recognized underlying etiologies. These findings challenge a widely held belief that nearly 90% of DGA is due to chromosome 22q11.2 deletion. This study also calls attention to the heterogeneity of DGA, highlights similarities and differences between those with and without a chromosome 22q11.2 deletion, and attempts to resolve some confusing features of conditions associated with DGA.

  17. Clinical Implications of the BIM Deletion Polymorphism in Advanced Lung Adenocarcinoma Treated With Gefitinib.

    Science.gov (United States)

    Yuan, Jupeng; Li, Bo; Zhang, Nasha; Zhu, Hui; Zhou, Liqing; Zhang, Li; Yang, Ming

    2018-02-19

    Proapoptotic protein Bcl-2-like 11 (BIM) is a crucial tumor suppressor gene in lung cancer development. A 2903-bp genomic deletion polymorphism is present in BIM intron 2, which alters RNA splicing and impairs the generation of the death-inducing isoform of BIM and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In the present study, we investigated the clinical implications of this genetic polymorphism in patients with advanced lung adenocarcinoma treated with gefitinib. After genotyping the BIM deletion polymorphism in 111 patients with stage IIIB or IV lung adenocarcinoma receiving gefitinib, the hazard ratio (HR) and 95% confidence interval (CI) for progression-free survival and overall survival were estimated using Cox proportional hazards models. Possession of ≥ 1 deletion allele of the BIM polymorphism was observed in 18.02% of the patients. The BIM deletion polymorphism was an independent indicator of a shorter PFS (7.5 months vs. 11.3 months; HR, 2.38; 95% CI, 1.30-4.34; P = .005) and shorter OS (9.9 months vs. 27.5 months; HR, 2.53; 95% CI, 1.37-4.65; P = .003). Additionally, patients carrying the BIM deletion allele were more likely to experience acquired gefitinib-resistant disease. Our results indicate that the BIM deletion polymorphism might be a promising germline biomarker for gefitinib treatment in Chinese patients with lung adenocarcinoma. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. [Mitochondrial DNA4568 deletions in guinea-pig associated with presbycusis].

    Science.gov (United States)

    Wei, Xue-mei; Yang, Yuan; Liang, Chuang-yu; Zheng, Zhong

    2006-12-01

    To determine weather or not the mtDNA(4568) deletions in guinea-pig contribute to the development of presbycusis. Forty-four guinea-pigs were divided into 2 groups: group A (young control group, normal hearing, 22 guineas) and group B (aged group). The group B was subdivided into group B(1) (old normal hearing, 6 guineas) and group B(2) (old hearing loss, 16 guineas). First the guineas were tested by auditory brainstem response (ABR), and then the Cortis's tissues, auditory nerve tissues, brain and blood were harvested and the total DNA was extracted. The mtDNA(4568) deletion was analyzed by PCR. Hearing loss was occurred with age. The mtDNA(4568) deletion incidence of aged group in all tissues was significant higher than that of young control group (Ppresbycusis (B(2) group) were significant higher than that of aged normal hearing group (B(1) group) (Ppresbycusis and aged normal hearing group (P> 0.05). mtDNA(4568) deletion of guinea-pig possibly contributes to aging and mtDNA(4568) deletion in Cortis's and auditory nerve tissues of guinea-pig may be associated with presbycusis. There is no enough evidence to prove that the mtDNA(4568) deletions in brain and blood are related with presbycusis.

  19. PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1994-05-01

    From 1971--1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF{sub 1} mice irradiated with {sup 60}Co {gamma}-rays or JANUS fission-spectrum neutrons. Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice were analyzed for mRb deletions. In all normal mouse tissues studies all six mRb exon fragments were present on Southern blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, 1 of 6 tumors from {gamma}-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5{prime} region of the mRb gene.

  20. Rare Deletions at 16p13.11 Predispose to a Diverse Spectrum of Sporadic Epilepsy Syndromes

    Science.gov (United States)

    Heinzen, Erin L.; Radtke, Rodney A.; Urban, Thomas J.; Cavalleri, Gianpiero L.; Depondt, Chantal; Need, Anna C.; Walley, Nicole M.; Nicoletti, Paola; Ge, Dongliang; Catarino, Claudia B.; Duncan, John S.; Kasperavičiūtė, Dalia; Tate, Sarah K.; Caboclo, Luis O.; Sander, Josemir W.; Clayton, Lisa; Linney, Kristen N.; Shianna, Kevin V.; Gumbs, Curtis E.; Smith, Jason; Cronin, Kenneth D.; Maia, Jessica M.; Doherty, Colin P.; Pandolfo, Massimo; Leppert, David; Middleton, Lefkos T.; Gibson, Rachel A.; Johnson, Michael R.; Matthews, Paul M.; Hosford, David; Kälviäinen, Reetta; Eriksson, Kai; Kantanen, Anne-Mari; Dorn, Thomas; Hansen, Jörg; Krämer, Günter; Steinhoff, Bernhard J.; Wieser, Heinz-Gregor; Zumsteg, Dominik; Ortega, Marcos; Wood, Nicholas W.; Huxley-Jones, Julie; Mikati, Mohamad; Gallentine, William B.; Husain, Aatif M.; Buckley, Patrick G.; Stallings, Ray L.; Podgoreanu, Mihai V.; Delanty, Norman; Sisodiya, Sanjay M.; Goldstein, David B.

    2010-01-01

    Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions. PMID:20398883

  1. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

    Science.gov (United States)

    Heinzen, Erin L; Radtke, Rodney A; Urban, Thomas J; Cavalleri, Gianpiero L; Depondt, Chantal; Need, Anna C; Walley, Nicole M; Nicoletti, Paola; Ge, Dongliang; Catarino, Claudia B; Duncan, John S; Kasperaviciūte, Dalia; Tate, Sarah K; Caboclo, Luis O; Sander, Josemir W; Clayton, Lisa; Linney, Kristen N; Shianna, Kevin V; Gumbs, Curtis E; Smith, Jason; Cronin, Kenneth D; Maia, Jessica M; Doherty, Colin P; Pandolfo, Massimo; Leppert, David; Middleton, Lefkos T; Gibson, Rachel A; Johnson, Michael R; Matthews, Paul M; Hosford, David; Kälviäinen, Reetta; Eriksson, Kai; Kantanen, Anne-Mari; Dorn, Thomas; Hansen, Jörg; Krämer, Günter; Steinhoff, Bernhard J; Wieser, Heinz-Gregor; Zumsteg, Dominik; Ortega, Marcos; Wood, Nicholas W; Huxley-Jones, Julie; Mikati, Mohamad; Gallentine, William B; Husain, Aatif M; Buckley, Patrick G; Stallings, Ray L; Podgoreanu, Mihai V; Delanty, Norman; Sisodiya, Sanjay M; Goldstein, David B

    2010-05-14

    Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions. Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. Osteocyte-specific deletion of Fgfr1 suppresses FGF23.

    Directory of Open Access Journals (Sweden)

    Zhousheng Xiao

    Full Text Available Increases in fibroblastic growth factor 23 (FGF23 or Fgf23 production by osteocytes result in hypophosphatemia and rickets in the Hyp mouse homologue of X-linked hypophosphatemia (XLH. Fibroblastic growth factor (FGF signaling has been implicated in the pathogenesis of Hyp. Here, we conditionally deleted FGF receptor 1 (FGFR1 or Fgfr1 in osteocytes of Hyp mice to investigate the role of autocrine/paracrine FGFR signaling in regulating FGF23 production by osteocytes. Crossing dentin matrix protein 1 (Dmp1-Cre;Fgfr1null/+ mice with female Hyp;Fgfr1flox/flox mice created Hyp and Fgfr1 (Fgfr1Dmp1-cKO-null mice (Hyp;Fgfr1Dmp1-cKO with a 70% decrease in bone Fgfr1 transcripts. Fgfr1Dmp1-cKO-null mice exhibited a 50% reduction in FGF23 expression in bone and 3-fold reduction in serum FGF23 concentrations, as well as reductions in sclerostin (Sost, phosphate regulating endopeptidase on X chromosome (PHEX or Phex, matrix extracellular phosphoglycoprotein (Mepe, and Dmp1 transcripts, but had no demonstrable alterations in phosphate or vitamin D homeostasis or skeletal morphology. Hyp mice had hypophosphatemia, reductions in 1,25(OH2D levels, rickets/osteomalacia and elevated FGF2 expression in bone. Compared to Hyp mice, compound Hyp;Fgfr1Dmp1-cKO-null mice had significant improvement in rickets and osteomalacia in association with a decrease in serum FGF23 (3607 to 1099 pg/ml, an increase in serum phosphate (6.0 mg/dl to 9.3 mg/dl and 1,25(OH2D (121±23 to 192±34 pg/ml levels, but only a 30% reduction in bone FGF23 mRNA expression. FGF23 promoter activity in osteoblasts was stimulated by FGFR1 activation and inhibited by overexpression of a dominant negative FGFR1(TK-, PLCγ and MAPK inhibitors. FGF2 also stimulated the translation of an FGF23 cDNA transfected into osteoblasts via a FGFR1 and PI3K/Akt-dependent mechanism. Thus, activation of autocrine/paracrine FGF pathways is involved in the pathogenesis of Hyp through FGFR1-dependent regulation of FGF

  3. Grin1 receptor deletion within CRF neurons enhances fear memory.

    Directory of Open Access Journals (Sweden)

    Georgette Gafford

    Full Text Available Corticotropin releasing factor (CRF dysregulation is implicated in mood and anxiety disorders such as posttraumatic stress disorder (PTSD. CRF is expressed in areas engaged in fear and anxiety processing including the central amygdala (CeA. Complicating our ability to study the contribution of CRF-containing neurons to fear and anxiety behavior is the wide variety of cell types in which CRF is expressed. To manipulate specific subpopulations of CRF containing neurons, our lab has developed a mouse with a Cre recombinase gene driven by a CRF promoter (CRFp3.0Cre (Martin et al., 2010. In these studies, mice that have the gene that encodes NR1 (Grin1 flanked by loxP sites (floxed were crossed with our previously developed CRFp3.0Cre mouse to selectively disrupt Grin1 within CRF containing neurons (Cre+/fGrin1+. We find that disruption of Grin1 in CRF neurons did not affect baseline levels of anxiety, locomotion, pain sensitivity or exploration of a novel object. However, baseline expression of Grin1 was decreased in Cre+/fGrin1+ mice as measured by RTPCR. Cre+/fGrin1+ mice showed enhanced auditory fear acquisition and retention without showing any significant effect on fear extinction. We measured Gria1, the gene that encodes AMPAR1 and the CREB activator Creb1 in the amygdala of Cre+/fGrin1+ mice after fear conditioning. Both Gria1 and Creb1 were enhanced in the amygdala after training. To determine if the Grin1-expressing CRF neurons within the CeA are responsible for the enhancement of fear memory in adults, we infused a lentivirus with Cre driven by a CRF promoter (LV pCRF-Cre/fGrin1+ into the CeA of floxed Grin1 mice. Cre driven deletion of Grin1 specifically within CRF expressing cells in the CeA also resulted in enhanced fear memory acquisition and retention. Altogether, these findings suggest that selective disruption of Grin1 within CeA CRF neurons strongly enhances fear memory.

  4. [From gene to disease; mutations in the WFS1-gene as the cause of juvenile type I diabetes mellitus with optic atrophy (Wolfram syndrome)

    NARCIS (Netherlands)

    Pennings, R.J.E.; Dikkeschei, L.D.; Cremers, C.W.R.J.; Ouweland, J.M.W. van den

    2002-01-01

    Wolfram syndrome patients are mainly characterised by juvenile onset diabetes mellitus and optic atrophy. A synonym is the acronym DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy, deafness. Diabetes insipidus and sensorineural high-frequency hearing impairment are important additional

  5. Gene expression patterns of chicken neuregulin 3 in association with copy number variation and frameshift deletion.

    Science.gov (United States)

    Abe, Hideaki; Aoya, Daiki; Takeuchi, Hiro-Aki; Inoue-Murayama, Miho

    2017-07-21

    Neuregulin 3 (NRG3) plays a key role in central nervous system development and is a strong candidate for human mental disorders. Thus, genetic variation in NRG3 may have some impact on a variety of phenotypes in non-mammalian vertebrates. Recently, genome-wide screening for short insertions and deletions in chicken (Gallus gallus) genomes has provided useful information about structural variation in functionally important genes. NRG3 is one such gene that has a putative frameshift deletion in exon 2, resulting in premature termination of translation. Our aims were to characterize the structure of chicken NRG3 and to compare expression patterns between NRG3 isoforms. Depending on the presence or absence of the 2-bp deletion in chicken NRG3, 3 breeds (red junglefowl [RJF], Boris Brown [BB], and Hinai-jidori [HJ]) were genotyped using flanking primers. In the commercial breeds (BB and HJ), approximately 45% of individuals had at least one exon 2 allele with the 2-bp deletion, whereas there was no deletion allele in RJF. The lack of a homozygous mutant indicated the existence of duplicated NRG3 segments in the chicken genome. Indeed, highly conserved elements consisting of exon 1, intron 1, exon 2, and part of intron 2 were found in the reference RJF genome, and quantitative PCR detected copy number variation (CNV) between breeds as well as between individuals. The copy number of conserved elements was significantly higher in chicks harboring the 2-bp deletion in exon 2. We identified 7 novel transcript variants using total mRNA isolated from the amygdala. Novel isoforms were found to lack the exon 2 cassette, which probably harbored the premature termination codon. The relative transcription levels of the newly identified isoforms were almost the same between chick groups with and without the 2-bp deletion, while chicks with the deletion showed significant suppression of the expression of previously reported isoforms. A putative frameshift deletion and CNV in chicken

  6. Prognostic impact of IKZF1 deletion in adults with common B-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Yao, Qiu-Mei; Liu, Kai-Yan; Gale, Robert Peter; Jiang, Bin; Liu, Yan-Rong; Jiang, Qian; Jiang, Hao; Zhang, Xiao-Hui; Zhang, Mei-Jie; Chen, Shan-Shan; Huang, Xiao-Jun; Xu, Lan-Ping; Ruan, Guo-Rui

    2016-04-11

    Interrogate the impact of IKZF1 deletion on therapy-outcomes of adults with common B-cell acute lymphoblastic leukemia. One hundred sixty-five consecutive adults with common B-cell ALL were tested for IKZF1 deletion and for BCR/ABL. Deletions in IKZF1 were detected using multiplex RQ-PCR, multiplex fluorescent PCR, sequence analysis and multiplex ligation-dependent probe amplification (MLPA). BCR/ABL was detected using RQ-PCR. All subjects received chemotherapy and some also received an allotransplant and tyrosine kinase-inhibitors. Multivariate analyses were done to identify associations between IKZF1 deletion and other variables on non-relapse mortality (NRM), cumulative incidence of relapse (CIR), leukemia-free survival (LFS) and survival. Amongst subjects achieving complete remission those with IKZF1 deletion had similar 5-year non-relapse mortality (NRM) (11% [2-20%] vs. 16% [4-28%]; P = 0.736), a higher 5-year cumulative incidence of relapse (CIR) (55% [35-76%] vs. 25% [12-38%]; P = 0.004), and worse 5-year leukemia-free survival (LFS) (33% [16-52%] vs. 59% [42-73%]; P = 0.012) and survival (48% [33-62%] vs. 75% [57-86%]; P = 0.002). In multivariate analyses IKZF1 deletion was associated with an increased relapse (relative risk [RR] =2.7, [1.4-5.2]; P = 0.002), a higher risk of treatment-failure (inverse of LFS; RR = 2.1, [1.2-3.6]; P = 0.007) and a higher risk of death (RR = 2.8, [1.5-5.5]; P = 0.002). The adverse impact of IKZF1 deletion on outcomes was stronger in subjects without vs. with BCR-ABL1 and in subjects receiving chemotherapy-only vs. an allotransplant. IKZF1 deletion was independently-associated with a higher relapse risk and worse LFS and survival in adults with common B-cell ALL after adjusting for other prognostic variables and differences in therapies. These data suggest IKZF1 deletion may be a useful prognostic variable in adults with common B-cell ALL, especially in persons without BCR-ABL1 and those receiving chemotherapy

  7. Interleukin 3 gene is located on human chromosome 5 and is deleted in myeloid leukemias with a deletion of 5q

    International Nuclear Information System (INIS)

    Le Beau, M.M.; Epstein, N.D.; O'Brien, S.J.; Nienhuis, A.W.; Yang, Y.C.; Clark, S.C.; Rowley, J.D.

    1987-01-01

    The gene IL-3 encodes interleukin 3, a hematopoietic colony-stimulating factor (CSF) that is capable of supporting the proliferation of a broad range of hematopoietic cell types. By using somatic cell hybrids and in situ chromosomal hybridization, the authors localized this gene to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, IL-3 was found to be deleted in the 5q-chromosome of one patient with refractory anemia who had a del(5)(q15q33.3), of three patients with refractory anemia (two patients) or acute nonlymphocytic leukemia (ANLL) de novo who had a similar distal breakpoint [del(5)(q13q33.3)], and of a fifth patient, with therapy-related ANLL, who had a similar distal breakpoint in band q33[del(5)(q14q33.3)]. Southern blot analysis of somatic cell hybrids retaining the normal or the deleted chromosome 5 from two patients with the refractory anemia 5q- syndrome indicated that IL-3 sequences were absent from the hybrids retaining the deleted chromosome 5 but not from hybrids that had a cytologically normal chromosome 5. Thus, a small segment of chromosome 5 contains IL-3, GM-CSF, CSF-1, and FMS. The findings and earlier results indicating that GM-CSF, CSF-1, and FMS were deleted in the 5q- chromosome, suggest that loss of IL-3 or of other CSF genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q)

  8. Structural plasticity of green fluorescent protein to amino acid deletions and fluorescence rescue by folding-enhancing mutations.

    Science.gov (United States)

    Liu, Shu-su; Wei, Xuan; Dong, Xue; Xu, Liang; Liu, Jia; Jiang, Biao

    2015-07-25

    Green fluorescent protein (GFP) and its derivative fluorescent proteins (FPs) are among the most commonly used reporter systems for studying gene expression and protein interaction in biomedical research. Most commercially available FPs have been optimized for their oligomerization state to prevent potential structural constraints that may interfere with the native function of fused proteins. Other approach to reducing structural constraints may include minimizing the structure of GFPs. Previous studies in an enhanced GFP variant (EGFP) identified a series of deletions that can retain GFP fluorescence. In this study, we interrogated the structural plasticity of a UV-optimized GFP variant (GFP(UV)) to amino acid deletions, characterized the effects of deletions and explored the feasibility of rescuing the fluorescence of deletion mutants using folding-enhancing mutations. Transposon mutagenesis was used to screen amino acid deletions in GFP that led to fluorescent and nonfluorescent phenotypes. The fluorescent GFP mutants were characterized for their whole-cell fluorescence and fraction soluble. Fluorescent GFP mutants with internal deletions were purified and characterized for their spectral and folding properties. Folding-ehancing mutations were introduced to deletion mutants to rescue their compromised fluorescence. We identified twelve amino acid deletions that can retain the fluorescence of GFP(UV). Seven of these deletions are either at the N- or C- terminus, while the other five are located at internal helices or strands. Further analysis suggested that the five internal deletions diminished the efficiency of protein folding and chromophore maturation. Protein expression under hypothermic condition or incorporation of folding-enhancing mutations could rescue the compromised fluorescence of deletion mutants. In addition, we generated dual deletion mutants that can retain GFP fluorescence. Our results suggested that a "size-minimized" GFP may be developed by

  9. The first Dutch SDHB founder deletion in paraganglioma – pheochromocytoma patients

    Directory of Open Access Journals (Sweden)

    Devilee Peter

    2009-04-01

    Full Text Available Abstract Background Germline mutations of the tumor suppressor genes SDHB, SDHC and SDHD play a major role in hereditary paraganglioma and pheochromocytoma. These three genes encode subunits of succinate dehydrogenase (SDH, the mitochondrial tricarboxylic acid cycle enzyme and complex II component of the electron transport chain. The majority of variants of the SDH genes are missense and nonsense mutations. To date few large deletions of the SDH genes have been described. Methods We carried out gene deletion scanning using MLPA in 126 patients negative for point mutations in the SDH genes. We then proceeded to the molecular characterization of deletions, mapping breakpoints in each patient and used haplotype analysis to determine whether the deletions are due to a mutation hotspot or if a common haplotype indicated a single founder mutation. Results A novel deletion of exon 3 of the SDHB gene was identified in nine apparently unrelated Dutch patients. An identical 7905 bp deletion, c.201-4429_287-933del, was found in all patients, resulting in a frameshift and a predicted truncated protein, p.Cys68HisfsX21. Haplotype analysis demonstrated a common haplotype at the SDHB locus. Index patients presented with pheochromocytoma, extra-adrenal PGL and HN-PGL. A lack of family history was seen in seven of the nine cases. Conclusion The identical exon 3 deletions and common haplotype in nine patients indicates that this mutation is the first Dutch SDHB founder mutation. The predominantly non-familial presentation of these patients strongly suggests reduced penetrance. In this small series HN-PGL occurs as frequently as pheochromocytoma and extra-adrenal PGL.

  10. Type I oculocutaneous albinism (OCA1) associated with a large deletion of the tyrosinase (TYR) gene

    Energy Technology Data Exchange (ETDEWEB)

    Spritz, R.A.; Wick, P.A.; Holmes, S.A.; Schnur, R.E. [Univ. of Wisconsin, Madison, WI (United States)]|[Children`s Hospital of Philadelphia, PA (United States)

    1994-09-01

    OCA1 is an autosomal recessive disorder in which the biosynthesis of melanin is reduced or absent in skin, hair, and eyes, due to deficient enzymatic activity of tyrosinase. TYR consists of 5 exons spanning over 65 kb at 11q14-q21. Analyses of TYR in >400 unrelated patients with OCA1 have identified more than 50 different point mutations; however, no large deletions have been detected. Here we report a large deletion of TYR in a Caucasian boy with OCA1B. Simultaneous SSCP/heteroduplex screening and DNA sequence analysis indicated that the patient was apparently homozygous for a previously described TYR mutation, adjacent to the 3` splice site of IVS2 (-7, t{r_arrow}a). To distinguish between possible gene deletion vs. maternal uniparental isodisomy, we characterized several chromosome 11 polymorphisms. Maternal uniparental isodisomy was excluded by the patient`s heterozygosity for alleles at D11S35 (11q21-122) and HBG2 (11p15.5). In addition, the patient failed to inherit paternal alleles at an MboI RFLP in exon 1 of TYR and at a TaqI RFLP in the promoter region of the gene. To detect a possible submicroscopic deletion, we performed quantitative Southern blot hybridization using a full length TYR cDNA. Compared with controls, both the patient and his father appeared deleted for two or three TYR-derived PstI fragments; the two TYRL-derived fragments appeared normal. These data indicate that the patient and his father have a partial TYR deletion, including at least exons 1, 2, and IVS2. Based on the organization of the gene, this deletion is at least 50 kb in size. The patient is thus hemizygous for the maternally-inherited mutation in IVS2, accounting for his OCA1B phenotype.

  11. Multi-exon deletions of the FBN1 gene in Marfan syndrome

    Directory of Open Access Journals (Sweden)

    Schrijver Iris

    2001-10-01

    Full Text Available Abstract Background Mutations in the fibrillin -1 gene (FBN1 cause Marfan syndrome (MFS, an autosomal dominant multi-system connective tissue disorder. The 200 different mutations reported in the 235 kb, 65 exon-containing gene include only one family with a genomic multi-exon deletion. Methods We used long-range RT-PCR for mutation detection and long-range genomic PCR and DNA sequencing for identification of deletion breakpoints, allele-specific transcript analyses to determine stability of the mutant RNA, and pulse-chase studies to quantitate fibrillin synthesis and extracellular matrix deposition in cultured fibroblasts. Southern blots of genomic DNA were probed with three overlapping fragments covering the FBN1 coding exons Results Two novel multi-exon FBN1 deletions were discovered. Identical nucleotide pentamers were found at or near the intronic breakpoints. In a Case with classic MFS, an in-frame deletion of exons 42 and 43 removed the C-terminal 24 amino acids of the 5th LTBP (8-cysteine domain and the adjacent 25th calcium-binding EGF-like (6-cysteine domain. The mutant mRNA was stable, but fibrillin synthesis and matrix deposition were significantly reduced. A Case with severe childhood-onset MFS has a de novo deletion of exons 44–46 that removed three EGF-like domains. Fibrillin protein synthesis was normal, but matrix deposition was strikingly reduced. No genomic rearrangements were detected by Southern analysis of 18 unrelated MFS samples negative for FBN1 mutation screening. Conclusions Two novel deletion cases expand knowledge of mutational mechanisms and genotype/phenotype correlations of fibrillinopathies. Deletions or mutations affecting an LTBP domain may result in unstable mutant protein cleavage products that interfere with microfibril assembly.

  12. Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes.

    Science.gov (United States)

    Komulainen, Tuomas; Hautakangas, Milla-Riikka; Hinttala, Reetta; Pakanen, Salla; Vähäsarja, Vesa; Lehenkari, Petri; Olsen, Päivi; Vieira, Päivi; Saarenpää-Heikkilä, Outi; Palmio, Johanna; Tuominen, Hannu; Kinnunen, Pietari; Majamaa, Kari; Rantala, Heikki; Uusimaa, Johanna

    2015-01-01

    To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions. Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content by quantitative real-time PCR and for deletions by long-range PCR. Direct sequencing of mtDNA maintenance genes and whole-exome sequencing were used to study the genetic aetiologies of the diseases. Clinical and laboratory findings were collected. Muscle samples were obtained from 104 paediatric patients with neuromuscular diseases. mtDNA depletion was found in three patients with severe early-onset encephalomyopathy or myopathy. Two of these patients presented with novel types of mitochondrial DNA depletion syndromes associated with increased serum creatine kinase (CK) and multiorgan disease without mutations in any of the known mtDNA maintenance genes; one patient had pathologic endoplasmic reticulum (ER) membranes in muscle. The third patient with mtDNA depletion was diagnosed with merosine-deficient muscular dystrophy caused by a homozygous mutation in the LAMA2 gene. Two patients with an early-onset Kearns-Sayre/Pearson-like phenotype harboured a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content. Novel encephalomyopathic mtDNA depletion syndrome with structural alterations in muscle ER was identified. mtDNA depletion may also refer to secondary mitochondrial changes related to muscular dystrophy. We suggest that a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content associated with Kearns-Sayre/Pearson syndromes may be secondary changes caused by mutations in an unknown nuclear gene.

  13. Detection of the deletion on Yp11.2 in a Chinese population.

    Science.gov (United States)

    Chen, Wenjing; Wu, Weiwei; Cheng, Jianding; Zhang, Yinming; Chen, Yong; Sun, Hongyu

    2014-01-01

    Sex determination tests based on Amelogenin gene as part of commercial PCR multiplex reaction kits have been widely applied in forensic DNA analysis. Mutations that cause dropout of Y chromosomal Amelogenin gene (AMELY) could lead to errors in gender determination and mixture interpretation. To infer the mechanism and estimate the dropout frequency of AMELY and adjacent Y-STRs, we studied 3 samples with AMELY dropout combined with DYS458 and/or DYS456 and 37 samples with DYS456 dropout. DYS456, DYS458 and AMELY are located in the Yp11.2 region. The singleplex amplification system showed the null alleles could be caused by fragment deletion in Yp11.2 rather than a point mutation in the primer binding region. After detection of the 17 Y-STR and 77 STS markers, the deletion map showed different patterns. The DYS456-AMELY-DYS458 deletion pattern was the largest, breaking from 3.60 Mb to 8.29 Mb in the Y chromosome, and the overall frequency was 0.0077%. The AMELY-DYS458 deletion pattern was broke from 6.74 Mb to 9.17 Mb, with a 0.0155% frequency. The DYS456 negative pattern was concentrated in two main deletion regions, with a 0.8220% frequency. The frequency of all negative pattern was 0.0155%. All the AMELY-DYS458 and DYS456-AMELY-DYS458, and 92% of the DYS456 deletion patterns belonged to Hg O3, the rest belonged to Hg Q. The DYS456 deletion pattern was first reported in Chinese population. The current and previous findings suggest additional gender test for ambiguous sex determination may be required. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  14. Utilization of deletion bins to anchor and order sequences along the wheat 7B chromosome.

    Science.gov (United States)

    Belova, Tatiana; Grønvold, Lars; Kumar, Ajay; Kianian, Shahryar; He, Xinyao; Lillemo, Morten; Springer, Nathan M; Lien, Sigbjørn; Olsen, Odd-Arne; Sandve, Simen R

    2014-09-01

    A total of 3,671 sequence contigs and scaffolds were mapped to deletion bins on wheat chromosome 7B providing a foundation for developing high-resolution integrated physical map for this chromosome. Bread wheat (Triticum aestivum L.) has a large, complex and highly repetitive genome which is challenging to assemble into high quality pseudo-chromosomes. As part of the international effort to sequence the hexaploid bread wheat genome by the international wheat genome sequencing consortium (IWGSC) we are focused on assembling a reference sequence for chromosome 7B. The successful completion of the reference chromosome sequence is highly dependent on the integration of genetic and physical maps. To aid the integration of these two types of maps, we have constructed a high-density deletion bin map of chromosome 7B. Using the 270 K Nimblegen comparative genomic hybridization (CGH) array on a set of cv. Chinese spring deletion lines, a total of 3,671 sequence contigs and scaffolds (~7.8 % of chromosome 7B physical length) were mapped into nine deletion bins. Our method of genotyping deletions on chromosome 7B relied on a model-based clustering algorithm (Mclust) to accurately predict the presence or absence of a given genomic sequence in a deletion line. The bin mapping results were validated using three different approaches, viz. (a) PCR-based amplification of randomly selected bin mapped sequences (b) comparison with previously mapped ESTs and (c) comparison with a 7B genetic map developed in the present study. Validation of the bin mapping results suggested a high accuracy of the assignment of 7B sequence contigs and scaffolds to the 7B deletion bins.

  15. Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts.

    Science.gov (United States)

    Irum, Bushra; Khan, Shahid Y; Ali, Muhammad; Daud, Muhammad; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Iqbal, Hira; Khan, Arif O; Al Obaisi, Saif; Naeem, Muhammad Asif; Nasir, Idrees A; Khan, Shaheen N; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O; Riazuddin, S Amer

    2016-01-01

    The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family.

  16. DELISHUS: an efficient and exact algorithm for genome-wide detection of deletion polymorphism in autism

    Science.gov (United States)

    Aguiar, Derek; Halldórsson, Bjarni V.; Morrow, Eric M.; Istrail, Sorin

    2012-01-01

    Motivation: The understanding of the genetic determinants of complex disease is undergoing a paradigm shift. Genetic heterogeneity of rare mutations with deleterious effects is more commonly being viewed as a major component of disease. Autism is an excellent example where research is active in identifying matches between the phenotypic and genomic heterogeneities. A considerable portion of autism appears to be correlated with copy number variation, which is not directly probed by single nucleotide polymorphism (SNP) array or sequencing technologies. Identifying the genetic heterogeneity of small deletions remains a major unresolved computational problem partly due to the inability of algorithms to detect them. Results: In this article, we present an algorithmic framework, which we term DELISHUS, that implements three exact algorithms for inferring regions of hemizygosity containing genomic deletions of all sizes and frequencies in SNP genotype data. We implement an efficient backtracking algorithm—that processes a 1 billion entry genome-wide association study SNP matrix in a few minutes—to compute all inherited deletions in a dataset. We further extend our model to give an efficient algorithm for detecting de novo deletions. Finally, given a set of called deletions, we also give a polynomial time algorithm for computing the critical regions of recurrent deletions. DELISHUS achieves significantly lower false-positive rates and higher power than previously published algorithms partly because it considers all individuals in the sample simultaneously. DELISHUS may be applied to SNP array or sequencing data to identify the deletion spectrum for family-based association studies. Availability: DELISHUS is available at http://www.brown.edu/Research/Istrail_Lab/. Contact: Eric_Morrow@brown.edu and Sorin_Istrail@brown.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:22689755

  17. Genomic findings in patients with clinical suspicion of 22q11.2 deletion syndrome.

    Science.gov (United States)

    Koczkowska, Magdalena; Wierzba, Jolanta; Śmigiel, Robert; Sąsiadek, Maria; Cabała, Magdalena; Ślężak, Ryszard; Iliszko, Mariola; Kardaś, Iwona; Limon, Janusz; Lipska-Ziętkiewicz, Beata S

    2017-02-01

    Chromosome 22q11.2 deletion syndrome, one of the most common human genomic syndromes, has highly heterogeneous clinical presentation. Patients usually harbor a 1.5 to 3 Mb hemizygous deletion at chromosome 22q11.2, resulting in pathognomic TBX1, CRKL and/or MAPK1 haploinsufficiency. However, there are some individuals with clinical features resembling the syndrome who are eventually diagnosed with genomic disorders affecting other chromosomal regions. The objective of this study was to evaluate the additive value of high-resolution array-CGH testing in the cohort of 41 patients with clinical features of 22q11.2 deletion syndrome and negative results of standard cytogenetic diagnostic testing (karyotype and FISH for 22q11.2 locus). Array-CGH analysis revealed no aberrations at chromosomes 22 or 10 allegedly related to the syndrome. Five (12.2 %) patients were found to have other genomic imbalances, namely 17q21.31 microdeletion syndrome (MIM#610443), 1p36 deletion syndrome (MIM#607872), NF1 microduplication syndrome (MIM#613675), chromosome 6pter-p24 deletion syndrome (MIM#612582) and a novel interstitial deletion at 3q26.31 of 0.65 Mb encompassing a dosage-dependent gene NAALADL2. Our study demonstrates that the implementation of array-CGH into the panel of classic diagnostic procedures adds significantly to their efficacy. It allows for detection of constitutional genomic imbalances in 12 % of subjects with negative result of karyotype and FISH targeted for 22q11.2 region. Moreover, if used as first-tier genetic test, the method would provide immediate diagnosis in ∼40 % phenotypic 22q11.2 deletion subjects.

  18. Total alpha-globin gene cluster deletion has high frequency in Filipinos

    Energy Technology Data Exchange (ETDEWEB)

    Hunt, J.A.; Haruyama, A.Z.; Chu, B.M. [Kapiolani Medical Center, Honolulu, HI (United States)] [and others

    1994-09-01

    Most {alpha}-thalassemias [Thal] are due to large deletions. In Southeast Asians, the (--{sup SEA}) double {alpha}-globin gene deletion is common, 3 (--{sup Tot}) total {alpha}-globin cluster deletions are known: Filipino (--{sup Fil}), Thai (--{sup Thai}), and Chinese (--{sup Chin}). In a Hawaii Thal project, provisional diagnosis of {alpha}-Thal-1 heterozygotes was based on microcytosis, normal isoelectric focusing, and no iron deficiency. One in 10 unselected Filipinos was an {alpha}-Thal-1 heterozygote, 2/3 of these had a (--{sup Tot}) deletion: a {var_sigma}-cDNA probe consistently showed fainter intensity of the constant 5.5 kb {var_sigma}{sub 2} BamHI band, with no heterzygosity for {var_sigma}-globin region polymorphisms; {alpha}-cDNA or {var_sigma}-cDNA probes showed no BamHI or BglII bands diagnostic of the (--{sup SEA}) deletion; bands for the (-{alpha}) {alpha}-Thal-2 single {alpha}-globin deletions were only seen in Hb H cases. A reliable monoclonal anti-{var_sigma}-peptide antibody test for the (--{sup SEA}) deletion was always negative in (--{sup Tot}) samples. Southern digests with the Lo probe, a gift from D. Higgs of Oxford Univ., confirmed that 49 of 50 (--{sup Tot}) chromosomes in Filipinos were (--{sup Fil}). Of 20 {alpha}-Thal-1 hydrops born to Filipinos, 11 were (--{sup Fil}/--{sup SEA}) compound heterozygotes; 9 were (--{sup SEA}/--{sup SEA}) homozygotes, but none was a (--{sup Fil}/--{sup Fil}).

  19. Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients.

    Science.gov (United States)

    Broadbent, Hannah; Farran, Emily K; Chin, Esther; Metcalfe, Kay; Tassabehji, May; Turnpenny, Peter; Sansbury, Francis; Meaburn, Emma; Karmiloff-Smith, Annette

    2014-01-01

    Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. WE REPORT ON VISUOSPATIAL COGNITION IN TWO INDIVIDUALS WITH CONTRASTING PARTIAL DELETIONS IN THE WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB's atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed.

  20. Deletion lengthening at chromosomes 6q and 16q targets multiple tumor suppressor genes and is associated with an increasingly poor prognosis in prostate cancer

    DEFF Research Database (Denmark)

    Kluth, Martina; Jung, Simon; Habib, Omar

    2017-01-01

    317 patients for 6q and 16q deletion length heterogeneity and found that the deletion expanded within 50-60% of 6q and 16q deleted cancers. Taken together, these data suggest continuous "deletion lengthening" as a key mechanism for prostate cancer progression leading to parallel down regulation......Prostate cancer is characterized by recurrent deletions that can considerably vary in size. We hypothesized that large deletions develop from small deletions and that this "deletion lengthening" might have a "per se" carcinogenic role through a combinatorial effect of multiple down regulated genes.......In vitroknockdown of 37 genes located inside the 6q12-q22 deletion region identified 4 genes with additive tumor suppressive effects, further supporting a role of the deletion size for cancer aggressiveness. Employing fluorescencein-situhybridization analysis on prostate cancer tissue microarrays, we determined...

  1. Isolation and Genetic Analysis of Extragenic Suppressors of the Hyper-Deletion Phenotype of the Saccharomyces Cerevisiae Hpr1δ Mutation

    OpenAIRE

    Santos-Rosa, H.; Aguilera, A.

    1995-01-01

    The HPR1 gene of Saccharomyces cerevisae is involved in maintaining low levels of deletions between DNA repeats. To understand how deletions initiate in the absence of the Hpr1 protein and the mechanisms of recombination leading to deletions in S. cerevisiae, we have isolated mutations as suppressors of the hyper-deletion phenotype of the hpr1δ mutation. The mutations defined five different genes called HRS for hyper-recombination suppression. They suppress the hyper-deletion phenotype of hpr...

  2. A macaque's-eye view of human insertions and deletions: differences in mechanisms.

    Directory of Open Access Journals (Sweden)

    Erika M Kvikstad

    2007-09-01

    Full Text Available Insertions and deletions (indels cause numerous genetic diseases and lead to pronounced evolutionary differences among genomes. The macaque sequences provide an opportunity to gain insights into the mechanisms generating these mutations on a genome-wide scale by establishing the polarity of indels occurring in the human lineage since its divergence from the chimpanzee. Here we apply novel regression techniques and multiscale analyses to demonstrate an extensive regional indel rate variation stemming from local fluctuations in divergence, GC content, male and female recombination rates, proximity to telomeres, and other genomic factors. We find that both replication and, surprisingly, recombination are significantly associated with the occurrence of small indels. Intriguingly, the relative inputs of replication versus recombination differ between insertions and deletions, thus the two types of mutations are likely guided in part by distinct mechanisms. Namely, insertions are more strongly associated with factors linked to recombination, while deletions are mostly associated with replication-related features. Indel as a term misleadingly groups the two types of mutations together by their effect on a sequence alignment. However, here we establish that the correct identification of a small gap as an insertion or a deletion (by use of an outgroup is crucial to determining its mechanism of origin. In addition to providing novel insights into insertion and deletion mutagenesis, these results will assist in gap penalty modeling and eventually lead to more reliable genomic alignments.

  3. Clinical and molecular consequences of exon 78 deletion in DMD gene.

    Science.gov (United States)

    Traverso, Monica; Assereto, Stefania; Baratto, Serena; Iacomino, Michele; Pedemonte, Marina; Diana, Maria Cristina; Ferretti, Marta; Broda, Paolo; Minetti, Carlo; Gazzerro, Elisabetta; Madia, Francesca; Bruno, Claudio; Zara, Federico; Fiorillo, Chiara

    2018-03-19

    We present a 13-year-old patient with persistent increase of serum Creatine Kinase (CK) and myalgia after exertion. Skeletal muscle biopsy showed marked reduction of dystrophin expression leading to genetic analysis of DMD gene by MLPA, which detected a single deletion of exon 78. To the best of our knowledge, DMD exon 78 deletion has never been described in literature and, according to prediction, it should lead to loss of reading frame in the dystrophin gene. To further assess the actual effect of exon 78 deletion, we analysed cDNA from muscle mRNA. This analysis confirmed the absence of 32 bp of exon 78. Exclusion of exon 78 changes the open reading frame of exon 79 and generate a downstream stop codon, producing a dystrophin protein of 3703 amino acids instead of 3685 amino acids. Albeit loss of reading frame usually leads to protein degradation and severe phenotype, in this case, we demonstrated that deletion of DMD exon 78 can be associated with a functional protein able to bind DGC complex and a very mild phenotype. This study adds a novel deletion in DMD gene in human and helps to define the compliance between maintaining/disrupting the reading frame and clinical form of the disease.

  4. Large deletions play a minor but essential role in congenital coagulation factor VII and X deficiencies.

    Science.gov (United States)

    Rath, M; Najm, J; Sirb, H; Kentouche, K; Dufke, A; Pauli, S; Hackmann, K; Liehr, T; Hübner, C A; Felbor, U

    2015-01-01

    Congenital factor VII (FVII) and factor X (FX) deficiencies belong to the group of rare bleeding disorders which may occur in separate or combined forms since both the F7 and F10 genes are located in close proximity on the distal long arm of chromosome 13 (13q34). We here present data of 192 consecutive index cases with FVII and/or FX deficiency. 10 novel and 53 recurrent sequence alterations were identified in the F7 gene and 5 novel as well as 11 recurrent in the F10 gene including one homozygous 4.35 kb deletion within F7 (c.64+430_131-6delinsTCGTAA) and three large heterozygous deletions involving both the F7 and F10 genes. One of the latter proved to be cytogenetically visible as a chromosome 13q34 deletion and associated with agenesis of the corpus callosum and psychomotor retardation. Large deletions play a minor but essential role in the mutational spectrum of the F7 and F10 genes. Copy number analyses (e. g. MLPA) should be considered if sequencing cannot clarify the underlying reason of an observed coagulopathy. Of note, in cases of combined FVII/FX deficiency, a deletion of the two contiguous genes might be part of a larger chromosomal rearrangement.

  5. Boyer-Moore Algorithm in Retrieving Deleted Short Message Service in Android Platform

    Science.gov (United States)

    Rahmat, R. F.; Prayoga, D. F.; Gunawan, D.; Sitompul, O. S.

    2018-02-01

    Short message service (SMS) can be used as digital evidence of disclosure of crime because it can strengthen the charges against the offenders. Criminals use various ways to destroy the evidence, including by deleting SMS. On the Android OS, SMS is stored in a SQLite database file. Deletion of SMS data is not followed by bit deletion in memory so that it is possible to rediscover the deleted SMS. Based on this case, the mobile forensic needs to be done to rediscover the short message service. The proposed method in this study is Boyer-Moore algorithm for searching string matching. An auto finds feature is designed to rediscover the short message service by searching using a particular pattern to rematch a text with the result of the hex value conversion in the database file. The system will redisplay the message for each of a match. From all the testing results, the proposed method has quite a high accuracy in rediscovering the short message service using the used dataset. The search results to rediscover the deleted SMS depend on the possibility of overwriting process and the vacuum procedure on the database file.

  6. Differential effects of N- and C-terminal deletions on the two activities of rubisco activase.

    Science.gov (United States)

    Esau, B D; Snyder, G W; Portis, A R

    1996-02-01

    Spinach (Spinacea oleracea) leaf ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco) activase was subjected to limited proteolysis with trypsin and directed deletions were made by modifying the spinach rubisco activase cDNA and expressing the 41-kDa isoform in Escherichia coli. Protein exposed to trypsin displayed a more rapid loss of the ability to promote the activation of decarbamylated rubisco than ATP hydrolysis (e.g., 10 and 50% activity remaining, respectively, after 1 h). A series of N-terminal deletions exhibited near abolition of rubisco activation after the 12th residue, a conserved tryptophan, was deleted. Conversely, a deletion of 19 residues at the C-terminus increased rubisco activation with little effect on ATP hydrolysis, resulting in an increased efficiency of activation. The C-terminal deletion mutant was further modified by a site-directed mutation in the ATP binding region (Q109E) which was previously observed to increase the efficiency of activation (J. B. Shen and W. L. Ogren, 1991, Plant Physiol. 99, 1201-1207). The efficiency of activation with this double mutant was greater than that for either of the original mutants. The results indicate that a conserved tryptophan in the N-terminal portion of rubisco activase is critical for promotion of the activation of rubisco, consistent with a possible role in interaction with rubisco. The C-terminus appears to have a regulatory effect on both rubisco activation and ATP hydrolysis.

  7. Rb and p53 gene deletions in lung adenocarcinomas from irradiated and control mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Y.; Woloschak, G.E. [Argonne National Lab., IL (United States). Center for Mechanistic Biology and Biotechnology

    1997-08-01

    This study was conducted on mouse lung adenocarcinoma tissues that were formalin-treated and paraffin-embedded 25 years ago to investigate the large gene deletions of mRb and p53 in B6CF{sub 1} male mice. A total of 80 lung tissue samples from irradiated mice and 40 lung samples from nonirradiated controls were randomly selected and examined in the mRb portion of this study. The results showed a significant (P < 0.05) higher percentage of mRb deletions in lung adenocarcinomas from mice exposed to 60 once-weekly {gamma}-ray doses than those from mice receiving 24 once-weekly {gamma}-ray doses at low doses and low dose rates; however, the percentage was not significantly different (P > 0.05) from that for spontaneous lung adenocarcinomas or lung adenocarcinomas from mice exposed to single-dose {gamma} irradiation at a similar total dose. mRb fragments 3 (71%) and 5 (67%), the parts of the gene that encoded the pocket binding region of Rb protein to adenovirus E1A and SV40 T-antigen, were the most frequently deleted fragments. p53 gene deletion analysis was carried out on normal lungs and lung adenocarcinomas that were initially found to bear mRb deletions. Exons 1,4,5,6, and 9 were chosen to be analyzed.

  8. Multiplex PCR screening detects small p53 deletions and insertions in human ovarian cancer cell lines.

    Science.gov (United States)

    Runnebaum, I B; Tong, X W; Moebus, V; Heilmann, V; Kieback, D G; Kreienberg, R

    1994-06-01

    Mutations at the p53 tumor suppressor gene locus are a frequent genetic alteration associated with human ovarian carcinoma. Little information exists regarding whether mutational events occur other than point mutations and large deletions, causing loss of heterozygosity. Small intragenic deletions and insertions in the p53 gene have been observed in various human neoplasias. We developed a multiplex polymerase chain reaction (MPCR) screening assay to amplify the complete p53 coding region from genomic DNA in a single step. Deletions and/or insertions were found in six out of 11 newly established ovarian carcinoma cell lines. MPCR detected deletions as small as 2 bp, as confirmed by nucleotide sequence analysis. Most of the observed alterations (6/7) were homozygous or hemizygous. Structural aberrations of the p53 gene possibly leading to loss of p53 cell cycle control may be a consequence of a slipped-mispairing mechanism in rapid DNA replication during repetitious ovulation and wound repair of ovarian epithelial cells. MPCR may be a valuable tool for screening for possible p53 deletion and insertion mutations not only in ovarian cancer but also in other malignancies.

  9. RBPJ is disrupted in a case of proximal 4p deletion syndrome with epilepsy.

    Science.gov (United States)

    Nakayama, Tojo; Saitsu, Hirotomo; Endo, Wakaba; Kikuchi, Atsuo; Uematsu, Mitsugu; Haginoya, Kazuhiro; Hino-fukuyo, Naomi; Kobayashi, Tomoko; Iwasaki, Masaki; Tominaga, Teiji; Kure, Shigeo; Matsumoto, Naomichi

    2014-06-01

    Proximal 4p deletion syndrome is characterized clinically by mental retardation, minor dysmorphic facial features, and is occasionally complicated with epilepsy. More than 20 cases of proximal 4p deletion syndrome have been reported, but the causative gene(s) remain elusive. We describe here a 2-year-old female patient with a common manifestation of proximal 4p deletion syndrome and infantile epileptic encephalopathy possessing a de novo balanced translocation t(4;13)(p15.2;q12.13). The patient was diagnosed as infantile spasms at 9 months of age. She presented with dysmorphic facial features and global developmental delay, compatible with proximal 4p deletion syndrome. Using fluorescence in situ hybridization, we determined the translocation breakpoint at 4p15.2 to be within RBPJ. RBPJ is a transcription factor in the Notch/RBPJ signaling pathway, playing a crucial role in the developing human brain, and particularly telencephalon development. Our findings, combined with those of previous studies, strongly suggest that RBPJ is causative for proximal 4p deletion syndrome and epilepsy in this case. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  10. [Changes of biological behavioral of E. coli K1 after ppk1 gene deletion].

    Science.gov (United States)

    Peng, Liang; Pan, Jiayun; Luo, Su; Yang, Zhenghui; Huang, Mufang; Cao, Hong

    2014-06-01

    To study the changes in biological behaviors of meningitis E. coli K1 strain E44 after deletion of polyphosphate kinase 1 (ppk1) gene and explore the role of ppk1 in the pathogenesis of E. coli K1-induced meningitis. The wild-type strain E. coli K1 and ppk1 deletion mutant were exposed to heat at 56 degrees celsius; for 6 min, and their survival rates were determined. The adhesion and invasion of the bacteria to human brain microvascular endothelial cells (HBMECs) were observed using electron microscopy and quantitative tests. HBMECs were co-incubated with wild-type strain or ppk1 deletion mutant, and the cytoskeleton rearrangement was observed under laser scanning confocal microscope. The survival rate of the ppk1 deletion mutant was significantly lower than that of the wild-type strain after heat exposure. The ppk1 deletion mutant also showed lowered cell adhesion and invasion abilities and weakened ability to induce cytoskeleton rearrangement in HBMECs. ppk1 gene is important for E.coli K1 for heat resistance, cell adhesion and invasion, and for inducing cytoskeletal rearrangement in HBMECs.

  11. Selective neuronal PTEN deletion: can we take the brakes off of growth without losing control?

    Directory of Open Access Journals (Sweden)

    Erin A Gutilla

    2016-01-01

    Full Text Available The limited ability for injured adult axons to regenerate is a major cause for limited functional recovery after injury to the nervous system, motivating numerous efforts to uncover mechanisms capable of enhancing regeneration potential. One promising strategy involves deletion or knockdown of the phosphatase and tensin (PTEN gene. Conditional genetic deletion of PTEN before, immediately following, or several months after spinal cord injury enables neurons of the corticospinal tract (CST to regenerate their axons across the lesion, which is accompanied by enhanced recovery of skilled voluntary motor functions mediated by the CST. Although conditional genetic deletion or knockdown ofPTEN in neurons enables axon regeneration, PTEN is a well-known tumor suppressor and mutations of the PTEN gene disrupt brain development leading to neurological abnormalities including macrocephaly, seizures, and early mortality. The long-term consequences of manipulating PTEN in the adult nervous system, as would be done for therapeutic intervention after injury, are only now being explored. Here, we summarize evidence indicating that long-term deletion of PTEN in mature neurons does not cause evident pathology; indeed, cortical neurons that have lived without PTEN for over 1 year appear robust and healthy. Studies to date provide only a first look at potential negative consequences of PTEN deletion or knockdown, but the absence of any detectable neuropathology supports guarded optimism that interventions to enable axon regeneration after injury are achievable.

  12. Size unlimited markerless deletions by a transconjugative plasmid-system in Bacillus licheniformis.

    Science.gov (United States)

    Rachinger, Michael; Bauch, Melanie; Strittmatter, Axel; Bongaerts, Johannes; Evers, Stefan; Maurer, Karl-Heinz; Daniel, Rolf; Liebl, Wolfgang; Liesegang, Heiko; Ehrenreich, Armin

    2013-09-20

    Conjugative shuttle vectors of the pKVM series, based on an IncP transfer origin and the pMAD vector with a temperature sensitive replication were constructed to establish a markerless gene deletion protocol for Bacilli without natural competence such as the exoenzyme producer Bacillus licheniformis. The pKVM plasmids can be conjugated to strains of B. licheniformis and B. subtilis. For chromosomal gene deletion, regions flanking the target gene are fused and cloned in a pKVM vector prior to conjugative transfer from Escherichia coli to B. licheniformis. Appropriate markers on the vector backbone allow for the identification of the integration at the target locus and thereafter the vector excision, both events taking place via homologous recombination. The functionality of the deletion system was demonstrated with B. licheniformis by a markerless 939 bp in-frame deletion of the yqfD gene and the deletion of a 31 kbp genomic segment carrying a PBSX-like prophage. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome.

    Science.gov (United States)

    Beygo, J; Buiting, K; Seland, S; Lüdecke, H-J; Hehr, U; Lich, C; Prager, B; Lohmann, D R; Wieczorek, D

    2012-01-01

    Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterized by facial anomalies and ear defects. TCS is caused by mutations in the TCOF1 gene and follows autosomal dominant inheritance. Recently, mutations in the POLR1D and POLR1C genes have also been identified to cause TCS. However, in a subset of patients no causative mutation could be found yet. Inter- and intrafamilial phenotypic variability is high as is the variety of mainly family-specific mutations identified throughout TCOF1. No obvious correlation between pheno- and genotype could be observed. The majority of described point mutations, small insertions and deletions comprising only a few nucleotides within TCOF1 lead to a premature termination codon. We investigated a cohort of 112 patients with a tentative clinical diagnosis of TCS by multiplex ligation-dependent probe amplification (MLPA) to search for larger deletions not detectable with other methods used. All patients were selected after negative screening for mutations in TCOF1, POLR1D and POLR1C. In 1 patient with an unequivocal clinical diagnosis of TCS, we identified a 3.367 kb deletion. This deletion abolishes exon 3 and is the first described single exon deletion within TCOF1. On RNA level we observed loss of this exon which supposedly leads to haploinsufficiency of TREACLE, the nucleolar phosphoprotein encoded by TCOF1.

  14. Antibodies with higher bactericidal activity induced by a Neisseria gonorrhoeae Rmp deletion mutant strain.

    Directory of Open Access Journals (Sweden)

    Guocai Li

    Full Text Available Neisseria gonorrhoeae (N. gonorrhoeae outer membrane protein reduction modifiable protein (Rmp has strong immunogenicity. However, anti-Rmp antibodies block rather than preserve the antibacterial effects of protective antibodies, which hampers the development of vaccines for gonococcal infections. We herein constructed an Rmp deletion mutant strain of N. gonorrhoeae by gene homologous recombination. The 261-460 nucleotide residues of Rmp gene amplified from N. gonorrhoeae WHO-A strain were replaced with a kanamycin-resistant Kan gene amplified from pET-28a. The resultant hybridized DNA was transformed into N. gonorrhoeae WHO-A strain. PCR was used to screen the colonies in which wild-type Rmp gene was replaced with a mutant gene fragment. Western blotting revealed that the Rmp deletion mutant strain did not express Rmp protein. Rmp deletion did not alter the morphological and Gram staining properties of the mutant strain that grew slightly more slowly than the wild-type one. Rmp gene mutated stably throughout 25 generations of passage. Antibody-mediated complement-dependent cytotoxicity assay indicated that the antibodies induced by the mutant strain had evidently higher bactericidal activities than those induced by the wild-type strain. Further modification of the Rmp deletion mutant strain is still required in the development of novel live attenuated vaccines for gonorrhea by Opa genes deletion or screening of phenotypic variant strains that do not express Opa proteins.

  15. Abnormal Speech Motor Control in Individuals with 16p11.2 Deletions.

    Science.gov (United States)

    Demopoulos, Carly; Kothare, Hardik; Mizuiri, Danielle; Henderson-Sabes, Jennifer; Fregeau, Brieana; Tjernagel, Jennifer; Houde, John F; Sherr, Elliott H; Nagarajan, Srikantan S

    2018-01-19

    Speech and motor deficits are highly prevalent (>70%) in individuals with the 600 kb BP4-BP5 16p11.2 deletion; however, the mechanisms that drive these deficits are unclear, limiting our ability to target interventions and advance treatment. This study examined fundamental aspects of speech motor control in participants with the 16p11.2 deletion. To assess capacity for control of voice, we examined how accurately and quickly subjects changed the pitch of their voice within a trial to correct for a transient perturbation of the pitch of their auditory feedback. When compared to controls, 16p11.2 deletion carriers show an over-exaggerated pitch compensation response to unpredictable mid-vocalization pitch perturbations. We also examined sensorimotor adaptation of speech by assessing how subjects learned to adapt their sustained productions of formants (speech spectral peak frequencies important for vowel identity), in response to consistent changes in their auditory feedback during vowel production. Deletion carriers show reduced sensorimotor adaptation to sustained vowel identity changes in auditory feedback. These results together suggest that 16p11.2 deletion carriers have fundamental impairments in the basic mechanisms of speech motor control and these impairments may partially explain the deficits in speech and language in these individuals.

  16. Deletions in the fifth alpha helix of HIV-1 matrix block virus release

    Energy Technology Data Exchange (ETDEWEB)

    Sanford, Bridget; Li, Yan; Maly, Connor J.; Madson, Christian J. [Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178 (United States); Chen, Han [Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE (United States); Zhou, You [Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE (United States); Nebraska Center for Virology, Lincoln, NE (United States); Belshan, Michael, E-mail: michaelbelshan@creighton.edu [Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178 (United States); Nebraska Center for Virology, Lincoln, NE (United States)

    2014-11-15

    The matrix (MA) protein of HIV-1 is the N-terminal component of the Gag structural protein and is critical for the early and late stages of viral replication. MA contains five α-helices (α1–α5). Deletions in the N-terminus of α5 as small as three amino acids impaired virus release. Electron microscopy of one deletion mutant (MA∆96-120) showed that its particles were tethered to the surface of cells by membranous stalks. Immunoblots indicated all mutants were processed completely, but mutants with large deletions had alternative processing intermediates. Consistent with the EM data, MA∆96-120 retained membrane association and multimerization capability. Co-expression of this mutant inhibited wild type particle release. Alanine scanning mutation in this region did not affect virus release, although the progeny virions were poorly infectious. Combined, these data demonstrate that structural ablation of the α5 of MA inhibits virus release. - Highlights: • Deletions were identified in the C-terminus of matrix that block virus release. • These deletion mutants still multimerized and associated with membranes. • TEM showed the mutant particles were tethered to the cell surface. • Amino acid mutagenesis of the region did not affect release. • The data suggests that disruption of matrix structure blocks virus release.

  17. Polymerase chain reaction detection of retinoblastoma gene deletions in paraffin-embedded mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1991-01-01

    A Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene using microtomed sections from paraffin-embedded radiation-induced and spontaneous tumors as the DNA source. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments relative to control PCR products on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death. Spontaneous tumors as well as those from irradiated mice (569 cGy of 60 Co γ rays or 60 cGy of JANUS neutrons) were analyzed. Tumors in six neutron-irradiated mice also had no mRb deletions. However, one of six tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  18. Deletions induced by gamma rays in the genome of Escherichia coli

    International Nuclear Information System (INIS)

    Raha, Manidipa; Hutchinson, Franklin

    1991-01-01

    An Escherichia coli lysogen was constructed with a lambda phage bearing a lacZ gene surrounded by about 100 x 10 3 base-pairs of dispensable DNA. The lacZ mutants induced by gamma rays in this lysogen were more than 10% large deletions, ranging in size from 0.6 x 10 -3 to 70 x 10 3 base-pairs. These deletions were centered, not on lacZ, but on a ColE1 origin of DNA replication located 1.2 x 10 3 bases downstream from lacZ, suggesting that this origin of replication was involved in the process by which deletions were formed. In agreement with this hypothesis, a lysogen of the same phage without the ColE1 origin showed a very much lower percentage of radiation-induced deletions, as did a second lysogen of a lambda phage without any known plasmid origin of replication. Indirect evidence is presented for radiation-induced deletions centered on the lambda origin of DNA replication in a lysogen. (author)

  19. Deletions in the fifth alpha helix of HIV-1 matrix block virus release

    International Nuclear Information System (INIS)

    Sanford, Bridget; Li, Yan; Maly, Connor J.; Madson, Christian J.; Chen, Han; Zhou, You; Belshan, Michael

    2014-01-01

    The matrix (MA) protein of HIV-1 is the N-terminal component of the Gag structural protein and is critical for the early and late stages of viral replication. MA contains five α-helices (α1–α5). Deletions in the N-terminus of α5 as small as three amino acids impaired virus release. Electron microscopy of one deletion mutant (MA∆96-120) showed that its particles were tethered to the surface of cells by membranous stalks. Immunoblots indicated all mutants were processed completely, but mutants with large deletions had alternative processing intermediates. Consistent with the EM data, MA∆96-120 retained membrane association and multimerization capability. Co-expression of this mutant inhibited wild type particle release. Alanine scanning mutation in this region did not affect virus release, although the progeny virions were poorly infectious. Combined, these data demonstrate that structural ablation of the α5 of MA inhibits virus release. - Highlights: • Deletions were identified in the C-terminus of matrix that block virus release. • These deletion mutants still multimerized and associated with membranes. • TEM showed the mutant particles were tethered to the cell surface. • Amino acid mutagenesis of the region did not affect release. • The data suggests that disruption of matrix structure blocks virus release

  20. [Unexpected discovery of a fetus with DMD gene deletion using single nucleotide polymorphism array].

    Science.gov (United States)

    Lin, Shaobin; Zhou, Yu; Zhou, Bingyi; Gu, Heng

    2017-08-10

    To investigate the value of single nucleotide polymorphism array (SNP array) for the identification of de novo mutations in the DMD gene among fetuses. G-banded karyotyping and SNP array were performed on a fetus with intrauterine growth restriction but without family history of Duchenne/Becker muscular dystrophy (DMD/BMD). Multiplex ligation-dependent probe amplification (MLPA) was subsequently applied on amniocytes and maternal peripheral blood sample to detect DMD gene deletion/duplication mutations. Karyotyping of amniocytes showed a normal 46, XY karyotype. SNP array on amniocytes detected a 116 kb deletion (chrX: 32 455 741-32 571 504) at Xp21.1 with breakpoints at introns 16 and 30 respectively, encompassing exons 17-29 of the DMD gene. In addition, MLPA analysis of the DMD gene on amniocytes confirmed the deletion of exons 17 to 29 identified by SNP array. However, no deletion/duplication mutation was detected by MLPA in the mother. The de novo deletion of exons 17 to 29 of the DMD gene detected in the fetus may result in BMD or DMD. SNP array can improve the efficiency for detecting genomic disorders in fetuses with unidentified pathogenic genes, negative family history and nonspecific phenotypes.

  1. Primary lymphedema and other lymphatic anomalies are associated with 22q11.2 deletion syndrome.

    Science.gov (United States)

    Unolt, Marta; Barry, Jessica; Digilio, Maria Cristina; Marino, Bruno; Bassett, Anne; Oechslin, Erwin; Low, David W; Belasco, Jean B; Kallish, Staci; Sullivan, Kathleen; Zackai, Elaine H; McDonald-McGinn, Donna M

    2018-02-12

    Lymphedema is an abnormal accumulation of interstitial fluid within the tissues. Primary lymphedema is caused by aberrant lymphangiogenesis and it has been historically classified based on age at presentation. Although most cases are sporadic, primary lymphedema may be familial or present in association with chromosomal abnormalities and syndromic disorders. To the best of our knowledge, primary lymphedema has never been described in patients with 22q11.2 deletion syndrome. We identified 4 patients with 22q11.2 deletion syndrome and primary lymphedema via our International 22q11.2 Deletion Syndrome Consortium. All patients underwent comprehensive clinical, laboratory and imaging assessments to rule out other causes of lymphedema. All patients had de novo typical deletions and family histories were negative for lymphedema. We report the novel association of primary lymphedema with 22q11.2 deletion syndrome. Importantly, animal models demonstrated Tbx1 playing a critical role in lymphangiogenesis by reducing Vegfr3 expression in lymphatic endothelial cells. Moreover, the VEGFR3 pathway is essential for lymphangiogenesis with mutations identified in hereditary primary lymphedema. Accordingly, our findings provide a new insight into understanding cellular mechanisms of lymphangiogenesis disorders. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  2. Opitz GBBB syndrome and the 22q11.2 deletion

    Energy Technology Data Exchange (ETDEWEB)

    Lacassie, Y.; Arriaza, M.I. [Louisiani State Univ. Medical Center and Children`s Hospital, New Orleans, LA (United States)

    1996-03-29

    Recently, McDonald-McGinn et al. reported the presence of a deletion 22q11.2 in a family with autosomal dominant inheritance and in a sporadic case with the Opitz GBBB syndrome. The presence of a vascular ring in these patients prompted them to look for this deletion, since this anomaly may be associated with the 22q11.2 deletion. They reviewed the Opitz GBBB syndrome and the 22q11.2 microdeletion syndrome, finding considerable overlap of manifestations. They proposed that, in some patients, the Opitz GBBB syndrome may be due to a 22q11.2 deletion. We recently examined a newborn boy referred because of MCA. The cardinal findings in this patient (hypertelorism, hypospadias with descended testicles, characteristic nose and truncus arteriosus type I) were suggestive of the Opitz GBBB syndrome and of the velocardiofacial syndrome. The chromosomes were apparently normal (46,XY), but the FISH study showed a 22q11.2 deletion. The patient developed hypocalcemia with very low level of PTH and heart failure requiring surgery. His immunological status was normal except that CD4 cells were mildly low and natural killer cells were increased in number. The family history was noncontributory, but the full evaluation of the family is pending. The mother at first glance presents apparent hypertelorism. 3 refs.

  3. Congenital respiratory tract disorders in 22q11.2 deletion syndrome.

    Science.gov (United States)

    Verheij, Emmy; Speleman, Lucienne; Mink van der Molen, Aebele B; Thomeer, Henricus G X M

    2018-01-01

    Respiratory tract disorders have been reported in patients with 22q11.2 deletion syndrome, however infrequently. This study describes the respiratory tract disorders encountered in a cohort of 278 patients with 22q11.2 deletion syndrome. We conducted a retrospective, cross-sectional, study at a single tertiary referral center. We identified the patients with 22q11.2 deletion syndrome and with an upper and/or lower respiratory tract disorder at our otorhinolaryngologic department. The different disorders were described. Out of 278 patients referred to the otorhinolaryngologic department, we identified 14 patients with a laryngeal and/or tracheal disorder. Nine patients had more than one congenital disorder in this anatomical area. Disorders included a choanal stenosis (n = 1), laryngeal web (n = 5), laryngeal cleft (n = 2), subglottic stenosis (n = 3), pharyngo-, laryngo-, tracheo- and/or bronchomalacia (n = 11) and tracheal stenosis (n = 1). Different types of respiratory tract disorders can be present in patients with 22q11.2 deletion syndrome. Clinicians should be aware of this clinical association for timely and accurate diagnosis and treatment. In addition, the diagnosis 22q11.2 deletion syndrome should be considered in patients presenting with a congenital respiratory tract disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Neuropsychiatric aspects of 22q11.2 deletion syndrome: considerations in the prenatal setting

    Science.gov (United States)

    Bassett, Anne S.; Costain, Gregory; Marshall, Christian R.

    2016-01-01

    Most major neuropsychiatric outcomes of concern to families are not detectable by prenatal ultrasound. The introduction of genome-wide chromosomal microarray analysis to prenatal clinical diagnostic testing has increased the detection of pathogenic 22q11.2 deletions, which cause the most common genomic disorder. The recent addition of this and other microdeletions to non-invasive prenatal screening methods using cell-free fetal DNA has further propelled interest in outcomes. Conditions associated with 22q11.2 deletions include intellect ranging from intellectual disability to average, schizophrenia and other treatable psychiatric conditions, epilepsy, and early-onset Parkinson’s disease. However, there is currently no way to predict how severe the lifetime expression will be. Available evidence suggests no major role in these neuropsychiatric outcomes for the congenital cardiac or most other structural anomalies that may be detectable on ultrasound. This article provides an outline of the lifetime neuropsychiatric phenotype of 22q11.2 deletion syndrome that will be useful to clinicians involved in prenatal diagnosis and related genetic counselling. The focus is on information that will be most relevant to two common situations: detection of a 22q11.2 deletion in a fetus or newborn, and new diagnosis of 22q11.2 deletion syndrome in a parent without a previous molecular diagnosis. PMID:27718271

  5. Terminal 14q32.33 deletion as a novel cause of agammaglobulinemia.

    Science.gov (United States)

    Geier, Christoph B; Piller, Alexander; Eibl, Martha M; Ciznar, Peter; Ilencikova, Denisa; Wolf, Hermann M

    2017-10-01

    Over the past decades, a pleiotropic spectrum of B-cell intrinsic defects leading to early onset agammaglobulinemia and absent B cells has been described. Herein we report terminal 14q32.33 deletion as a novel cause of agammaglobulinemia. We describe a 20-year old man with a 1MB terminal 14q32.33 deletion resulting in a loss of the entire Immunoglobulin heavy chain gene region of chromosome 14. The patient presented with absent serum immunoglobulin levels and absent circulating B cells since age 2. The clinical picture was dominated by severe episodes of recurrent upper respiratory tract infections. In the literature, the most prevalent features of terminal 14q32.33 deletions include mental disability, facial malformation, hypotonia, seizures, and visual problems with retinal abnormalities. Neither increased susceptibility to infections nor agammaglobulinemia have been described as a manifestation of terminal 14q32.33 deletion. Thus, our findings expand the known clinical spectrum of terminal 14q32.33 deletion to include susceptibility to infections. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Abnormal auditory and language pathways in children with 16p11.2 deletion

    Directory of Open Access Journals (Sweden)

    Jeffrey I. Berman

    2015-01-01

    Full Text Available Copy number variations at chromosome 16p11.2 contribute to neurodevelopmental disorders, including autism spectrum disorder (ASD. This study seeks to improve our understanding of the biological basis of behavioral phenotypes common in ASD, in particular the prominent and prevalent disruption of spoken language seen in children with the 16p11.2 BP4–BP5 deletion. We examined the auditory and language white matter pathways with diffusion MRI in a cohort of 36 pediatric deletion carriers and 45 age-matched controls. Diffusion MR tractography of the auditory radiations and the arcuate fasciculus was performed to generate tract specific measures of white matter microstructure. In both tracts, deletion carriers exhibited significantly higher diffusivity than that of controls. Cross-sectional diffusion parameters in these tracts changed with age with no group difference in the rate of maturation. Within deletion carriers, the left-hemisphere arcuate fasciculus mean and radial diffusivities were significantly negatively correlated with clinical language ability, but not non-verbal cognitive ability. Diffusion metrics in the right-hemisphere arcuate fasciculus were not predictive of language ability. These results provide insight into the link between the 16p11.2 deletion, abnormal auditory and language pathway structures, and the specific behavioral deficits that may contribute to neurodevelopmental disorders such as ASD.

  7. Duchenne muscular dystrophy in a female with compound heterozygous contiguous exon deletions.

    Science.gov (United States)

    Takeshita, Eri; Minami, Narihiro; Minami, Kumiko; Suzuki, Mikiya; Awashima, Takeya; Ishiyama, Akihiko; Komaki, Hirofumi; Nishino, Ichizo; Sasaki, Masayuki

    2017-06-01

    Females with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) mutations rarely exhibit clinical symptoms from childhood, although potential mechanisms for symptoms associated with DMD and BMD in females have been reported. We report the case of a female DMD patient with a clinical course indistinguishable from that of a male DMD patient, and who possessed compound heterozygous contiguous exon deletions in the dystrophin gene. She exhibited Gowers' sign, calf muscle hypertrophy, and a high serum creatine kinase level at 2 years. Her muscle pathology showed most of the fibers were negative for dystrophin immunohistochemical staining. She lost ambulation at 11 years. Multiplex ligation-dependent probe amplification analysis of this gene detected one copy of exons 48-53; she was found to be a BMD carrier with an in-frame deletion. Messenger RNA from her muscle demonstrated out-of-frame deletions of exons 48-50 and 51-53 occurring on separate alleles. Genomic DNA from her lymphocytes demonstrated the accurate deletion region on each allele. To our knowledge, this is the first report on a female patient possessing compound heterozygous contiguous exon deletions in the dystrophin gene, leading to DMD. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. CDC73 intragenic deletion in familial primary hyperparathyroidism associated with parathyroid carcinoma.

    Science.gov (United States)

    Korpi-Hyövälti, Eeva; Cranston, Treena; Ryhänen, Eeva; Arola, Johanna; Aittomäki, Kristiina; Sane, Timo; Thakker, Rajesh V; Schalin-Jäntti, Camilla

    2014-09-01

    CDC73 mutations frequently underlie the hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism (FIHP), and parathyroid carcinoma. It has also been suggested that CDC73 deletion analysis should be performed in those patients without CDC73 mutations. To investigate for CDC73 deletion in a family with FIHP previously reported not to have CDC73 mutations. Eleven members (six affected with primary hyperparathyroidism and five unaffected) were ascertained from the family, and multiplex ligation-dependent probe amplification was performed to detect CDC73 deletion using leukocyte DNA. A previously unreported deletion of CDC73 involving exons 1-10 was detected in five affected members and two unaffected members who were 26 and 39 years of age. Two affected members had parathyroid carcinomas at the ages of 18 and 32 years, and they had Ki-67 proliferation indices of 5 and 14.5% and did not express parafibromin, encoded by CDC73. Primary hyperparathyroidism in the other affected members was due to adenomas and atypical adenomas, and none had jaw tumors. Two affected members had thoracic aortic aneurysms, which in one member occurred with parathyroid carcinoma and renal cysts. A previously unreported intragenic deletion of exons 1 to 10 of CDC73 was detected in a three-generation family with FIHP, due to adenomas, atypical adenomas, and parathyroid carcinomas. In addition, two affected males had thoracic aortic aneurysms, which may represent another associated clinical feature of this disorder.

  9. 22q11.2 Deletion Syndrome Is Associated With Impaired Auditory Steady-State Gamma Response

    DEFF Research Database (Denmark)

    Larsen, Kit Melissa; Pellegrino, Giovanni; Birknow, Michelle Rosgaard

    2017-01-01

    The 22q11.2 deletion syndrome confers a markedly increased risk for schizophrenia. 22q11.2 deletion carriers without manifest psychotic disorder offer the possibility to identify functional abnormalities that precede clinical onset. Since schizophrenia is associated with a reduced cortical gamma...... response to auditory stimulation at 40 Hz, we hypothesized that the 40 Hz auditory steady-state response (ASSR) may be attenuated in nonpsychotic individuals with a 22q11.2 deletion. Eighteen young nonpsychotic 22q11.2 deletion carriers and a control group of 27 noncarriers with comparable age range (12...... Hz click stimulation. Both gamma power and inter-trial phase coherence of the ASSR were markedly reduced in the 22q11.2 deletion group. The ability to phase lock cortical gamma activity to regular auditory 40 Hz stimulation correlated with the individual expression of negative symptoms in deletion...

  10. Prediction of radiosensitivity of human tumor cell lines in vitro by determining 4977bp deletion in mitochondrial DNA

    International Nuclear Information System (INIS)

    Rong Qinglin; Cao Yongzhen; Zhang Yaowen; Zhao Xinran; Wang Qin; Li Jin; Liu Qiang

    2008-01-01

    Objective: To evaluate the possibility of predicting the radiosensitivity of tumor cell lines using the assay of the mtDNA4977bp deletion. Methods: The mtDNA4977bp deletion of HepG 2 cells and PC-3 cells were detected by nested PCR after irradiated by various doses of x-ray. Results: The radiation-induced mtDNA4977bp deletion of the tumor cell lines of HepG 2 and PC-3 were detected after irradiated. There was a dose dependent in the mtDNA4977bp deletion of two tumor cell lines. The deletion rate of HepG 2 was higher significantly than that of PC-3 at each point of radiation dose (P 2 was higher than that of PC-3. Conclusion: The assay of the mtDNA4977bp deletion may be an approach to predict the radiosensitivity of tumor cells. (authors)

  11. Complex mutations & subpopulations of deletions at exon 19 of EGFR in NSCLC revealed by next generation sequencing: potential clinical implications.

    Directory of Open Access Journals (Sweden)

    Antonio Marchetti

    Full Text Available Microdeletions at exon 19 are the most frequent genetic alterations affecting the Epidermal Growth Factor Receptor (EGFR gene in non-small cell lung cancer (NSCLC and they are strongly associated with response to treatment with tyrosine kinase inhibitors. A series of 116 NSCLC DNA samples investigated by Sanger Sequencing (SS, including 106 samples carrying exon 19 EGFR deletions and 10 without deletions (control samples, were subjected to deep next generation sequencing (NGS. All samples with deletions at SS showed deletions with NGS. No deletions were seen in control cases. In 93 (88% cases, deletions detected by NGS were exactly corresponding to those identified by SS. In 13 cases (12% NGS resolved deletions not accurately characterized by SS. In 21 (20% cases the NGS showed presence of complex (double/multiple frameshift deletions producing a net in-frame change. In 5 of these cases the SS could not define the exact sequence of mutant alleles, in the other 16 cases the results obtained by SS were conventionally considered as deletions plus insertions. Different interpretative hypotheses for complex mutations are discussed. In 46 (43% tumors deep NGS showed, for the first time to our knowledge, subpopulations of DNA molecules carrying EGFR deletions different from the main one. Each of these subpopulations accounted for 0.1% to 17% of the genomic DNA in the different tumors investigated. Our findings suggest that a region in exon 19 is highly unstable in a large proportion of patients carrying EGFR deletions. As a corollary to this study, NGS data were compared with those obtained by immunohistochemistry using the 6B6 anti-mutant EGFR antibody. The immunoreaction was E746-A750del specific. In conclusion, NGS analysis of EGFR exon 19 in NSCLCs allowed us to formulate a new interpretative hypothesis for complex mutations and revealed the presence of subpopulations of deletions with potential pathogenetic and clinical impact.

  12. Three types of preS1 start codon deletion variants in the natural course of chronic hepatitis B infection.

    Science.gov (United States)

    Choe, Won Hyeok; Kim, Hong; Lee, So-Young; Choi, Yu-Min; Kwon, So Young; Moon, Hee Won; Hur, Mina; Kim, Bum-Joon

    2017-12-12

    Naturally occurring hepatitis B virus variants carrying a deletion in the preS1 start codon region may evolve during long-lasting virus-host interactions in chronic hepatitis B (CHB). The aim of this study was to determine the immune phase-specific prevalent patterns of preS1 start codon deletion variants and related factors during the natural course of CHB. A total of 399 CHB patients were enrolled. Genotypic analysis of three different preS1 start codon deletion variants (classified by deletion size: 15-base pair [bp], 18-bp, and 21-bp deletion variants) was performed. PreS1 start codon deletion variants were detected in 155 of 399 patients (38.8%). The predominant variant was a 15-bp deletion in the immune-tolerance phase (18/50, 36%) and an 18-bp deletion in the immune-clearance phase (69/183, 37.7%). A 21-bp deletion was the predominant variant in the low replicative phase (3/25, 12.0%) and reactivated hepatitis Be antigen (HBeAg)-negative phase (22/141, 15.6%). The 15-bp and 18-bp deletion variants were more frequently found in HBeAg-positive patients (P start codon deletion variants changes according to the immune phases of CHB infection, and each variant type is associated with different clinical parameters. PreS1 start codon deletion variants might interact with the host immune response differently according to their variant types. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  13. How to diagnose the 22q11.2 deletion syndrome in patients with schizophrenia: a case report

    Science.gov (United States)

    2013-01-01

    The 22q11.2 deletion syndrome is caused by a microdeletion of chromosome 22. One third of all patients with 22q11.2 deletion develop schizophrenia-like symptoms. In general, the prevalence of 22q11.2 deletion in patients with schizophrenia is 1%–2%. The 22q11.2 deletion is one of the major known genetic risk factors for schizophrenia. However, clinical differences in the phenotypes between patients with schizophrenia who are 22q11.2 deletion carriers and those who are not are still unknown. Therefore, it may be difficult to diagnose 22q11.2 deletion in patients with schizophrenia on the basis of clinical symptoms. To date, only two Japanese patients with the deletion have been identified through microdeletion studies of patients with schizophrenia in the Japanese population. Herein, we report the case study of a 48-year-old Japanese woman with 22q11.2 deletion who had a 30-year history of schizophrenia. Based on craniofacial anomalies, unpredictable agitation, hypocalcemia, and brain imaging finding, we suspected the 22q11.2 deletion in clinical populations and diagnosed the deletion using fluorescence in situ hybridization analysis. To find common phenotypes in Japanese patients with the deletion who have schizophrenia-like symptoms, we compared phenotypes among three Japanese cases. The common phenotypes were an absence of congenital cardiovascular anomalies and the presence of current findings of low intellectual ability, agitation, and hypocalcemia. We propose that hypocalcemia and agitation in patients with schizophrenia may derive from the 22q11.2 deletion, particularly when these phenotypes are coupled with schizophrenia-like symptoms. PMID:24063534

  14. Interstitial deletion of 5q33.3q35.1 in a boy with severe mental retardation

    OpenAIRE

    Lee, Jin Hwan; Kim, Hyo Jeong; Yoon, Jung Min; Cheon, Eun Jung; Lim, Jae Woo; Ko, Kyong Og; Lee, Gyung Min

    2016-01-01

    Constitutional interstitial deletions of the long arm of chromosome 5 (5q) are quite rare, and the corresponding phenotype is not yet clearly delineated. Severe mental retardation has been described in most patients who present 5q deletions. Specifically, the interstitial deletion of chromosome 5q33.3q35.1, an extremely rare chromosomal aberration, is characterized by mental retardation, developmental delay, and facial dysmorphism. Although the severity of mental retardation varies across cas...

  15. Structural and dynamic changes associated with beneficial engineered single-amino-acid deletion mutations in enhanced green fluorescent protein.

    Science.gov (United States)

    Arpino, James A J; Rizkallah, Pierre J; Jones, D Dafydd

    2014-08-01

    Single-amino-acid deletions are a common part of the natural evolutionary landscape but are rarely sampled during protein engineering owing to limited and prejudiced molecular understanding of mutations that shorten the protein backbone. Single-amino-acid deletion variants of enhanced green fluorescent protein (EGFP) have been identified by directed evolution with the beneficial effect of imparting increased cellular fluorescence. Biophysical characterization revealed that increased functional protein production and not changes to the fluorescence parameters was the mechanism that was likely to be responsible. The structure EGFP(D190Δ) containing a deletion within a loop revealed propagated changes only after the deleted residue. The structure of EGFP(A227Δ) revealed that a `flipping' mechanism was used to adjust for residue deletion at the end of a β-strand, with amino acids C-terminal to the deletion site repositioning to take the place of the deleted amino acid. In both variants new networks of short-range and long-range interactions are generated while maintaining the integrity of the hydrophobic core. Both deletion variants also displayed significant local and long-range changes in dynamics, as evident by changes in B factors compared with EGFP. Rather than being detrimental, deletion mutations can introduce beneficial structural effects through altering core protein properties, folding and dynamics, as well as function.

  16. Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome

    DEFF Research Database (Denmark)

    Starnawska, A; Hansen, C S; Sparsø, T

    2017-01-01

    Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous...... deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate...

  17. Novel 31.2 kb α0 Deletion in a Palestinian Family with α-Thalassemia

    DEFF Research Database (Denmark)

    Brieghel, Christian; Birgens, Henrik; Frederiksen, Henrik

    2015-01-01

    A previously unknown α(0) deletion, designated - -(DANE), was found in three generations of a Danish family of Palestinian origin. Six patients were heterozygous and three patients had deletional Hb H (β4) disease with a compound heterozygosity for the common -α(3.7) (rightward) deletion. Multiplex...... ligation-dependent probe amplification (MLPA) supplemented by repeated polymerase chain reaction (PCR) amplification identified the 5' and 3' breakpoints in the α-globin gene cluster. This novel 31.2 kb deletion (NG_000006.1: g.8800_40007del31208) leads to the removal of the HBZ, HBA2 and HBA1 genes....

  18. A New Intergenic α-Globin Deletion (α-αΔ125) Found in a Kabyle Population.

    Science.gov (United States)

    Singh, Amrathlal Rabbind; Lacan, Philippe; Cadet, Estelle; Bignet, Patricia; Dumesnil, Cécile; Vannier, Jean-Pierre; Joly, Philippe; Rochette, Jacques

    2016-01-01

    We have identified a deletion of 125 bp (α-α(Δ125)) (NG_000006.1: g.37040_37164del) in the α-globin gene cluster in a Kabyle population. A combination of singlex and multiplex polymerase chain reaction (PCR)-based assays have been used to identify the molecular defect. Sequencing of the abnormal PCR amplification product revealed a novel α1-globin promoter deletion. The endpoints of the deletion were characterized by sequencing the deletion junctions of the mutated allele. The observed deletion was located 378 bp upstream of the α1-globin gene transcription initiation site and leaves the α2 gene intact. In some patients, the α-α(Δ125) deletion was shown to segregate with Hb S (HBB: c.20A>T) and/or Hb C (HBB: c.19G>A) or a β-thalassemic allele. The α-α(Δ125) deletion has no discernible effect on red cell indices when inherited with no other abnormal globin genes. The family study demonstrated that the deletion is heritable. This is the only example of an intergenic α2-α1 non coding DNA deletion, leaving the α2-globin gene and the α1 coding part intact.

  19. The mitochondrial DNA 4,977-bp deletion and its implication in copy number alteration in colorectal cancer

    Science.gov (United States)

    2011-01-01

    Background Qualitative and quantitative changes in human mitochondrial DNA (mtDNA) have been implicated in various cancer types. A 4,977 bp deletion in the major arch of the mitochondrial genome is one of the most common mutations associated with a variety of human diseases and aging. Methods We conducted a comprehensive study on clinical features and mtDNA of 104 colorectal cancer patients in the Wenzhou area of China. In particular, using a quantitative real time PCR method, we analyzed the 4,977 bp deletion and mtDNA content in tumor tissues and paired non-tumor areas from these patients. Results We found that the 4,977 bp deletion was more likely to be present in patients of younger age (≤65 years, p = 0.027). In patients with the 4,977 bp deletion, the deletion level decreased as the cancer stage advanced (p = 0.031). Moreover, mtDNA copy number in tumor tissues of patients with this deletion increased, both compared with that in adjacent non-tumor tissues and with in tumors of patients without the deletion. Such mtDNA content increase correlated with the levels of the 4,977 bp deletion and with cancer stage (p deletion may play a role in the early stage of colorectal cancer, and it is also implicated in alteration of mtDNA content in cancer cells. PMID:21232124

  20. The benefits and limitations of cell-free DNA screening for 22q11.2 deletion syndrome.

    Science.gov (United States)

    Dugoff, Lorraine; Mennuti, Michael T; McDonald-McGinn, Donna M

    2017-01-01

    Cell-free DNA testing is increasingly being used to screen pregnant women for fetal aneuploidy. This technology may also identify microdeletion syndromes, including 22q11.2 deletion syndrome, the most common microdeletion syndrome, and the 22q11.2 duplication syndrome. The purpose of this paper is to provide an overview of the 22q11.2 deletion syndrome, to review the early experience with cell-free DNA screening for this deletion and to consider the potential benefits that may be associated with prenatal detection of the deletion. © 2016 John Wiley & Sons, Ltd. © 2016 John Wiley & Sons, Ltd.