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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, we know little of mutational spectrum in the Chinese population. Thus, here we report the identification of somatic mutations for Chinese PTC using 402 tumor-normal pairs (Discovery: 91 pairs via exome sequencing; validation: 311 pairs via Sanger sequencing). We observed three distinct mutational signatures, evidently different from the two mutational signatures among Caucasian PTCs. Ten significantly mutated genes were identified, most previously uncharacterized. Notably, we found that long non-coding RNA (lncRNA) GAS8-AS1 is the seconda...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Pan, W., Zhou, L., Ge, M., Zhang, B., Yang, X., Xiong, X., Fu, G., Zhang, J., Nie, X., Li, H., Tang, X., Wei, J., Shao, M., Zheng, J., Yuan, Q., Tan, W., Wu, C., Yang, M., Lin, D. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis
In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Hinds, D. A., Buil, A., Ziemek, D., Martinez-Perez, A., Malik, R., Folkersen, L., Germain, M., Mälarstig, A., Brown, A., Soria, J. M., Dichgans, M., Bing, N., Franco-Cereceda, A., Souto, J. C., Dermitzakis, E. T., Hamsten, A., Worrall, B. B., Tung Tags: Association Studies Articles Source Type: research
A general framework for meta-analyzing dependent studies with overlapping subjects in association mapping
Meta-analysis strategies have become critical to augment power of genome-wide association studies (GWAS). To reduce genotyping or sequencing cost, many studies today utilize shared controls, and these individuals can inadvertently overlap among multiple studies. If these overlapping individuals are not taken into account in meta-analysis, they can induce spurious associations. In this article, we propose a general framework for adjusting association statistics to account for overlapping subjects within a meta-analysis. The key idea of our method is to transform the covariance structure of the data, so it can be used in dow...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Han, B., Duong, D., Sul, J. H., de Bakker, P. I. W., Eskin, E., Raychaudhuri, S. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila
Defects in organelle dynamics underlie a number of human degenerative disorders, and whole exome sequencing (WES) is a powerful tool for studying genetic changes that affect the cellular machinery. WES may uncover variants of unknown significance (VUS) that require functional validation. Previously, a pathogenic de novo variant in the middle domain of DNM1L (p.A395D) was identified in a single patient with a lethal defect of mitochondrial and peroxisomal fission. We identified two additional patients with infantile encephalopathy and partially overlapping clinical features, each with a novel VUS in the middle domain of DNM...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Chao, Y.-H., Robak, L. A., Xia, F., Koenig, M. K., Adesina, A., Bacino, C. A., Scaglia, F., Bellen, H. J., Wangler, M. F. Tags: Articles Source Type: research
Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression
Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-enc...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Smith, J., Read, M. L., Hoffman, J., Brown, R., Bradshaw, B., Campbell, C., Cole, T., Navas, J. D., Eatock, F., Gundara, J. S., Lian, E., Mcmullan, D., Morgan, N. V., Mulligan, L., Morrison, P. J., Robledo, M., Simpson, M. A., Smith, V. E., Stewart, S., T Tags: ARTICLES Source Type: research
Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle and ciliary defects
We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies, thoracic dysplasia, pulmonary hypoplasia and protruding abdomen. Single nucleotide polymorphism homozygosity mapping and whole exome sequencing identified a novel homozygous stop-gain mutation in NEK9 (c.1489C>T; p.Arg497*) as the cause of this disorder. NEK9 encodes a never in mitosis gene A-related kinase involved in regulating spindle organization, chromosome alignment, cytokinesis and cell cycle progression. This is the fir...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Casey, J. P., Brennan, K., Scheidel, N., McGettigan, P., Lavin, P. T., Carter, S., Ennis, S., Dorkins, H., Ghali, N., Blacque, O. E., Mc Gee, M. M., Murphy, H., Lynch, S. A. Tags: ARTICLES Source Type: research
SLC52A3, A Brown-Vialetto-van Laere syndrome candidate gene is essential for mouse development, but dispensable for motor neuron differentiation
Riboflavin, also known as vitamin B2, is essential for cellular reduction-oxidation reactions, but is not readily synthesized by mammalian cells. It has been proposed that riboflavin absorption occurs through solute carrier family 52 members (SLC52) A1, A2 and A3. These transporters are also candidate genes for the childhood onset-neural degenerative syndrome Brown–Vialetto–Van Laere (BVVL). Although riboflavin is an essential nutrient, why mutations in its transporters result in a neural cell-specific disorder remains unclear. Here, we provide evidence that Slc52a3 is the mouse ortholog of SLC52A3 and show tha...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Intoh, A., Suzuki, N., Koszka, K., Eggan, K. Tags: ARTICLES Source Type: research
Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation
The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open-reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly-dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of i...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Kanekura, K., Yagi, T., Cammack, A. J., Mahadevan, J., Kuroda, M., Harms, M. B., Miller, T. M., Urano, F. Tags: ARTICLES Source Type: research
Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes
Oxidative damage to mitochondria (MT) is a major mechanism for aging and neurodegeneration. We have developed a novel synthetic antioxidant, XJB-5-131, which directly targets MT, the primary site and primary target of oxidative damage. XJB-5-131 prevents the onset of motor decline in an HdhQ(150/150) mouse model for Huntington's disease (HD) if treatment starts early. Here, we report that XJB-5-131 attenuates or reverses disease progression if treatment occurs after disease onset. In animals with well-developed pathology, XJB-5-131 promotes weight gain, prevents neuronal death, reduces oxidative damage in neurons, suppress...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Polyzos, A., Holt, A., Brown, C., Cosme, C., Wipf, P., Gomez-Marin, A., Castro, M. R., Ayala-Pena, S., McMurray, C. T. Tags: ARTICLES Source Type: research
Motor deficits associated with Huntington's disease occur in the absence of striatal degeneration in BACHD transgenic mice
In this study, we carried out a series of extensive behavioural and neuropathological tests on BACHD mice, to validate this mouse for preclinical research. Transgenic C57BL/6J BACHD and litter-matched wild-type mice were examined in a battery of motor and cognitive function tests at regular intervals up to 12 months of age. Brains from these mice were also analysed for signs of neurodegeneration and striatal and cortical volume sizes compared using anatomic 16.4T magnetic resonance imaging (MRI) brain scans. BACHD mice showed progressive motor impairments on rotarod and balance beam tests starting from 3 months of age, wer...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Mantovani, S., Gordon, R., Li, R., Christie, D. C., Kumar, V., Woodruff, T. M. Tags: ARTICLES Source Type: research
The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts
We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 x 10–8) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left–right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be ...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Shore, R., Covill, L., Pettigrew, K. A., Brandler, W. M., Diaz, R., Xu, Y., Tello, J. A., Talcott, J. B., Newbury, D. F., Stein, J., Monaco, A. P., Paracchini, S. Tags: Articles Source Type: research
Defining functional classes of Barth syndrome mutation in humans
The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patie...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Lu, Y.-W., Galbraith, L., Herndon, J. D., Lu, Y.-L., Pras-Raves, M., Vervaart, M., Van Kampen, A., Luyf, A., Koehler, C. M., McCaffery, J. M., Gottlieb, E., Vaz, F. M., Claypool, S. M. Tags: ARTICLES Source Type: research
Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington's disease
The objective of this study was to determine the protective effects of the mitochondria-targeted molecules MitoQ and SS31 in striatal neurons that stably express mutant huntingtin (Htt) (STHDhQ111/Q111) in Huntington's disease (HD). We studied mitochondrial and synaptic activities by measuring mRNA and the protein levels of mitochondrial and synaptic genes, mitochondrial function, and ultra-structural changes in MitoQ- and SS31-treated mutant Htt neurons relative to untreated mutant Htt neurons. We used gene expression analysis, biochemical methods, transmission electron microscopy (TEM) and confocal microscopy methods. In...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Yin, X., Manczak, M., Reddy, P. H. Tags: ARTICLES Source Type: research
Tissue-specific models of spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult stages
Spinal muscular atrophy (SMA) is an autosomal recessive disease linked to survival motor neuron (SMN) protein deficiency. While SMN protein is expressed ubiquitously, its deficiency triggers tissue-specific hallmarks, including motor neuron death and muscle atrophy, leading to impaired motor functions and premature death. Here, using stable miR-mediated knockdown technology in zebrafish, we developed the first vertebrate system allowing transgenic spatio-temporal control of the smn1 gene. Using this new model it is now possible to investigate normal and pathogenic SMN function(s) in specific cell types, independently or in...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Laird, A. S., Mackovski, N., Rinkwitz, S., Becker, T. S., Giacomotto, J. Tags: ARTICLES Source Type: research
