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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck
With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in ~1:5000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in the severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limi...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Wilson, I. J., Carling, P. J., Alston, C. L., Floros, V. I., Pyle, A., Hudson, G., Sallevelt, S. C. E. H., Lamperti, C., Carelli, V., Bindoff, L. A., Samuels, D. C., Wonnapinij, P., Zeviani, M., Taylor, R. W., Smeets, H. J. M., Horvath, R., Chinnery, P. F Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Genomic determinants of somatic copy number alterations across human cancers
Somatic copy number alterations (SCNAs) play an important role in carcinogenesis. However, the impact of genomic architecture on the global patterns of SCNAs in cancer genomes remains elusive. In this work, we conducted multiple linear regression (MLR) analyses of the pooled SCNA data from The Cancer Genome Atlas (TCGA) Pan-Cancer project. We performed MLR analyses for 11 individual cancer types and three different kinds of SCNAs—amplifications and deletions, telomere-bound and interstitial SCNAs and local SCNAs. Our MLR model explains >30% of the pooled SCNA breakpoint variation, with the explanatory power rangin...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Zhang, Y., Xu, H., Frishman, D. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer
Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 x 10–6]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-speci...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Stacey, S. N., Kehr, B., Gudmundsson, J., Zink, F., Jonasdottir, A., Gudjonsson, S. A., Sigurdsson, A., Halldorsson, B. V., Agnarsson, B. A., Benediktsdottir, K. R., Aben, K. K. H., Vermeulen, S. H., Cremers, R. G., Panadero, A., Helfand, B. T., Cooper, P Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Exome arrays capture polygenic rare variant contributions to schizophrenia
Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci, but it is also evident from studies of copy number variants (CNVs) and from exome-sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13 688 individuals (...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Richards, A. L., Leonenko, G., Walters, J. T., Kavanagh, D. H., Rees, E. G., Evans, A., Chambert, K. D., Moran, J. L., Goldstein, J., Neale, B. M., McCarroll, S. A., Pocklington, A. J., Holmans, P. A., Owen, M. J., O'Donovan, M. C. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics
Induced pluripotent stem cell (iPSC)-derived cortical neurons potentially present a powerful new model to understand corticogenesis and neurological disease. Previous work has established that differentiation protocols can produce cortical neurons, but little has been done to characterize these at cellular resolution. In particular, it is unclear to what extent in vitro two-dimensional, relatively disordered culture conditions recapitulate the development of in vivo cortical layer identity. Single-cell multiplex reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to interrogate the expression of...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Handel, A. E., Chintawar, S., Lalic, T., Whiteley, E., Vowles, J., Giustacchini, A., Argoud, K., Sopp, P., Nakanishi, M., Bowden, R., Cowley, S., Newey, S., Akerman, C., Ponting, C. P., Cader, M. Z. Tags: ARTICLES Source Type: research
Familial prion protein mutants inhibit Hrd1-mediated retrotranslocation of misfolded proteins by depleting misfolded protein sensor BiP
Similar to many proteins trafficking through the secretory pathway, cellular prion protein (PrP) partly retrotranslocates from the endoplasmic reticulum to the cytosol through the endoplasmic reticulum-associated degradation (ERAD) pathway in an attempt to alleviate accumulation of cellular misfolded PrP. Surprisingly, familial PrP mutants fail to retrotranslocate and simultaneously block normal cellular PrP retrotranslocation. That impairments in retrotranslocation of misfolded proteins could lead to global disruptions in cellular homeostasis prompted further investigations into PrP mutant retrotranslocation defects. A ga...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Peters, S. L., Dery, M.-A., LeBlanc, A. C. Tags: ARTICLES Source Type: research
Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset
Spinal muscular atrophy (SMA) is a genetic disease characterized by atrophy of muscle and loss of spinal motor neurons. SMA is caused by deletion or mutation of the survival motor neuron 1 (SMN1) gene, and the nearly identical SMN2 gene fails to generate adequate levels of functional SMN protein due to a splicing defect. Currently, several therapeutics targeted to increase SMN protein are in clinical trials. An outstanding issue in the field is whether initiating treatment in symptomatic older patients would confer a therapeutic benefit, an important consideration as the majority of patients with milder forms of SMA are di...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Feng, Z., Ling, K. K. Y., Zhao, X., Zhou, C., Karp, G., Welch, E. M., Naryshkin, N., Ratni, H., Chen, K. S., Metzger, F., Paushkin, S., Weetall, M., Ko, C.-P. Tags: ARTICLES Source Type: research
LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function
In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Sloan, M., Alegre-Abarrategui, J., Potgieter, D., Kaufmann, A.-K., Exley, R., Deltheil, T., Threlfell, S., Connor-Robson, N., Brimblecombe, K., Wallings, R., Cioroch, M., Bannerman, D. M., Bolam, J. P., Magill, P. J., Cragg, S. J., Dodson, P. D., Wade-Mar Tags: ARTICLES Source Type: research
Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy
Adult-onset inherited myopathies with similar pathological features, including hereditary inclusion body myopathy (hIBM) and limb-girdle muscular dystrophy (LGMD), are a genetically heterogeneous group of muscle diseases. It is unclear whether these inherited myopathies initiated by mutations in distinct classes of genes are etiologically related. Here, we exploit a genetic model system to establish a mechanistic link between diseases caused by mutations in two distinct genes, hnRNPA2B1 and DNAJB6. Hrb98DE and mrj are the Drosophila melanogaster homologs of human hnRNPA2B1 and DNAJB6, respectively. We introduced disease-ho...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Li, S., Zhang, P., Freibaum, B. D., Kim, N. C., Kolaitis, R.-M., Molliex, A., Kanagaraj, A. P., Yabe, I., Tanino, M., Tanaka, S., Sasaki, H., Ross, E. D., Taylor, J. P., Kim, H. J. Tags: ARTICLES Source Type: research
Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain
We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six new de novo missense diagnoses in TBL1XR1 from the Deciphering Developmental Disorders study, together with population variation data, we show that the β-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely ...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Laskowski, R. A., Tyagi, N., Johnson, D., Joss, S., Kinning, E., McWilliam, C., Splitt, M., Thornton, J. M., Firth, H. V., the DDD Study, Wright, C. F. Tags: ARTICLES Source Type: research
A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium
In conclusion, we identified the first pathogenic mutation in MAPKAPK3 associated with a retinal disease. These findings shed new lights on Bruch's membrane/RPE pathophysiology and will open studies of this signaling pathway in diseases with RPE and Bruch's membrane alterations, such as age-related macular degeneration. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Meunier, I., Lenaers, G., Bocquet, B., Baudoin, C., Piro-Megy, C., Cubizolle, A., Quiles, M., Jean-Charles, A., Cohen, S. Y., Merle, H., Gaudric, A., Labesse, G., Manes, G., Pequignot, M., Cazevieille, C., Dhaenens, C.-M., Fichard, A., Ronkina, N., Arthur Tags: ARTICLES Source Type: research
Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations
In conclusion, we demonstrate that small Cterm-derived peptides can be effective tools to rescue cellular defects caused by mutations in a wide range of mt-tRNAs. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Perli, E., Fiorillo, A., Giordano, C., Pisano, A., Montanari, A., Grazioli, P., Campese, A. F., Di Micco, P., Tuppen, H. A., Genovese, I., Poser, E., Preziuso, C., Taylor, R. W., Morea, V., Colotti, G., d'Amati, G. Tags: ARTICLES Source Type: research
