Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression
Down syndrome (DS) is caused by a triplication of chromosome 21 (HSA21). Increased oxidative stress, decreased neurogenesis and synaptic dysfunction from HSA21 gene overexpression are thought to cause mental retardation, dementia and seizure in this disorder. Recent epigenetic studies have raised the possibility that DNA methylation has significant effects on DS neurodevelopment. Here, we performed methylome profiling in normal and DS fetal cortices and observed a significant hypermethylation in ~4% of probes in the DS samples compared with age-matched normals. The probes with differential methylation were distributed acro...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Lu, J., Mccarter, M., Lian, G., Esposito, G., Capoccia, E., Delli-Bovi, L. C., Hecht, J., Sheen, V. Tags: ARTICLES Source Type: research
NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1
Neurofibromatosis type 1 (NF1) is a common neurogenetic condition characterized by significant clinical heterogeneity. A major barrier to developing precision medicine approaches for NF1 is an incomplete understanding of the factors that underlie its inherent variability. To determine the impact of the germline NF1 gene mutation on the optic gliomas frequently encountered in children with NF1, we developed genetically engineered mice harboring two representative NF1-patient-derived Nf1 gene mutations (c.2542G>C;p.G848R and c.2041C>T;p.R681X). We found that each germline Nf1 gene mutation resulted in different levels ...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Toonen, J. A., Anastasaki, C., Smithson, L. J., Gianino, S. M., Li, K., Kesterson, R. A., Gutmann, D. H. Tags: Articles Source Type: research
Acute and crucial requirement for MeCP2 function upon transition from early to late adult stages of brain maturation
This study reveals a new postnatal developmental stage, which coincides with full-brain maturation, where the structure/function of the brain is extremely sensitive to levels of MeCP2 and loss of MeCP2 leads to precipitous collapse of the neuronal networks and incompatibility with life within days. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Du, F., Nguyen, M. V. C., Karten, A., Felice, C. A., Mandel, G., Ballas, N. Tags: ARTICLES Source Type: research
{alpha}B-Crystallin overexpression in astrocytes modulates the phenotype of the BACHD mouse model of Huntington's disease
Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the huntingtin (htt) protein. The polyQ expansion increases the propensity of htt to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins are predicted to slow disease progression in HD models. αB-crystallin (αBc) or HspB5 is a well-characterized member of the small heat shock protein (sHsp) family that reduces mutant htt (mhtt) aggregation and toxicity in vitro and in Drosophila models of HD. Here, we determined if overexpressing αBc in vivo modulates...
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Authors: Oliveira, A. O., Osmand, A., Outeiro, T. F., Muchowski, P. J., Finkbeiner, S. Tags: ARTICLES Source Type: research
Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
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Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Front Cover
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - July 4, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes
Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score ...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Machiela, M. J., Lan, Q., Slager, S. L., Vermeulen, R. C. H., Teras, L. R., Camp, N. J., Cerhan, J. R., Spinelli, J. J., Wang, S. S., Nieters, A., Vijai, J., Yeager, M., Wang, Z., Ghesquieres, H., McKay, J., Conde, L., de Bakker, P. I. W., Cox, D. G., Bur Tags: ASSOCIATION STUDIES ARTICLE Source Type: research
A low absolute number of expanded transcripts is involved in myotonic dystrophy type 1 manifestation in muscle
Muscular manifestation of myotonic dystrophy type 1 (DM1), a common inheritable degenerative multisystem disorder, is mainly caused by expression of RNA from a (CTG·CAG)n-expanded DM1 locus. Here, we report on comparative profiling of expression of normal and expanded endogenous or transgenic transcripts in skeletal muscle cells and biopsies from DM1 mouse models and patients in order to help us in understanding the role of this RNA-mediated toxicity. In tissue of HSALR mice, the most intensely used ‘muscle-only’ model in the DM1 field, RNA from the α-actin (CTG)250 transgene was at least 1000-fold...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Gudde, A. E. E. G., Gonzalez-Barriga, A., van den Broek, W. J. A. A., Wieringa, B., Wansink, D. G. Tags: ARTICLES Source Type: research
Haploinsufficiency of RCBTB1 is associated with Coats disease and familial exudative vitreoretinopathy
In this study, we identified two heterozygous frameshift mutations in RCBTB1 from three Taiwanese cases through exome sequencing. In patient-derived lymphoblastoid cell lines (LCLs), the protein level of RCBTB1 is approximately half that of unaffected control LCLs, which is indicative of a haploinsufficiency mechanism. By employing transient transfection and reporter assays for the transcriptional activity of β-catenin, we demonstrated that RCBTB1 participates in the Norrin/FZD4 signaling pathway and that knockdown of RCBTB1 by shRNA significantly reduced nuclear accumulation of β-catenin under Norrin and Wnt3a t...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Wu, J.-H., Liu, J.-H., Ko, Y.-C., Wang, C.-T., Chung, Y.-C., Chu, K.-C., Liu, T.-T., Chao, H.-M., Jiang, Y.-J., Chen, S.-J., Chung, M.-Y. Tags: ARTICLES Source Type: research
Allelic series of Huntington's disease knock-in mice reveals expression discorrelates
Identifying molecular drivers of pathology provides potential therapeutic targets. Differentiating between drivers and coincidental molecular alterations presents a major challenge. Variation unrelated to pathology further complicates transcriptomic, proteomic and metabolomic studies which measure large numbers of individual molecules. To overcome these challenges towards the goal of determining drivers of Huntington's disease (HD), we generated an allelic series of HD knock-in mice with graded levels of phenotypic severity for comparison with molecular alterations. RNA-sequencing analysis of this series reveals high numbe...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Kumar, A., Zhang, J., Tallaksen-Greene, S., Crowley, M. R., Crossman, D. K., Morton, A. J., Van Groen, T., Kadish, I., Albin, R. L., Lesort, M., Detloff, P. J. Tags: ARTICLES Source Type: research
Interactome network analysis identifies multiple caspase-6 interactors involved in the pathogenesis of HD
Caspase-6 (CASP6) has emerged as an important player in Huntington disease (HD), Alzheimer disease (AD) and cerebral ischemia, where it is activated early in the disease process. CASP6 also plays a key role in axonal degeneration, further underscoring the importance of this protease in neurodegenerative pathways. As a protein's function is modulated by its protein–protein interactions, we performed a high-throughput yeast-2-hybrid (Y2H) screen against ~17 000 human proteins to gain further insight into the function of CASP6. We identified a high-confidence list of 87 potential CASP6 interactors. From this list, 61% a...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Riechers, S.-P., Butland, S., Deng, Y., Skotte, N., Ehrnhoefer, D. E., Russ, J., Laine, J., Laroche, M., Pouladi, M. A., Wanker, E. E., Hayden, M. R., Graham, R. K. Tags: ARTICLES Source Type: research
ALS mouse model SOD1G93A displays early pathology of sensory small fibers associated to accumulation of a neurotoxic splice variant of peripherin
Growing evidence suggests that amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease that primarily affects motor neurons and, though less evidently, other neuronal systems. About 75% of sporadic and familial ALS patients show a subclinical degeneration of small-diameter fibers, as measured by loss of intraepidermal nerve fibers (IENFs), but the underlying biological causes are unknown. Small-diameter fibers are derived from small-diameter sensory neurons, located in dorsal root ganglia (DRG), whose biochemical hallmark is the expression of type III intermediate filament peripherin. We tested here ...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Sassone, J., Taiana, M., Lombardi, R., Porretta-Serapiglia, C., Freschi, M., Bonanno, S., Marcuzzo, S., Caravello, F., Bendotti, C., Lauria, G. Tags: ARTICLES Source Type: research
ATR promotes cilia signalling: links to developmental impacts
Mutations in ATR (ataxia telangiectasia and RAD3-related) cause Seckel syndrome (ATR-SS), a microcephalic primordial dwarfism disorder. Hitherto, the clinical manifestation of ATR deficiency has been attributed to its canonical role in DNA damage response signalling following replication fork stalling/collapse. Here, we show that ATR regulates cilia-dependent signalling in a manner that can be uncoupled from its function during replication. ATR-depleted or patient-derived ATR-SS cells form cilia of slightly reduced length but are dramatically impaired in cilia-dependent signalling functions, including growth factor and Son...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Stiff, T., Casar Tena, T., O'Driscoll, M., Jeggo, P. A., Philipp, M. Tags: ARTICLES Source Type: research
