A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2
The most common congenital disorder of glycosylation (CDG), phosphomannomutase 2 (PMM2)-CDG, is caused by mutations in PMM2 that limit availability of mannose precursors required for protein N-glycosylation. The disorder has no therapy and there are no models to test new treatments. We generated compound heterozygous mice with the R137H and F115L mutations in Pmm2 that correspond to the most prevalent alleles found in patients with PMM2-CDG. Many Pmm2R137H/F115L mice died prenatally, while survivors had significantly stunted growth. These animals and cells derived from them showed protein glycosylation deficiencies similar...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Chan, B., Clasquin, M., Smolen, G. A., Histen, G., Powe, J., Chen, Y., Lin, Z., Lu, C., Liu, Y., Cang, Y., Yan, Z., Xia, Y., Thompson, R., Singleton, C., Dorsch, M., Silverman, L., Su, S.-S. M., Freeze, H. H., Jin, S. Tags: ARTICLES Source Type: research
Cell-type-specific miR-431 dysregulation in a motor neuron model of spinal muscular atrophy
Spinal muscular atrophy (SMA) is an autosomal-recessive pediatric neurodegenerative disease characterized by selective loss of spinal motor neurons. It is caused by mutation in the survival of motor neuron 1, SMN1, gene and leads to loss of function of the full-length SMN protein. microRNAs (miRNAs) are small RNAs that are involved in post-transcriptional regulation of gene expression. Prior studies have implicated miRNAs in the pathogenesis of motor neuron disease. We hypothesized that motor neuron-specific miRNA expression changes are involved in their selective vulnerability in SMA. Therefore, we sought to determine the...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Wertz, M. H., Winden, K., Neveu, P., Ng, S.-Y., Ercan, E., Sahin, M. Tags: ARTICLES Source Type: research
Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy
Intermediate filaments (IFs) are cytoskeletal polymers that extend from the nucleus to the cell membrane, giving cells their shape and form. Abnormal accumulation of IFs is involved in the pathogenesis of number neurodegenerative diseases, but none as clearly as giant axonal neuropathy (GAN), a ravaging disease caused by mutations in GAN, encoding gigaxonin. Patients display early and severe degeneration of the peripheral nervous system along with IF accumulation, but it has been difficult to link GAN mutations to any particular dysfunction, in part because GAN null mice have a very mild phenotype. We therefore established...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Israeli, E., Dryanovski, D. I., Schumacker, P. T., Chandel, N. S., Singer, J. D., Julien, J. P., Goldman, R. D., Opal, P. Tags: ARTICLES Source Type: research
FLNC myofibrillar myopathy results from impaired autophagy and protein insufficiency
This study therefore identifies both BAG3 reduction and autophagy promotion as potential therapies for FLNCW2710X myofibrillar myopathy, and identifies protein insufficiency due to sequestration, compounded by impaired autophagy, as the cause. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Ruparelia, A. A., Oorschot, V., Ramm, G., Bryson-Richardson, R. J. Tags: ARTICLES Source Type: research
Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Subscriptions Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Front Cover
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease
Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (~2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Offenbacher, S., Divaris, K., Barros, S. P., Moss, K. L., Marchesan, J. T., Morelli, T., Zhang, S., Kim, S., Sun, L., Beck, J. D., Laudes, M., Munz, M., Schaefer, A. S., North, K. E. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Integrated analyses of gene expression and genetic association studies in a founder population
Genome-wide association studies (GWASs) have become a standard tool for dissecting genetic contributions to disease risk. However, these studies typically require extraordinarily large sample sizes to be adequately powered. Strategies that incorporate functional information alongside genetic associations have proved successful in increasing GWAS power. Following this paradigm, we present the results of 20 different genetic association studies for quantitative traits related to complex diseases, conducted in the Hutterites of South Dakota. To boost the power of these association studies, we collected RNA-sequencing data fro...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Cusanovich, D. A., Caliskan, M., Billstrand, C., Michelini, K., Chavarria, C., De Leon, S., Mitrano, A., Lewellyn, N., Elias, J. A., Chupp, G. L., Lang, R. M., Shah, S. J., Decara, J. M., Gilad, Y., Ober, C. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription
The Werner syndrome (WS) is a prototypic adult Mendelian progeroid syndrome in which signs of premature aging are associated with genomic instability and an elevated risk of cancer. The WRN RECQ helicase protein binds and unwinds G-quadruplex (G4) DNA substrates in vitro, and we identified significant enrichment in G4 sequence motifs at the transcription start site and 5' ends of first introns (false discovery rate < 0.001) of genes down-regulated in WS patient fibroblasts. This finding provides strong evidence that WRN binds G4 DNA structures at many chromosomal sites to modulate gene expression. WRN appears to bind a ...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Tang, W., Robles, A. I., Beyer, R. P., Gray, L. T., Nguyen, G. H., Oshima, J., Maizels, N., Harris, C. C., Monnat, R. J. Tags: ARTICLES Source Type: research
Heterozygous mutation of Ush1g/Sans in mice causes early-onset progressive hearing loss, which is recovered by reconstituting the strain-specific mutation in Cdh23
Most clinical reports have suggested that patients with congenital profound hearing loss have recessive mutations in deafness genes, whereas dominant alleles are associated with progressive hearing loss (PHL). Jackson shaker (Ush1gjs) is a mouse model of recessive deafness that exhibits congenital profound deafness caused by the homozygous mutation of Ush1g/Sans on chromosome 11. We found that C57BL/6J-Ush1gjs/+ heterozygous mice exhibited early-onset PHL (ePHL) accompanied by progressive degeneration of stereocilia in the cochlear outer hair cells. Interestingly, ePHL did not develop in mutant mice with the C3H/HeN backgr...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Miyasaka, Y., Shitara, H., Suzuki, S., Yoshimoto, S., Seki, Y., Ohshiba, Y., Okumura, K., Taya, C., Tokano, H., Kitamura, K., Takada, T., Hibino, H., Shiroishi, T., Kominami, R., Yonekawa, H., Kikkawa, Y. Tags: ARTICLES Source Type: research
ARL3 regulates trafficking of prenylated phototransduction proteins to the rod outer segment
In conclusion, this study identifies ARL3 as a key player in prenylated protein trafficking in rod photoreceptor cells and establishes the potential role for ARL3 dysregulation in the pathogenesis of RP2-related forms of XLRP. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Wright, Z. C., Singh, R. K., Alpino, R., Goldberg, A. F. X., Sokolov, M., Ramamurthy, V. Tags: ARTICLES Source Type: research
DNA methylation profiling in human Huntington's disease brain
Despite extensive progress in Huntington's disease (HD) research, very little is known about the association of epigenetic variation and HD pathogenesis in human brain tissues. Moreover, its contribution to the tissue-specific transcriptional regulation of the huntingtin gene (HTT), in which HTT expression levels are highest in brain and testes, is currently unknown. To investigate the role of DNA methylation in HD pathogenesis and tissue-specific expression of HTT, we utilized the Illumina HumanMethylation450K BeadChip array to measure DNA methylation in a cohort of age-matched HD and control human cortex and liver tissue...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: De Souza, R. A. G., Islam, S. A., McEwen, L. M., Mathelier, A., Hill, A., Mah, S. M., Wasserman, W. W., Kobor, M. S., Leavitt, B. R. Tags: ARTICLES Source Type: research
Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR
Mutations in RPGR (retinitis pigmentosa GTPase regulator) are the most common cause of X-linked RP, a severe blindness disorder. RPGR mutations result in clinically variable disease with early- to late-onset phenotypic presentation. Molecular mechanisms underlying such heterogeneity are unclear. Here we show that phenotypic expression of Rpgr-loss in mice is influenced genetically by the loss of Cep290, a human ciliopathy gene. We found that Rpgrko/Y mice with a heterozygous hypomorphic allele of Cep290 (Cep290rd16/+) but not of a heterozygous null allele of Cep290 (Cep290null/+) or of other ciliopathy genes, Rpgrip1, Nphp...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Rao, K. N., Zhang, W., Li, L., Ronquillo, C., Baehr, W., Khanna, H. Tags: ARTICLES Source Type: research
