Characterization of macrozoospermia-associated AURKC mutations in a mammalian meiotic system
This study is the first to assess the function of mutant alleles of AURKC that affect human fertility in a mammalian meiotic system. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Fellmeth, J. E., Ghanaim, E. M., Schindler, K. Tags: ARTICLES Source Type: research
Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is an important cause of dementia in individuals under age 65. Common variants in the TMEM106B gene were previously discovered by genome-wide association to confer genetic risk for FTLD-TDP (p = 1 x 10– 11, OR = 1.6). Furthermore, TMEM106B may act as a genetic modifier affecting age at onset and age at death in the Mendelian subgoup of FTLD-TDP due to expansions of the C9orf72 gene. Evidence suggests that TMEM106B variants increase risk for developing FTLD-TDP by increasing expression of Transmembrane Protein 106B (TMEM106B), a lysosomal protein. To ...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Busch, J. I., Unger, T. L., Jain, N., Tyler Skrinak, R., Charan, R. A., Chen-Plotkin, A. S. Tags: ARTICLES Source Type: research
BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE
Bestrophin1 (BEST1) is expressed in human retinal pigment epithelium (RPE) and mutations in the BEST1 gene commonly cause retinal dysfunction and macular degeneration. BEST1 is presumed to assemble into a calcium-activated chloride channel and be involved in chloride transport but there is no direct evidence in live human RPE cells to support this idea. To test whether BEST1 functions as a chloride channel in living tissue, BEST1-mutant RPE (R218H, L234P, A243T) were generated from patient-derived induced pluripotent stem cells and compared with wild-type RPE in a retinal environment, using a biosensor that visualizes calc...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Moshfegh, Y., Velez, G., Li, Y., Bassuk, A. G., Mahajan, V. B., Tsang, S. H. Tags: ARTICLES Source Type: research
CRISPR/Cas9-mediated mutation of PHEX in rabbit recapitulates human X-linked hypophosphatemia (XLH)
In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and precl...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Sui, T., Yuan, L., Liu, H., Chen, M., Deng, J., Wang, Y., Li, Z., Lai, L. Tags: ARTICLES Source Type: research
Glucocerebrosidase modulates cognitive and motor activities in murine models of Parkinsons disease
This study provides robust in vivo evidence that augmentation of CNS glucocerebrosidase activity is a potential therapeutic strategy for PD, regardless of the mutation status of GBA1. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Rockenstein, E., Clarke, J., Viel, C., Panarello, N., Treleaven, C. M., Kim, C., Spencer, B., Adame, A., Park, H., Dodge, J. C., Cheng, S. H., Shihabuddin, L. S., Masliah, E., Sardi, S. P. Tags: ARTICLES Source Type: research
Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype
Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency. A fundamental question in DMD pathogenesis and dystrophin gene therapy is whether muscle health depends on continuous dystrophin expression throughout the life. Published data suggest that transient dystrophin expression in early life might offer permanent protection. To study the consequences of adulthood dystrophin loss, we generated two strains of floxed mini-dystrophin transgenic mice on the dystrophin-null background. Muscle diseases were prevented in skeletal muscle of the YL238 strain and the heart of the SJ13 strain by selective expression of a t...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Wasala, N. B., Lai, Y., Shin, J.-H., Zhao, J., Yue, Y., Duan, D. Tags: ARTICLES Source Type: research
Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease
In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these fin...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Teo, R. T. Y., Hong, X., Yu-Taeger, L., Huang, Y., Tan, L. J., Xie, Y., To, X. V., Guo, L., Rajendran, R., Novati, A., Calaminus, C., Riess, O., Hayden, M. R., Nguyen, H. P., Chuang, K.-H., Pouladi, M. A. Tags: ARTICLES Source Type: research
Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Subscriptions Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Front Cover
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Genome-wide interrogation reveals hundreds of long intergenic noncoding RNAs that associate with cardiometabolic traits
Long intergenic noncoding RNAs (lincRNAs) play important roles in disease, but the vast majority of these transcripts remain uncharacterized. We defined a set of 54 944 human lincRNAs by drawing on four publicly available lincRNA datasets, and annotated ~2.5 million single nucleotide polymorphisms (SNPs) from each of 15 cardiometabolic genome-wide association study datasets into these lincRNAs. We identified hundreds of lincRNAs with at least one trait-associated SNP: 898 SNPs in 343 unique lincRNAs at 5% false discovery rate, and 469 SNPs in 146 unique lincRNAs meeting Bonferroni-corrected P < 0.05. An additional 64 tr...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Ballantyne, R. L., Zhang, X., Nunez, S., Xue, C., Zhao, W., Reed, E., Salaheen, D., Foulkes, A. S., Li, M., Reilly, M. P. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Genetic risk variants for autoimmune diseases that influence gene expression in thymus
In this study, we performed a cis expression quantitative trait locus (eQTL) screen restricted to 353 AID associated risk variants selected from the GWAS catalog to investigate whether these single nucleotide polymorphisms (SNPs) influence gene expression in thymus. Genotypes were obtained by Immunochip (Ichip) and tested against expression of surrounding genes (±1 Mb) in human thymic tissue (n = 42). We identified eight significant eQTLs located within seven genetic regions (FCRL3, RNASET2, C2orf74, NPIPB8, SIRPG, SYS1 and AJ006998.2) where the expression was associated with AID risk SNPs at a study-wide level of s...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Gabrielsen, I. S. M., Amundsen, S. S., Helgeland, H., Flam, S. T., Hatinoor, N., Holm, K., Viken, M. K., Lie, B. A. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
SUGP1 is a novel regulator of cholesterol metabolism
A large haplotype on chromosome 19p13.11 tagged by rs10401969 in intron 8 of SURP and G patch domain containing 1 (SUGP1) is associated with coronary artery disease (CAD), plasma LDL cholesterol levels, and other energy metabolism phenotypes. Recent studies have suggested that TM6SF2 is the causal gene within the locus, but we postulated that this locus could harbor additional CAD risk genes, including the putative splicing factor SUGP1. Indeed, we found that rs10401969 regulates SUGP1 exon 8 skipping, causing non-sense-mediated mRNA decay. Hepatic Sugp1 overexpression in CD1 male mice increased plasma cholesterol levels 2...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Kim, M. J., Yu, C.-Y., Theusch, E., Naidoo, D., Stevens, K., Kuang, Y.-L., Schuetz, E., Chaudhry, A. S., Medina, M. W. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Differential burden of rare protein truncating variants in Alzheimers disease patients compared to centenarians
We compared coding region variants of 53 cognitively healthy centenarians and 45 patients with Alzheimer’s disease (AD), all of Ashkenazi Jewish (AJ) ancestry. Despite the small sample size, the known AD risk variant APOE4 reached genome-wide significance, indicating the advantage of utilizing ‘super-controls’. We restricted our subsequent analysis to rare variants observed at most once in the 1000 Genomes database and having a minor allele frequency below 2% in our AJ sample. We compared the burden of predicted protein altering variants between cases and controls as normalized by the level of rare synony...
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Authors: Freudenberg-Hua, Y., Li, W., Abhyankar, A., Vacic, V., Cortes, V., Ben-Avraham, D., Koppel, J., Greenwald, B., Germer, S., T2D-GENES Consortium, Darnell, R. B., Barzilai, N., Freudenberg, J., Atzmon, G., Davies, P. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
