Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits
Prader–Willi syndrome (PWS) is a genetic disorder characterized by a variety of physiological and behavioral dysregulations, including hyperphagia, a condition that can lead to life-threatening obesity. Feeding behavior is a highly complex process with multiple feedback loops that involve both peripheral and central systems. The arcuate nucleus of the hypothalamus (ARH) is critical for the regulation of homeostatic processes including feeding, and this nucleus develops during neonatal life under of the influence of both environmental and genetic factors. Although much attention has focused on the metabolic and behavi...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Maillard, J., Park, S., Croizier, S., Vanacker, C., Cook, J. H., Prevot, V., Tauber, M., Bouret, S. G. Tags: ARTICLES Source Type: research
Differential molecular and behavioural alterations in mouse models of GABRG2 haploinsufficiency versus dominant negative mutations associated with human epilepsy
Genetic epilepsy is a common disorder with phenotypic variation, but the basis for the variation is unknown. Comparing the molecular pathophysiology of mutations in the same epilepsy gene may provide mechanistic insights into the phenotypic heterogeneity. GABRG2 is an established epilepsy gene, and mutations in it produce epilepsy syndromes with varying severities. The disease phenotype in some cases may be caused by simple loss of subunit function (functional haploinsufficiency), while others may be caused by loss-of-function plus dominant negative suppression and other cellular toxicity. Detailed molecular defects and th...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Warner, T. A., Shen, W., Huang, X., Liu, Z., Macdonald, R. L., Kang, J.-Q. Tags: ARTICLES Source Type: research
Sustained AMPK activation improves muscle function in a mitochondrial myopathy mouse model by promoting muscle fiber regeneration
Acute pharmacological activation of adenosine monophosphate (AMP)-kinase using 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) has been shown to improve muscle mitochondrial function by increasing mitochondrial biogenesis. We asked whether prolonged AICAR treatment is beneficial in a mouse model of slowly progressing mitochondrial myopathy (Cox10-Mef2c-Cre), and whether the compensatory mechanism is indeed an increase in mitochondrial biogenesis. We treated the animals for 3 months and found that sustained AMP-dependent kinase activation improved cytochrome c oxidase activity, rescued the motor phenotype and de...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Peralta, S., Garcia, S., Yin, H. Y., Arguello, T., Diaz, F., Moraes, C. T. Tags: ARTICLES Source Type: research
A Drosophila model of Huntington disease-like 2 exhibits nuclear toxicity and distinct pathogenic mechanisms from Huntington disease
Huntington disease-like 2 (HDL2) and Huntington disease (HD) are adult-onset neurodegenerative diseases characterized by movement disorders, psychiatric disturbances and cognitive decline. Brain tissue from HD and HDL2 patients shows degeneration of the striatum and ubiquitinated inclusions immunoreactive for polyglutamine (polyQ) antibodies. Despite these similarities, the diseases result from different genetic mutations. HD is caused by a CAG repeat expansion in the huntingtin (HTT) gene, while HDL2 results from an expansion at the junctophilin 3 (JPH3) locus. Recent evidence indicates that the HDL2 expansion may give ri...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Krench, M., Cho, R. W., Littleton, J. T. Tags: ARTICLES Source Type: research
iPSC-derived LewisX+CXCR4+{beta}1-integrin+ neural stem cells improve the amyotrophic lateral sclerosis phenotype by preserving motor neurons and muscle innervation in human and rodent models
Amyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs), leading to relentless muscle paralysis. In the early stage of the disease, MN loss and consequent muscle denervation are compensated by axonal sprouting and reinnervation by the remaining MNs, but this mechanism is insufficient in the long term. Here, we demonstrate that induced pluripotent stem cell-derived neural stem cells (NSCs), in particular the subpopulation positive for LewisX-CXCR4-β1-integrin, enhance neuronal survival and axonal growth of human ALS-derived MNs ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Nizzardo, M., Bucchia, M., Ramirez, A., Trombetta, E., Bresolin, N., Comi, G. P., Corti, S. Tags: ARTICLES Source Type: research
The unconventional secretion of ARMS2
In conclusion, in this work we show that ARMS2 is externalized via an unconventional pathway bypassing Golgi. Its intracellular separation from the classical secretion pathway suggests that the maturation of the protein requires a specific biochemical niche and/or may be needed to impede the premature formation of unwanted protein-protein interactions. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Kortvely, E., Hauck, S. M., Behler, J., Ho, N., Ueffing, M. Tags: ARTICLES Source Type: research
Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: ARTICLES Source Type: research
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Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: ARTICLES Source Type: research
Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: ARTICLES Source Type: research
Front Cover
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: ARTICLES Source Type: research
An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma
To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SNPs in 1,583 cases and 2,979 controls of southern Chinese ancestry revealed 1,257 top SNPs to be associated with NPC, which were brought forward for validation in 1,925 cases and 1,947 controls of southern Chinese. Further, 11 SNPs were selected for another independent validation in 3,538 cases and 3,644 contro...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Cui, Q., Feng, Q.-S., Mo, H.-Y., Sun, J., Xia, Y.-F., Zhang, H., Foo, J. N., Guo, Y.-M., Chen, L.-Z., Li, M., Liu, W.-S., Xu, M., Zhou, G., He, F., Yu, X., Jia, W.-H., Liu, J., Zeng, Y.-X., Bei, J.-X. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Lebers hereditary optic neuropathy-associated mitochondrial DNA mutation
In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p. 58I > V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G > A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T > C and m.11778G > A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G > A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less o cells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T > C mutations, only m.14502T > C o...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Jiang, P., Liang, M., Zhang, C., Zhao, X., He, Q., Cui, L., Liu, X., Sun, Y.-H., Fu, Q., Ji, Y., Bai, Y., Huang, T., Guan, M.-X. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells
Niemann-Pick type C disease (NP-C) is a progressive lysosomal lipid storage disease caused by mutations in the NPC1 and NPC2 genes. NPC1 is essential for transporting cholesterol and other lipids out of lysosomes, but little is known about the mechanisms that control its cellular abundance and localization. Here we show that a reduction of TMEM97, a cholesterol-responsive NPC1-binding protein, increases NPC1 levels in cells through a post-transcriptional mechanism. Reducing TMEM97 through RNA-interference reduces lysosomal lipid storage and restores cholesterol trafficking to the endoplasmic reticulum in cell models of NP-...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Ebrahimi-Fakhari, D., Wahlster, L., Bartz, F., Werenbeck-Ueding, J., Praggastis, M., Zhang, J., Joggerst-Thomalla, B., Theiss, S., Grimm, D., Ory, D. S., Runz, H. Tags: ARTICLES Source Type: research
Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta
This study demonstrates for the first time that AMTN mutations cause non-syndromic human AI and explores the human phenotype, comparing it with that of mice with disrupted Amtn function. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Smith, C. E. L., Murillo, G., Brookes, S. J., Poulter, J. A., Silva, S., Kirkham, J., Inglehearn, C. F., Mighell, A. J. Tags: ARTICLES Source Type: research
Ectodysplasin signalling deficiency in mouse models of hypohidrotic ectodermal dysplasia leads to middle ear and nasal pathology
We report that otitis media, rhinitis and nasopharyngitis occur at high frequency in Eda and Edar mutant mice and explore the pathogenic mechanisms related to glandular function, microbial and immune parameters in these lines. Nasopharynx auditory tube glands fail to develop in HED mutant mice and the functional implications include loss of lysozyme secretion, reduced mucociliary clearance and overgrowth of nasal commensal bacteria accompanied by neutrophil exudation. Heavy nasopharynx foreign body load and loss of gland protection alters the auditory tube gating function and the auditory tubes can become pathologically di...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Azar, A., Piccinelli, C., Brown, H., Headon, D., Cheeseman, M. Tags: ARTICLES Source Type: research
