The transcription coactivator ASC-1 is a regulator of skeletal myogenesis, and its deficiency causes a novel form of congenital muscle disease
Despite recent progress in the genetic characterization of congenital muscle diseases, the genes responsible for a significant proportion of cases remain unknown. We analysed two branches of a large consanguineous family in which four patients presented with a severe new phenotype, clinically marked by neonatal-onset muscle weakness predominantly involving axial muscles, life-threatening respiratory failure, skin abnormalities and joint hyperlaxity without contractures. Muscle biopsies showed the unreported association of multi-minicores, caps and dystrophic lesions. Genome-wide linkage analysis followed by gene and exome ...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Davignon, L., Chauveau, C., Julien, C., Dill, C., Duband-Goulet, I., Cabet, E., Buendia, B., Lilienbaum, A., Rendu, J., Minot, M. C., Guichet, A., Allamand, V., Vadrot, N., Faure, J., Odent, S., Lazaro, L., Leroy, J. P., Marcorelles, P., Dubourg, O., Ferr Tags: ARTICLES Source Type: research
Megalencephalic leukoencephalopathy with subcortical cysts protein-1 regulates epidermal growth factor receptor signaling in astrocytes
Mutations in the MLC1 gene, which encodes a protein expressed in brain astrocytes, are the leading cause of MLC, a rare leukodystrophy characterized by macrocephaly, brain edema, subcortical cysts, myelin and astrocyte vacuolation. Although recent studies indicate that MLC1 protein is implicated in the regulation of cell volume changes, the exact role of MLC1 in brain physiology and in the pathogenesis of MLC disease remains to be clarified. In preliminary experiments, we observed that MLC1 was poorly expressed in highly proliferating astrocytoma cells when compared with primary astrocytes, and that modulation of MLC1 expr...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Lanciotti, A., Brignone, M. S., Visentin, S., De Nuccio, C., Catacuzzeno, L., Mallozzi, C., Petrini, S., Caramia, M., Veroni, C., Minnone, G., Bernardo, A., Franciolini, F., Pessia, M., Bertini, E., Petrucci, T. C., Ambrosini, E. Tags: ARTICLES Source Type: research
Dimerization is required for GARS-mediated neurotoxicity in dominant CMT disease
Charcot–Marie–Tooth (CMT) disease is a genetically heterogeneous group of peripheral neuropathies. Mutations in several aminoacyl-tRNA synthetase (ARS) genes have been implicated in inherited CMT disease. There are 12 reported CMT-causing mutations dispersed throughout the primary sequence of the human glycyl-tRNA synthetase (GARS). While there is strong genetic evidence linking GARS mutations to CMT disease, the molecular pathology underlying the neuromuscular and sensory phenotypes is still not fully understood. In particular, it is unclear whether the mutations result in a toxic gain of function, a partial l...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Malissovas, N., Griffin, L. B., Antonellis, A., Beis, D. Tags: ARTICLES Source Type: research
The effect of non-coding DNA variations on P53 and cMYC competitive inhibition at cis-overlapping motifs
In this study, genome-wide analysis of ChIP-seq data from human cancer and mouse embryonic cells identified a significant number of putative regulatory elements with signals for both P53 and cMYC. Each co-occupied element contains, on average, two COMs, and one common SNP every two COMs. Gene ontology of predicted target genes for COMs showed that the majority are involved in DNA damage, apoptosis, cell cycle regulation, and RNA processing. EMSA results showed that both cMYC and P53 bind to cis-overlapping motifs within a ChIP-seq co-occupied region in Chr12. In vitro functional analysis of selected co-occupied elements ve...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Kin, K., Chen, X., Gonzalez-Garay, M., Fakhouri, W. D. Tags: ARTICLES Source Type: research
NLRP3 inflammasome activation drives bystander cone photoreceptor cell death in a P23H rhodopsin model of retinal degeneration
The molecular signaling leading to cell death in hereditary neurological diseases such as retinal degeneration is incompletely understood. Previous neuroprotective studies have focused on apoptotic pathways; however, incomplete suppression of cell death with apoptosis inhibitors suggests that other mechanisms are at play. Here, we report that different signaling pathways are activated in rod and cone photoreceptors in the P23H rhodopsin mutant rat, a model representing one of the commonest forms of retinal degeneration. Up-regulation of the RIP1/RIP3/DRP1 axis and markedly improved survival with necrostatin-1 treatment hig...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Viringipurampeer, I. A., Metcalfe, A. L., Bashar, A. E., Sivak, O., Yanai, A., Mohammadi, Z., Moritz, O. L., Gregory-Evans, C. Y., Gregory-Evans, K. Tags: ARTICLES Source Type: research
Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect in Golgi manganese homeostasis
This study not only provides novel insights into the molecular causes of glycosylation defects observed in TMEM165-deficient cells but also suggest that TMEM165 is a key determinant for the regulation of Golgi Mn2+ homeostasis. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Potelle, S., Morelle, W., Dulary, E., Duvet, S., Vicogne, D., Spriet, C., Krzewinski-Recchi, M.-A., Morsomme, P., Jaeken, J., Matthijs, G., De Bettignies, G., Foulquier, F. Tags: ARTICLES Source Type: research
Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa
A growing number of human diseases have been linked to defects in protein glycosylation that affects a wide range of organs. Among them, O-mannosylation is an unusual type of protein glycosylation that is largely restricted to the muscular and nerve system. Consistently, mutations in genes involved in the O-mannosylation pathway result in infantile-onset, severe developmental defects involving skeleton muscle, brain and eye, such as the muscle–eye–brain disease (MIM no. 253280). However, the functional importance of O-mannosylation in these tissues at later stages remains largely unknown. In our study, we have ...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Xu, M., Yamada, T., Sun, Z., Eblimit, A., Lopez, I., Wang, F., Manya, H., Xu, S., Zhao, L., Li, Y., Kimchi, A., Sharon, D., Sui, R., Endo, T., Koenekoop, R. K., Chen, R. Tags: ARTICLES Source Type: research
Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach
Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double h...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Marsollier, A.-C., Ciszewski, L., Mariot, V., Popplewell, L., Voit, T., Dickson, G., Dumonceaux, J. Tags: ARTICLES Source Type: research
Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer
This study investigates IIP pathophysiology in 12 families affected by IPF and lung cancer. We identified, in a multigenerational family, nine members carrying a heterozygous missense mutation with evidence of pathogenicity in SFTPA1 that encodes the surfactant protein (SP)-A1. The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated IIP/IPF, or IPF associated with lung adenocarcinoma, is located in the carbohydrate recognition domain (CRD) of SP-A1 and involves a residue invariant throughout evolution, not only in SP-A1, but also in its close paralog SP-A2 and other CRD-contai...
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Nathan, N., Giraud, V., Picard, C., Nunes, H., Dastot-Le Moal, F., Copin, B., Galeron, L., De Ligniville, A., Kuziner, N., Reynaud-Gaubert, M., Valeyre, D., Couderc, L.-J., Chinet, T., Borie, R., Crestani, B., Simansour, M., Nau, V., Tissier, S., Duquesno Tags: ARTICLES Source Type: research
Contents Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 22, 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 - March 22, 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 - March 22, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
Gene therapy for lysosomal storage disorders: a good start
Lysosomal storage disorders (LSDs) are a heterogeneous group of inherited diseases with a collective frequency of ~1 in 7000 births, resulting from the deficiency in one or more enzymes or transporters that normally reside within the lysosomes. Pathology results from the progressive accumulation of uncleaved lipids, glycoproteins and/or glycosaminoglycans in the lysosomes and secondary damages that affect the brain, viscera, bones and connective tissues. Most treatment modalities developed for LSD, including gene therapy (GT), are based on the lysosome-specific cross-correction mechanism, by which close proximity of normal...
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: Biffi, A. Tags: INVITED REVIEWS Source Type: research
Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia
RNA-targeting approaches are emerging as viable therapeutics that offer an alternative method to modulate traditionally ‘undrugable’ targets. In the case of dominantly inherited neurodegenerative diseases, gene suppression strategies can target the underlying cause of these intractable disorders. Polyglutamine diseases are caused by CAG expansions in discrete genes, making them ideal candidates for gene suppression therapies. Here, we discuss the current state of gene suppression approaches for Huntington's disease and the spinocerebellar ataxias, including the use of antisense oligonucleotides, short-interferi...
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: Keiser, M. S., Kordasiewicz, H. B., McBride, J. L. Tags: INVITED REVIEWS Source Type: research
