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we have demonstrated that CMT2D mice display a pathological phenotype restricted to the nervous system, and that GlyRS-mediated disruption of Nrp1/VEGF-A signalling appears to be permissive to capillary maturation and maintenance.
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ignificant alterations of the vesicle-associated membrane protein-associated protein B (VAPB) and its downstream pathways such as mitochondrial calcium uptake and autophagy were detected in dominant GARS mutations. The role of VAPB has been supported by similar results in the GarsC210R mice. Our data suggest that altered mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) may be important disease mechanisms
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In support of GARS variant pathogenicity, our patient shows striking phenotypic overlap with other patients having ARS-related recessive diseases; this observation is consistent with the essential function of GARS in both cellular locations. In summary, our clinical, genetic, and functional analyses expand the phenotypic spectrum associated with GARS variants
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In this Chinese Han population a novel Charcot-Marie-Tooth disease-associated gene mutations of GARS (c.794C>T) was discovered.
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At the active site, a glycyl-AMP molecule is synthesized and is waiting for the transfer of the glycyl moiety to occur.
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GlyRS functions as a chaperone that critically supports neddylation.
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Data indicate that dimerization is required for the dominant neurotoxicity of disease-associated GARS mutations and provide a rapid, tractable model for studying newly identified GARS variants for a role in human disease.
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one of the mRNAs isoforms tightly controls expression and localization of human GARS.
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This study reports two crystal structures of human GlyRS variants, in the free form and in complex with tRNA(Gly) respectively, and reveal new aspects of the glycylation mechanism.
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GARS mutations are an uncommon cause of Charcot-Marie-Tooth Disease (CMT) in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT.
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Our findings suggest that mutant GlyRS gains access to ectopic sub-compartments of the motor neuron, providing a possible explanation for the selective neuropathology caused by mutations in a widely expressed gene.
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Expression of three CMT-mutant GARS proteins in Drosophila induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan.
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The c.999G>T mutation is a novel mutation of the glycyl-tRNA synthetase gene that has not been previously reported. The phenotype of this family is Charcot-Marie-Tooth disease type 2D, which is first reported in Chinese population.
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we propose that the disease-causing L129P mutant of glycyl-tRNA synthetase is linked to a distribution defect in peripheral nerves in vivo.
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our data indicate that impaired function is a key component of GARS-mediated CMT disease and emphasize the need for careful genetic and functional evaluation before implicating a variant in disease onset.
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This study presents genetic evidence for common mutant-specific interactions between two CMT-associated aminoacyl-tRNA synthetases, lending support for a shared mechanism responsible for the synthetase-induced peripheral neuropathies.
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We developed an ELISA to detect anti-glycyl-tRNA synthetase by using recombinant protein
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Report crystal structures of wild type and mutant GlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop.
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we believe that these two novel GARS mutations are the underlying causes of the distal hereditary motor neuropathy type V phenotype
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GRS bound to different ERK-activated tumor cells, and released phosphatase 2A (PP2A) from CDH6.