{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The glycyl‐tRNA synthetase encoded by GARS1 is best known for its canonical role in protein synthesis by catalyzing the attachment of glycine to its cognate tRNA. However, studies in human patients and animal models have revealed that, in addition to its essential housekeeping function, mutant GlyRS acquires novel, toxic activities that underlie a selective degeneration of peripheral neurons. Dominant mutations in GARS1 cause forms of Charcot–Marie–Tooth disease type 2D and distal spinal muscular atrophy, in which the mutant enzyme retains aminoacylation activity yet displays aberrant interactions with key signaling receptors such as neuropilin‐1 that disrupt vascular endothelial growth factor signaling, and altered dimerization or mislocalization that compromises axonal integrity and neuromuscular junction architecture."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": " Moreover, structural analyses of wild‐type and mutant GlyRS have uncovered subtle long‐range effects—such as strengthened dimer interfaces—that may further contribute to the “gain‐of‐toxic‐function” phenotype. Together, these observations indicate that while GARS1 is indispensable for protein translation, mutations in this gene provoke deleterious neomorphic activities that specifically impact the nervous system, leading to axonal transport defects, impaired synaptic transmission, and ultimately, peripheral neuropathy.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kevin L Seburn, Leslie A Nangle, Gregory A Cox, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2006.08.027"}], "href": "https://doi.org/10.1016/j.neuron.2006.08.027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16982418"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16982418"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Leslie A Nangle, Wei Zhang, Wei Xie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0705055104"}], "href": "https://doi.org/10.1073/pnas.0705055104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17595294"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17595294"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Francesca Achilli, Virginie Bros-Facer, Hazel P Williams, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dis Model Mech (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dmm.002527"}], "href": "https://doi.org/10.1242/dmm.002527"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19470612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19470612"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Klaus Hirzel, Ulrike Müller, A Tobias Latal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hyperekplexia phenotype of glycine receptor alpha1 subunit mutant mice identifies Zn(2+) as an essential endogenous modulator of glycinergic neurotransmission."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2006.09.035"}], "href": "https://doi.org/10.1016/j.neuron.2006.09.035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17114051"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17114051"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wei Xie, Leslie A Nangle, Wei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0703908104"}], "href": "https://doi.org/10.1073/pnas.0703908104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17545306"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17545306"}]}]}]}