GARS1 – Charcot-Marie-Tooth disease type 2D

Autosomal dominant mutations in GARS1 (HGNC:4162) cause Charcot-Marie-Tooth disease type 2D (CMT2D), an axonal peripheral neuropathy with upper limb predominance ([PMID:26000875]). Clinical validity is supported by segregation of heterozygous missense variants across multiple pedigrees and de novo events. In a Chinese family, eight members manifested adolescent‐onset hand weakness and distal atrophy with minor sensory involvement ([PMID:26000875]). A Malian pedigree showed two affected siblings with hand muscle atrophy and NCS-confirmed axonal neuropathy ([PMID:31173493]). Infantile‐onset cases in a Chinese family with germline mosaicism and de novo presentations further underscore pathogenicity ([PMID:34898052], [PMID:26244500]). A cohort of eight unrelated patients demonstrates consistent phenotype variability and supports a definitive gene–disease relationship ([PMID:31985473]).

Heterozygous GARS1 variants are exclusively missense changes clustering in the catalytic and anticodon-binding domains. Notable alleles include c.999G>T (p.Glu333Asp) in the Chinese family ([PMID:26000875]), c.794C>A (p.Ser265Tyr) in the Malian pedigree ([PMID:31173493]), and c.997G>C (p.Glu333Gln) in germline mosaicism cases ([PMID:34898052]). De novo mutations such as c.598G>A (p.Asp200Asn) and c.598G>T (p.Asp200Tyr) cause severe early‐onset neuropathy ([PMID:26244500]). No loss-of-function or truncating alleles have been implicated, consistent with dominant toxic gain-of-function.

Functional assays demonstrate impaired GlyRS enzymatic activity and mislocalization. Yeast complementation and tRNA charging assays for nine CMT-associated variants reveal loss-of-function features ([PMID:25168514]). In hiPSC-derived motor neurons bearing p.Pro724His, acetylated α-tubulin levels and mitochondrial mobility are reduced, and HDAC6 inhibitors rescue these deficits ([PMID:34958183]).

Animal and cellular models recapitulate human neuropathy. Gars(C201R) mice exhibit reduced peripheral nerve axon diameter, slowed conduction, and NMJ denervation ([PMID:19470612]). In transversus abdominis muscles, NMJ maturation defects precede synaptic loss, highlighting early developmental vulnerability ([PMID:24368416]).

One variant, p.Ser581Leu, fails to impair GlyRS function, does not segregate with disease, and occurs in population databases, supporting its benign classification ([PMID:25168514]). No other studies dispute the GARS1–CMT2D association.

Overall, autosomal dominant GARS1 missense mutations converge on a gain-of-function pathogenic mechanism, with both loss of canonical tRNA-charging activity and neomorphic interactions driving selective peripheral axon degeneration. Definitive genetic and concordant functional evidence justify inclusion of GARS1 in diagnostic neuropathy panels. Key Take-home: GARS1 variant testing enables precise CMT2D diagnosis and informs genetic counseling.

References

• Neurological research | 2015 | A novel mutation of the glycyl-tRNA synthetase (GARS) gene associated with Charcot-Marie-Tooth type 2D in a Chinese family. PMID:26000875
• Molecular genetics & genomic medicine | 2019 | A novel mutation in the GARS gene in a Malian family with Charcot-Marie-Tooth disease. PMID:31173493
• Molecular genetics & genomic medicine | 2022 | Infantile-onset CMT2D/dSMA-V in a Chinese family with parental germline mosaicism for a novel mutation in the GARS1 gene. PMID:34898052
• Journal of neurogenetics | 2024 | A familial form of Charcot-Marie-Tooth disease (type 2d) caused by a previously unreported variant in GARS1. PMID:39599995
• PloS one | 2015 | Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease. PMID:26244500
• Journal of neuromuscular diseases | 2020 | Clinical and Genetic Features in a Series of Eight Unrelated Patients with Neuropathy Due to Glycyl-tRNA Synthetase (GARS) Variants. PMID:31985473
• Human mutation | 2014 | Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations. PMID:25168514
• Advanced biology | 2022 | HDAC6 Inhibition Corrects Electrophysiological and Axonal Transport Deficits in a Human Stem Cell-Based Model of Charcot-Marie-Tooth Disease (Type 2D). PMID:34958183
• Disease models & mechanisms | 2009 | 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. PMID:19470612
• Human molecular genetics | 2014 | Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice. PMID:24368416

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