Abstract
bioRxiv [Preprint]. 2026 Jul 9:2026.07.05.736541. doi: 10.64898/2026.07.05.736541.
ABSTRACT
Charcot-Marie-Tooth disease type 2D (CMT2D) results from gain-of-function mutations in GARS1, which encodes glycyl-tRNA synthetase (GlyRS), the enzyme responsible for charging transfer RNA (tRNA) with glycine. There are several CMT2D mouse models, but Gars ΔETAQ/+ is the only one that bears a patient-sourced mutation. Created using CRISPR/Cas9 to model a 12-nucleotide de novo GARS1 deletion identified in an unusually severe CMT2D patient, Gars ΔETAQ/+ mice have previously been shown to display several neuromuscular phenotypes; motor axon loss, denervated neuromuscular junctions (NMJs) and reduced muscle function. Here, we extend these analyses to provide a more comprehensive understanding of both motor and sensory nerve deficits across hind- and fore-limbs. At 3 months, Gars ΔETAQ/+ mice possess sex-independent alterations in the levels of neuropathy biomarkers - including decreased NfL and increased periaxin - alongside reduced muscle endurance and strength, and impairments in the sensory modalities of mechanosensation, proprioception and nociception. Underpinning these dysfunctions, we identified site-specific defects comprising altered sensory neuron populations, muscle spindle loss, reduced motor neuron size, disrupted NMJ innervation and maturation, and reduced axonal transport of signalling endosomes in vivo. Together, these experiments show that Gars ΔETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion, priming this CMT2D allele for testing treatments and evaluating mechanisms underlying peripheral nerve vulnerability.
PMID:42465429 | PMC:PMC13370441 | DOI:10.64898/2026.07.05.736541
UK DRI Authors
