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Marshalling evidence from multiple independent studies, mutations in MARS (HGNC:6898) have been robustly associated with Charcot-Marie-Tooth disease (MONDO_0015626), a progressive peripheral neuropathy. The disorder is characterized by motor and sensory deficits with features such as unsteady gait and pes cavus, underscoring the clinical heterogeneity of the disease (PMID:27717217).
Several case reports have identified heterozygous missense variants in MARS in patients presenting with CMT. For instance, a 13-year-old girl with progressive bilateral leg weakness was found to carry the c.2209C>T (p.Arg737Trp) mutation, and another study reported a patient with early childhood-onset CMT harboring the c.1189G>A (p.Ala397Thr) variant. These findings are further supported by additional reports describing a p.P800T mutation, with segregation analyses in affected families confirming an autosomal dominant inheritance pattern (PMID:29582526).
Family segregation data across multiple pedigrees reveal that the identified MARS variants co‐segregate with the disease phenotype over successive generations, with several affected relatives demonstrating clinical and electrophysiological abnormalities. This cumulative data from case reports and family studies provides compelling genetic evidence for a direct association between MARS mutations and CMT (PMID:31356216).
At the molecular level, the genetic evidence is reinforced by the identification of multiple pathogenic missense variants in key functional domains of MARS. The chosen variant, c.2209C>T (p.Arg737Trp), is one of several variants that disrupt the function of methionyl-tRNA synthetase, a disruption that is consistent with the underlying neuropathological findings observed in sural nerve biopsies. In-silico predictions and evolutionary conservation analyses further support the deleterious nature of these changes (PMID:29582526).
Functional studies have provided moderate yet supportive evidence with assays demonstrating abnormal protein activity, impaired tRNA charging, and corroborative structural modeling. These experimental results align with the clinical findings and underscore a mechanistic link between MARS dysfunction and the CMT phenotype, thereby bolstering the overall validity of the association (PMID:31356216).
In summary, the integrated genetic and functional evidence positions the MARS–Charcot-Marie-Tooth disease association in the strong ClinGen category. Key take‑home: MARS mutations serve as a robust molecular marker for autosomal dominant CMT, guiding diagnostic decision‑making, commercial genetic testing strategies, and informing future therapeutic research.
Gene–Disease AssociationStrongMultiple independent case reports and family studies, totaling at least 6 probands with autosomal dominant inheritance, support the association between MARS and Charcot-Marie-Tooth disease (PMID:27717217, PMID:29582526, PMID:31356216). Genetic EvidenceStrongAt least three distinct missense variants in MARS, including c.2209C>T (p.Arg737Trp) and c.1189G>A (p.Ala397Thr), have been identified in unrelated families; segregation analyses further reinforce pathogenicity. Functional EvidenceModerateExperimental assays such as yeast complementation, structural modeling, and nerve conduction studies demonstrate that MARS variants impair enzyme function, aligning with the CMT phenotype. |