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Charcot-Marie-Tooth disease type 2B (CMT2B) is an autosomal dominant axonal neuropathy caused by missense mutations in the RAB7A gene, encoding a small GTPase that regulates late endosomal trafficking. Patients present with prominent sensory loss, frequent foot ulcers and infections, and variable motor involvement, with recent evidence indicating autonomic nervous system dysfunction in affected kindreds. CMT2B has been reported in at least four unrelated families harboring distinct RAB7A variants, with multiple affected individuals segregating the mutations in autosomal dominant pedigrees. Functional studies across cell and animal models support a gain-of-function mechanism in which mutated RAB7A proteins exhibit enhanced GTP binding, impaired GTP hydrolysis, and aberrant interactions with endosomal effectors, leading to altered receptor trafficking. In vivo modeling in Drosophila expressing the L129F variant recapitulates sensory and motor deficits and reveals defective axonal vesicle pausing, confirming the pathological impact of hyperactive RAB7A on neuronal function. Together, genetic and experimental data establish a definitive gene–disease relationship, underpinning molecular diagnostics and informing potential therapeutic strategies targeting RAB7A hyperactivation.
Gene–Disease AssociationDefinitiveMultiple unrelated families (≥4) with segregating RAB7A missense variants and concordant functional and animal model data Genetic EvidenceStrongFour distinct AD missense variants identified in multiple pedigrees with autosomal dominant segregation ([PMID:22971099], [PMID:18501189], [PMID:18272684]) Functional EvidenceModerateBiochemical and cellular assays demonstrate hyperactive GTPase behavior; Drosophila model recapitulates neuropathy phenotype |