RAB7A – Charcot-Marie-Tooth disease type 2

Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy characterized by distal sensory loss, ulceromutilating complications, and variable motor involvement. RAB7A encodes a ubiquitously expressed small GTPase regulating late endocytic trafficking. Four missense variants (c.385C>T (p.Leu129Phe), c.471G>T (p.Lys157Asn), c.481A>G (p.Asn161Asp), c.484G>A (p.Val162Met)) have been identified in at least six probands across multiple families and segregate with Charcot-Marie-Tooth disease type 2 (PMID:18501189, PMID:18272684, PMID:20464402).

The inheritance pattern is autosomal dominant with segregation in four affected relatives. Linkage analyses exclude other CMT2 loci and confirm RAB7A involvement (PMID:9409358). The variant spectrum is restricted to gain-of-function missense alterations in conserved GTP-binding residues; no loss-of-function alleles have been reported.

Biochemical studies demonstrate that CMT2B-associated RAB7A mutants have elevated GTP loading, reduced hydrolysis, and enhanced effector interactions (e.g., RILP binding), leading to hyperactivation of endosomal trafficking (PMID:20028791, PMID:19754445). Cellular assays show impaired EGFR degradation, dysregulated NGF/TrkA signaling, and inhibited neurite outgrowth in PC12 and Neuro2A cells (PMID:20645406). Patient fibroblasts display altered autophagic flux and increased lysosomal activity (PMID:29130394).

In vivo modeling in Drosophila recapitulates sensory deficits and axonal transport delays upon neuronal expression of the p.Leu129Phe mutant, linking hyperactive Rab7 to impaired signaling endosome dynamics (PMID:24521780). Rescue experiments confirm that mutants dominantly activate Rab7 function after silencing of endogenous protein (PMID:18272684).

No conflicting reports dispute this association. The combination of robust segregation, variant recurrence, and extensive functional concordance supports a definitive gene-disease relationship.

Key take-home: Gain-of-function RAB7A missense mutations cause autosomal dominant CMT2B by hyperactivating endolysosomal trafficking and trophic signaling, underscoring the inclusion of RAB7A in diagnostic panels and the potential for targeting Rab7 activity therapeutically.

References

• Biochemical and biophysical research communications • 2008 • Characterization of the Rab7K157N mutant protein associated with Charcot-Marie-Tooth type 2B. PMID:18501189
• The Journal of neuroscience • 2008 • Functional characterization of Rab7 mutant proteins associated with Charcot-Marie-Tooth type 2B disease. PMID:18272684
• Acta neuropathologica • 2010 • CMT2B-associated Rab7 mutants inhibit neurite outgrowth. PMID:20464402
• Autophagy • 2018 • Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B. PMID:29130394
• Neurobiology of disease • 2014 • Human Rab7 mutation mimics features of Charcot-Marie-Tooth neuropathy type 2B in Drosophila. PMID:24521780
• Neurology • 1997 • Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A. PMID:9409358

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