UC San Diego

Charcot-Marie-Tooth type 2B (CMT2B) is a debilitating hereditary peripheral sensory neuropathy. Patients with this autosomal dominant disease lose pain sensation and experience muscle weakness and atrophy in distal limbs. Clinical manifestations of CMT2B include axonal dysfunction and degeneration of peripheral sensory neurons. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7, a regulator of late endocytic transport. Strong evidence suggests that CMT2B mutations enhance the cellular levels of activated Rab7 GTPase, thereby increasing lysosomal activity and autophagy. As a consequence, trafficking and signaling of neurotrophic factors such as nerve growth factor and epidermal growth factor in the long axons of peripheral sensory neurons are particularly vulnerable to premature degradation. A “gain of toxicity” model has, thus, been proposed based on these observations. In order to test the hypothesis that CMT2B mutations cause neural degeneration in a gene dosage-dependent, gain of toxicity manner, this study compares cutaneous autonomic innervation in footpad biopsies of wild-type, heterozygous and homozygous CMT2B mouse models. The results show significant neuronal degeneration associated with both disease genotypes compared to the wild-type control. In addition, disease phenotypes present in a gene dosage-dependent manner, with sensory deficits severely worsened in the homozygous model compared to the heterozygote. These results are consistent with data from previous behavioral tests showing a similar dosage-dependent effect of CMT2B mutant genes. Together, these findings affirm the gain of toxicity model of the disease and suggest that therapeutic development should aim to inhibit Rab7 hyperactivity in affected patients.