Rab7 and the CMT2B disease

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Biochem Soc Trans. 2009 Oct;37(Pt 5):1027-31.

Rab7 and the CMT2B disease.

Cogli L, Piro F, Bucci C.

DiSTeBA (Department of Environmental and Biological Sciences and Technologies),

University of Salento, Via Provinciale Monteroni, 73100 Lecce, Italy.

The CMT2B (Charcot-Marie-Tooth type 2B) disease is an autosomal dominant axonal

neuropathy. Sensory loss, distal muscle weakness and wasting, frequent foot

ulcers and amputations of the toes due to frequent infections characterize this

neuropathy. Four missense mutations in the rab7 gene have been identified as

causative of the disease.

Rab7 is a small G-protein of the Rab family that controls vesicular transport to

late endosomes and lysosomes in the endocytic pathway. The CMT2B-associated

mutant Rab7 proteins show altered nucleotide dissociation rates and impaired

GTPase activity. In addition, these mutant proteins are predominantly in the

GTP-bound form when expressed in human cells and they are able to rescue Rab7

function in Rab7-depleted cells.

Thus these mutations generate activated forms of Rab7 that are responsible for

the development of the disease. In spite of these results, there are still

important gaps in our understanding of the mechanism underlying CMT2B. Indeed,

how these mutations in the rab7 gene affect specifically peripheral neurons

leading to an axonal pathology in CMT2B is not clear, and it is a particularly

puzzling and challenging issue in view of the fact that Rab7 is a ubiquitous

protein. The present review discusses possible molecular mechanisms underlying

CMT2B.