CMT2B (Charcot–Marie–Tooth type 2B) disease is an autosomal dominant peripheral neuropathy whose onset is in the second or third decade of life, thus in adolescence or young adulthood. CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. Rab7 is a ubiquitous protein that regulates transport to late endosomes and lysosomes in the endocytic pathway. In neurons, Rab7 is important for endosomal trafficking and signalling of neurotrophins, and for retrograde axonal transport. Recent data on CMT2B-causing Rab7 mutant proteins show that these proteins exhibit altered koff rates and, as a consequence, they are mainly in the GTP-bound state and bind more strongly to Rab7 effector proteins. Notably, expression of CMT2B-causing Rab7 mutant proteins strongly inhibit neurite outgrowth in several cells lines and alter NGF (nerve growth factor) trafficking and signalling. These data indicate that Rab7 plays an essential role in neuronal cells and that CMT2B-causing Rab7 mutant proteins alter neuronal specific pathways, but do not fully explain why only peripheral neurons are affected in CMT2B. In the present paper, we discuss the current understanding of the molecular and cellular mechanisms underlying CMT2B, and we consider possible hypotheses in order to explain how alterations of Rab7 function lead to CMT2B.
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Conference Article| November 21 2012
Molecular basis of Charcot–Marie–Tooth type 2B disease
Cecilia Bucci 1
1Department of Environmental and Biological Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Monteroni 165, 73100 Lecce, Italy
1To whom correspondence should be addressed (firstname.lastname@example.org).
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Cecilia Bucci, Maria De Luca; Molecular basis of Charcot–Marie–Tooth type 2B disease. Biochem Soc Trans 1 December 2012; 40 (6): 1368–1372. doi: https://doi.org/10.1042/BST20120197
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