Molecular basis of Charcot–Marie–Tooth type 2B disease

Abstract

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.

Rab7 regulates primary cilia disassembly through cilia excision

“…Thus, our research suggests a possible connection between Rab7 and cilia dynamics in early embryonic development. In addition, Rab7 is reported to promote protrusion and neurite outgrowth (BasuRay et al, 2010;Raiborg et al, 2015;Ponomareva et al, 2016), and mutations in Rab7 are well characterized as causing Charcot-Marie-Tooth syndrome type 2B (CMT2B; Cogli et al, 2009;Bucci and De Luca, 2012), a peripheral neuropathy with an unknown pathogenic mechanism. Given the existence of neuronal primary cilia (Lee and Gleeson, 2011;Guemez-Gamboa et al, 2014), further research is needed to investigate whether Rab7-mediated cilia disassembly can account for CMT2B pathogenesis.…”

Emerging nexus between RAB GTPases, autophagy and neurodegeneration

“…11 Cultured Purkinje neurons require the activity of RAB7A for efficient clearance of autophagosomes on trophic factor depletion. 12 Specifically, RAB7A facilitates the crosstalk between endosomes and autophagosomes.…”

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

“…1 , 2 The CMT type 2B (CMT2B) is a dominant axonal form caused by 5 mutations (L129F, K157N, N161T, V162M and the recently identified N161I) in the RAB7A gene, 3–6 and it is characterized by prominent sensory loss, lower legs muscle atrophy, high frequency of foot ulcers and recurrent infections leading to toe amputations. 7–9 …”