The role of gap junctions in Charcot-Marie-Tooth disease.

Introduction Charcot–Marie–Tooth disease (CMT) encompasses a group of mostly non-syndromic inherited peripheral motor and sensory neuropathies, which are genetically heterogeneous and have a prevalence of ϳ17– 40:100,000 world-wide— one of the most common neuro-genetic disorders (Martyn and Hughes, 1997). The X-linked form of CMT (CMT1X) is the second most common form among all CMT patients with a frequency of 7–18% (average 12% internationally) (Nicolaou et al., 2010; Braathen et al., 2011). CMT1X is caused by Ͼ400 different mutations in the GJB1 gene that encodes the gap junction (GJ) protein connexin32 (Cx32). Cx32 forms both in-tercellular (between adjacent cells), as well as intracellular, " reflexive " (between layers of the same cell) GJs in both peripheral and central myelinating cells that play an important role in the homeostasis of my-elinated axons. In vitro and in vivo models of the disease have demonstrated impaired formation of GJs by mutant Cx32 and that loss of Cx32 function accounts for the peripheral neuropathy. An effective therapy for CMT1X remains to be developed.