Clinical and pathological observations in men lacking the gap junction protein connexin 32

The X-linked form of Charcot-Marie-Tooth disease has been associated with m utations in the connexin 32 (Cx 32) gene, which encodes a gap junction prot ein. The majority of identified mutations are missense, but a few nonsense mutations or frame-shifting microdeletions have been encountered. Functiona l assessments of the mutated gap junction protein have demonstrated altered or simple losses of function. Mutations segregate with a typical clinical phenotype, which is the result of an age-related, progressive neuropathy. T he mechanisms that cause the nerve damage are unknown. This report describe s the consequences of a unique deletion mutation that eliminates the entire coding sequence of Cx 32, resulting in the absence of the Cx 32 gap juncti on protein in affected, hemizygous men. The clinical expression of this uni que mutation was studied by the clinical, electrophysiological, and patholo gical evaluation of this kinship of five generations. The resulting severe neuropathy combines features of demyelination, notably in paranodal distrib ution, and distal accentuated axonal degeneration. The predicted absence of Cx 32 gap junctions is shown to be associated with a severe dysfunction of the axon-Schwann cell unit, Observed changes resemble those of Cx 32-null mice. No central nervous system changes were demonstrated. (C) 2000 John Wi ley & Sons, Inc.