Molecular genetics of X-linked Charcot-Marie-Tooth disease.

The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common molecularly designated form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive distal muscle atrophy and weakness, areflexia, and variable sensory abnormalities. Affected males have moderate-to-severe symptoms, whereas heterozygous females are usually mildly affected or even asymptomatic. Several patients also have manifestations of central nervous system involvement or hearing impairment. Electrophysiological and pathological studies of peripheral nerves show evidence of demyelinating neuropathy with prominent axonal degeneration. A large number of mutations in the GJB1 gene encoding the gap junction (GJ) protein connexin32 (Cx32) cause CMT1X. Cx32 is expressed by Schwann cells and oligodendrocytes, as well as by other tissues, and the GJ formed by Cx32 play an important role in the homeostasis of myelinated axons. The reported CMT1X mutations are diverse and affect both the promoter region as well as the coding region of GJB1. Many Cx32 mutants fail to form functional GJ, or form GJ with abnormal biophysical properties. Furthermore, Cx32 mutants are often retained intracellularly either in the endoplasmic reticulum or Golgi in which they could potentially have additional dominant-negative effects. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. No definite phenotype-genotype correlation has yet been established for CMT1X and effective molecular based therapeutics for this disease, remain to be developed.