X linked CMT Molecular Genetics

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Neuromolecular Med. 2006;8(1-2):107-22.

Molecular genetics of x-linked charcot-marie-tooth disease.

Kleopa KA, Scherer SS.

Department of Clinical Neurosciences, The Cyprus Institute of

Neurology and Genetics, Nicosia, Cyprus.

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.