X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry technique, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.

https://science.sciencemag.org/content/sci/262/5142/2039.full.pdf

Connexin mutations in X-linked Charcot-Marie-Tooth disease.

DNA deletion associated with hereditary neuropathy with liability to pressure palsies

A European collaboration on Charcot-Marie-Tooth type 1 (CMT1) disease and hereditary neuropathy with liability to pressure palsies (HNPP) was established to estimate the duplication and deletion frequency, respectively, on chromosome 17p11.2 and to make an inventory of mutations in the myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32) located on chromosomes 17p11.2, 1q21-q23 and Xq13.1, respectively. In 70.7% of 819 unrelated CMT1 patients, the 17p11.2 duplication was present. In 84.0% of 156 unrelated HNPP patients, the 17p11.2 deletion was present. In the nonduplicated CMT1 patients, several different mutations were identified in the myelin genes PMP22, MPZ and Cx32.

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Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study

P0, a major structural protein of peripheral myelin, is a homophilic adhesion molecule and maps to chromosome 1q22–q23, in the region of the locus for Charcot–Marie–Tooth neuropathy type 1B (CMT1B). We have investigated P0 as a candidate gene in two pedigrees with CMT1B and found point mutations which are completely linked with the disease (ẑ=5.5, Θ=0). The mutations, glutamate substitution for lysine 96 or aspartate 90, are located in the extracellular domain, which plays a significant role in myelin membrane adhesion. Individuals with CMT1B are heterozygous for the normal allele and the mutant allele. Our results indicate that P0 is a gene responsible for CMT1B.

Charcot–Marie–Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene

Charcot–Marie–Tooth disease 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy, associated with a DNA duplication on chromosome 17p11.2. A related disorder in the mouse, trembler (Tr), maps to mouse chromosome 11 which has syntenic homology to human chromosome 17p. Recently, the peripheral myelin protein–22 (pmp–22) gene was identified as the likely Tr locus. We have constructed a partial yeast artificial chromosome contig spanning the CMT1A gene region and mapped the PMP–22 gene to the duplicated region. These observations further implicate PMP–22 as a candidate gene for CMT1A, and suggest that over–expression of this gene may be one mechanism that produces the CMT1A phenotype.

Peripheral myelin protein–22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot–Marie–Tooth 1A

A large kindred with the X-linked dominant form of peroneal muscular atrophy (Charcot-Marie-Tooth disease) was analyzed for individual variation in the length of DNA fragments after restriction endonuclease digestion. A systematic search was performed for linkage with a series of cloned single-copy DNA sequences of known regional assignment to the human X chromosome. Close linkage was found with the pDP34 probe (DXYS1 locus, Xq13-q21), suggesting that the gene responsible for the disease is located on the proximal long arm of the X chromosome.

J. Mücke

Papers

X-linked dominant Charcot-Marie-Tooth disease: Suggestion of linkage with a cloned DNA sequence from the proximal Xq