Two novel connexin32 mutations cause early onset CMT X

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Two novel connexin32 mutations cause early onset X-linked Charcot-

Marie-Tooth disease

Geir J Braathen , Jette C Sand , Geir Bukholm and B

BMC Neurology 2007, 7:19 doi:10.1186/1471-2377-7-19

Published 9 July 2007

http://www.biomedcentral.com/1471-2377/7/19

Abstract (provisional)

Background

X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the

connexin32 gene that encodes a polypeptide which is arranged in

hexameric array and form gap junctions.

Methods

We describe two novel mutations in the connexin32 gene in two

Norwegian families.

Results

Family 1 had a c.225delG (R75fsX83) which causes a frameshift and

premature stop codon at position 247. This probably results in a

shorter non-functional protein structure. Affected individuals had

an early age at onset usually in the first decade. The symptoms were

more severe in men than women. All had severe muscle weakness in the

legs. Several abortions were observed in this family. Family 2 had a

c.536 G>A (C179Y) transition which causes a change of the highly

conserved cysteine residue, i.e. disruption of at least one of three

disulfide bridges. The mean age at onset was in the first decade.

Muscle wasting was severe and correlated with muscle weakness in

legs. The men and one woman also had symptom from their hands. The

neuropathy is demyelinating and the nerve conduction velocities were

in the intermediate range (25-49 m/s). Affected individuals had

symmetrical clinical findings, while the neurophysiology revealed

minor asymmetrical findings in nerve conduction velocity in 6 of 10

affected individuals.

Conclusions

The two novel mutations in the connexin32 gene are more severe than

the majority of previously described mutations possibly due to the

severe structural change of the gap junction they encode.