CMT 1X: POG11 A novel mutation in the nerve-specific 5'-UTR of the Cx32 gene cau

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J Neurol Neurosurg Psychiatry. 2010 Nov;81(11):e50.

POG11 A novel mutation in the nerve-specific 5'-UTR of the Cx32 gene causing

CMTX1.

S, Brandner S, Polke J, Manji H, Houlden H, Reilly MM.

Abstract

CMTX1 is the second most common cause of Charcot-Marie-Tooth disease (CMT),

usually caused by mutations in the Cx32 gene. Cx32 has two tissue-specific

promoters: P1, specific for liver and pancreas, and P2 which is nerve specific.

Over 300 mutations have been described in Cx32, spread throughout the coding

region. However, 10% of CMTX1 families do not have mutations in the coding

region. To date, 5 noncoding region mutations have been reported.

describe two families with X-linked inheritance and a phenotype consistent with

CMTX1 who did not have mutations in the Cx32 coding region. Family 1 were

negative for mutations in PMP22, MPZ, SPTLC1 and GDAP1 Family 2 were negative

for mutations in MPZ and rearrangements at chromosome 17p11.2.

The noncoding region of Cx32 was sequenced and an upstream exon-splicing variant

found at c.-373G>A which segregated with the disease in both families. This

variant is located at the last base of the nerve-specific 5'UTR exon and thus

may disrupt splicing of the nerve-specific transcript.

Online consensus splice-site programs predict a reduced score for the mutant

sequence vs the normal sequence. Two other mutations have previously been

described within the 5'UTR region, which created a potential donor splice site

and were shown to prevent translation of mutant mRNA. It is likely that other

mutations within the Cx32 noncoding regions account for the CMTX1 families who

do not have coding region mutations.