Mutations of the noncoding region of the connexin32 gene in X-linked dominant Charcot-Marie-Tooth neuropathy

Abstract

We studied two families with X-linked dominant Charcot-Marie-Tooth neuropathy. The clinical findings included onset around age 14 years, with moderate weakness of feet extensors and palmar and dorsal interossei, areflexia, distal hypesthesia, and slow progressivity. Motor nerve conduction velocities showed slowing (20 to 30 m/sec) and EMGs were normal. Genetic linkage analysis revealed positive lod scores with the markers of the Xq13.1 region in family 2, but was noninformative in family 1. There were no point mutations in the connexin32 gene coding region. Instead, family 1 revealed a T-to-G transversion at position -528 relative to the ATG start codon, whereas family 2 showed a C-to-T transition at position -458. The first mutation is located in the nerve-specific connexin32 promoter just upstream of the transcription start site, the second is located in the 5' untranslated region of the mRNA.

New Ways of Initiating Translation in Eukaryotes?

“…In the resulting mRNA, the elongated upORF overlaps the connexin 32 start site, thereby precluding reinitiation. This could explain the inability to translate connexin 32 in patients with Charcot-Marie-Tooth neuropathy (32).…”

Analysis of a Charcot-Marie-Tooth Disease Mutation Reveals an Essential Internal Ribosome Entry Site Element in the Connexin-32 Gene

“…Whereas most of the mutations that were found in patients with CMTX are located in the coding region of the connexin-32 gene, a few non-coding mutations were also described. One of these mutations, a C3 T transition found at position Ϫ458 in relation to the start codon, called mut-2 throughout this paper, was found in a family of CMTX patients (18). It resides in the 5Ј-UTR of the connexin-32 mRNA.…”

Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: Characterization of 14 C×32 mutations in 35 families

“…The absence of male-tomale transmission in large CMT pedigrees suggests X-linked disease (Hahn et al, 1990;Ionasescu, 1995). CMTX is mostly associated with mutations in exon 2 of the connexin 32 (C×32) gene mapped to chromosome Xq13 (Bergoffen et al, 1993a,b;Cherryson et al, 1994;Fairweather et al, 1994;Ionasescu et al, 1994Ionasescu et al, , 1996Orth et al, 1994;LeGuern et al, 1994;Bone et al, 1995;Nelis et al, 1996;Oterino et al, 1996;Tan et al, 1996;Schiavon et al, 996). The1,574-base pair (bp) cDNA of the C×32 gene encodes a 32-kDa protein, which is a member of the family of membrane-spanning proteins that assemble to form gap junctions (Kumar and Gilula, 1986).…”

“…These results demonstrate the high frequency (40%) of mutations in the coding region of the C×32 gene in CMT patients with intermediate MNCV that can be detected by SSCP. The remaining patients, however, might present mutations in the 5' regulatory sequence of C×32 (Ionasescu et al, 1996) in the Po and PMP22 genes, or in other genes that remain to be determined.…”