Point mutation associated with X-linked dominant Charcot-Marie-Tooth disease impairs the P2 promoter activity of human connexin-32 gene.

Abstract Many lines of evidence suggest that connexin-32 gap junction is involved in the exchange of information and metabolites in the peripheral nervous system. It has been shown that connexin-32 protein and mRNA are expressed in Schwann cells that function as myelinating cells of the peripheral nervous system. The physiological importance of connexin-32 gap junctions in regulating the normal function of myelinating Schwann cell is indicated by recent findings that X-linked dominant Charcot-Marie-Tooth disease, a hereditary peripheral neuropathy, is associated with the mutations of connexin-32 gene. Recently, we encountered a Taiwanese family affected with X-linked dominant Charcot-Marie-Tooth neuropathy. Therefore, we investigated the possible mutation in the coding and noncoding regions of the connexin-32 gene of affected members of this family. Our results suggest that a G-to-A transition at the position −215 (in relation to the transcription initiation site) of the nerve-specific P2 promoter region is associated with the pathogenesis of X-linked dominant Charcot-Marie-Tooth disease. Further experiments using the promoter assay indicate that G-to-A mutation at the position −215 greatly impairs the transcriptional activity of connexin-32 P2 promoter. These findings propose that a reduced expression of connexin-32 mRNA and protein in the myelin sheath could be responsible for the development of X-linked dominant Charcot-Marie-Tooth neuropathy.