title: 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.
authors.affiliation: Department of Physiology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan, ROC. hlwns@mail.cgu.edu.tw
authors.forename: H L
authors.initials: HL
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Wu
authors.forename: W T
authors.initials: WT
authors.lastname: Chang
authors.forename: A H
authors.initials: AH
authors.lastname: Li
authors.forename: M S
authors.initials: MS
authors.lastname: Chen
authors.forename: C Y
authors.initials: CY
authors.lastname: Wu
authors.forename: W
authors.initials: W
authors.lastname: Fang
mesh_terms: D000818:Animals; D016466:CHO Cells; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D017630:Connexins / Q000235:genetics*; D006224:Cricetinae; D005192:Family Health; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005799:Genes, Dominant; D017930:Genes, Reporter; D008040:Genetic Linkage; D005910:Glioma; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology; D008156:Luciferases; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D009474:Neurons / Q000737:chemistry / Q000502:physiology; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012583:Schwann Cells / Q000502:physiology; D013624:Taiwan; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D014960:X Chromosome; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D008156:Luciferases; D000097002:Gap Junction beta-1 Protein