title: Mutational analysis of the 5' non-coding region of GJB1 in a Taiwanese cohort with Charcot-Marie-Tooth neuropathy.
abstract: Mutations in the 5' non-coding region of GJB1 are rarely reported in patients with Charcot-Marie-Tooth disease (CMT). We therefore aimed to assess the frequency and identities of the GJB1 5' non-coding region mutations in a cohort of CMT. We analyzed the 5' non-coding region of GJB1 (including the promoter P2 and exon 1b) in 91 unrelated CMT patients without an identified genetic cause. Two mutations, c.-529T>C, and c.-459C>T, were identified in one patient each. One polymorphism, c.-713G>A, was also identified in 53 patients and 73 of the 100 control subjects. The luciferase reporter assays showed that c.-459C>T significantly reduced the luciferase expression with or without SOX10 activation, whereas c.-529T>C impaired the expression only with SOX10 co-expression. c.-713G>A had no apparent functional effect. Mutations in the 5' non-coding region of GJB1 account for 0.8% (2 of 251) of CMT and 2.2% (2 of 91) of genetically unassigned CMT in a Taiwanese cohort. As previously demonstrated, c.-459C>T and c.-529T>C may cause CMT through compromising GJB1 expression whereas c.-713G>A is a benign variant. This study highlights the pathogenic role of the GJB1 5' non-coding region mutations in CMT, and suggests that their identification should be considered for CMT patients without commonly observed mutations.
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.forename: Chung-Huang
authors.initials: CH
authors.lastname: Chen
authors.forename: An-Bon
authors.initials: AB
authors.lastname: Liu
authors.forename: Yun-Chung
authors.initials: YC
authors.lastname: Chen
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.forename: Kon-Ping
authors.initials: KP
authors.lastname: Lin
authors.forename: Shaw-Fang
authors.initials: SF
authors.lastname: Yet
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004558:Electric Stimulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D055757:SOXE Transcription Factors / Q000235:genetics; D013624:Taiwan; D014162:Transfection; D055815:Young Adult; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D055757:SOXE Transcription Factors; D000097002:Gap Junction beta-1 Protein; C527923:SOX10 protein, human
keywords: 5′ non-coding region; CMT; CX32; Charcot–Marie–Tooth disease; GJB1; HMSN; Promoter