title: A novel mutation in the nerve-specific 5'UTR of the GJB1 gene causes X-linked Charcot-Marie-Tooth disease.
abstract: X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common cause of CMT, and is usually caused by mutations in the gap junction protein beta 1 (GJB1) gene which codes for connexin 32 (CX32). CX32 has three tissue-specific promoters, P1 which is specific for liver and pancreas, P1a specific for liver, oocytes and embryonic stem cells, and P2 which is nerve-specific. Over 300 mutations have been described in GJB1, spread throughout the coding region. We describe two families with X-linked inheritance and a phenotype consistent with CMT1X who did not have mutations in the GJB1 coding region. The non-coding region of GJB1 was sequenced and an upstream exon-splicing variant found at approximately - 373G>A which segregated with the disease in both families and was not present in controls. This substitution is located at the last base of the nerve-specific 5'UTR 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. It is likely that other mutations within the GJB1 non-coding regions account for the CMT1X families who do not have coding region mutations.
authors.affiliation: MRC Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK. sinead.murphy@uclh.nhs.uk
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Murphy
authors.forename: James
authors.initials: J
authors.lastname: Polke
authors.forename: Hadi
authors.initials: H
authors.lastname: Manji
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.forename: Lilla
authors.initials: L
authors.lastname: Reiniger
authors.forename: Mary
authors.initials: M
authors.lastname: Sweeney
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease; D017630:Connexins / Q000235:genetics*; D004594:Electrophysiology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D055815:Young Adult; D000097002:Gap Junction beta-1 Protein
chemical_list: D020121:5' Untranslated Regions; D017630:Connexins; D000097002:Gap Junction beta-1 Protein