title: Mutations in noncoding regions ofGJB1are a major cause of X-linked CMT.
abstract: OBJECTIVE
  To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1).
  
  
  METHODS
  Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3' untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected.
  
  
  RESULTS
  Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5'UTR. A novel mutation, c.*15C>T, was detected in the 3' UTR ofGJB1in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3'UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population.
  
  
  CONCLUSIONS
  Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions.
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Tomaselli
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Rossor
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Horga
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Zane
authors.initials: Z
authors.lastname: Jaunmuktane
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Aisling
authors.initials: A
authors.lastname: Carr
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Saveri
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Piscosquito
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Matilde
authors.initials: M
authors.lastname: Laura
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Blake
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Roy
authors.initials: R
authors.lastname: Poh
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: James
authors.initials: J
authors.lastname: Polke
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (P.J.T., A.M.R., A.H., A.C., M.L., M.M.R.), Department of Neuropathology (Z.J.), and Department of Neurogenetics (R.P., J.P., H.H.), National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK; Clinic of Central and Peripheral Degenerative Neuropathies Unit (P.S., G.P., D.P.), Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy; Department of Clinical Neurophysiology (J.C.B.), Norfolk and Norwich University Hospital, Norfolk, UK. m.reilly@ucl.ac.uk.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D000293:Adolescent; D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012720:Severity of Illness Index; D012737:Sex Factors; D055815:Young Adult; D001616:beta-Galactosidase / Q000235:genetics*
chemical_list: C061901:GLB1 protein, human; D001616:beta-Galactosidase