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Neurology. 2017 Apr 11;88(15):1445-1453. doi: 10.1212/WNL.0000000000003819. Epub 2017 Mar 10.

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT.

Author information

1
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.
2
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.

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 of GJB1 in 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.

PMID:
28283593
PMCID:
PMC5386440
DOI:
10.1212/WNL.0000000000003819
[Indexed for MEDLINE]
Free PMC Article

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