Mutations in noncoding regions of GJB1 are 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 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.

An 8‐generation family with X‐linked Charcot–Marie–Tooth: Confirmation Of the pathogenicity Of a 3′ untranslated region mutation in GJB1 and its clinical features

“…The majority of mutations in GJB1 are missense but rare ones have been described in the 5′ UTR . Recently, a GJB1 mutation (c.*15C>T) in the 3′ UTR was reported in 2 nuclear families each with only a single affected male, precluding proof of cosegregation with disease . The present study has documented cosegregation of the c.*15C>T GJB1 mutation in 4 branches of a large family, with confirmation by linkage analysis.…”

“…Given the X‐linked inheritance pattern in the pedigree, GJB1 was analyzed by commercial laboratories on 2 separate occasions but no mutation was identified. With the report of GJB1 *15C>T, we reevaluated the available exome sequence of affected subject VII‐8 and found this variant …”

“…Tomeselli et al . speculated that this variant may create a 5′ donor splice site leading to aberrant splicing within the 3′ UTR . This could affect mRNA stability leading to decreased GJB1 protein Cx32 .…”

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association

“…It should be noted however that previous searches for such antibodies in MS have been negative 47. Finally, based on recent studies suggesting that GJB1 promoter mutations may be a more common cause of CMTX than previously suspected, this study is limited by the absence of promoter screening 48. Notwithstanding the above limitations, it remains surprising that the association between CMTX and MS has not been previously noted in reports of larger cohorts of patients with CMTX 49.…”

Structural variations causing inherited peripheral neuropathies: A paradigm for understanding genomic organization, chromatin interactions, and gene dysregulation

“…Gene dysregulation through aberrant transcriptional regulation is not unprecedented as a disease mechanism in IPN as point mutations have previously been reported in noncoding regulatory sequences (Tomaselli et al, 2017). Point mutations in the 5 0 untranslated region (UTR), 3 0 UTR (Ionasescu, Searby, Ionasescu, Neuhaus, & Werner, 1996) and the neural-specific promoter (P2) sequences of the GJB1 gene (Houlden et al, 2004) have been reported to cause CMTX1.…”