A novel mutation in the nerve‐specific 5′UTR of the <i>GJB1</i> gene causes X‐linked Charcot‐Marie‐Tooth disease

Murphy, Sinéad M.; Polke, James M.; Manji, Hadi; Blake, Julian; Reiniger, Lilla; Sweeney, Mary G.; Houlden, Henry; Brandner, Sebastian; Reilly, Mary M.

doi:10.1111/j.1529-8027.2011.00321.x

Cited by 29 publications

(19 citation statements)

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“…11 In table e-2, there is an overview of all mutations in the 5′ and 3′ UTR regions of GJB1 and the corresponding nomenclature based on counting directly from the ATG translation initiation codon, which has been previously used to describe a number of mutations. The previously reported mutations 9,12–15 c.-103C>T and c.-17G>A were detected in 2 (3 and 7) and 4 unrelated families (1, 2, 4, and 9), respectively, and segregated with the phenotype in all family members tested. Three novel mutations were identified: c.-146-90_-146-89insT in family 8, c.-17+1G>T in family 6, and c.*15C>T in families 5 and 10.…”

Section: Resultsmentioning

confidence: 65%

“…Four patients from family 1 (1-I.2, 1-II.2, 1-II.4, and 1-III.3) and all 4 patients from family 2 have been reported previously. 9 There was no male-to-male transmission in any of the pedigrees. From 1996 to 2016, 194 patients with mutations in the open reading frame of GJB1 were identified.…”

Section: Resultsmentioning

confidence: 93%

“…9 This mutation is located in the last base of exon 1b, which is one of the most highly conserved bases in splice-site consensus sequences. In silico splice site analysis predicted that this mutation may reduce the efficiency of splicing at this intron/exon boundary, leading to the inclusion of intron 1 and a mutant transcript.…”

Section: Discussionmentioning

confidence: 99%

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

Tomaselli¹,

Rossor²,

Horga³

et al. 2017

Neurology

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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.

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 93%

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

Tomaselli¹,

Rossor²,

Horga³

et al. 2017

Neurology

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“…(Thr118Met)C5[25–28] GJB1 NM_000166.5c.-17G > Ap. ?C5[35]2CMT2 PMP22 NM_000304.2c.353C > Tp. (Thr118Met)C5[25–28] PMP22 NM_000304.2c.281delGp.…”

Section: Resultsmentioning

confidence: 99%

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability

et al. 2015

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BackgroundInherited peripheral neuropathy (IPN) is a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with the different subtypes. Sequential gene screening is gradually being replaced by next generation sequencing (NGS) applications.MethodsWe designed and validated a targeted NGS panel assay including 56 genes associated with known causes of IPN. We report our findings following NGS panel testing of 448 patients with different types of clinically-suspected IPN.ResultsGenetic diagnosis was achieved in 137 patients (31 %) and involved 195 pathogenic variants in 31 genes. 93 patients had pathogenic variants in genes where a resulting phenotype follows dominant inheritance, 32 in genes where this would follow recessive inheritance, and 12 presented with X-linked disease.Almost half of the diagnosed patients (64) had a pathogenic variant either in genes not previously available for routine diagnostic testing in a UK laboratory (50 patients) or in genes whose primary clinical association was not IPN (14).Seven patients had a pathogenic variant in a gene not hitherto indicated from their phenotype and three patients had more than one pathogenic variant, explaining their complex phenotype and providing information essential for accurate prediction of recurrence risks.ConclusionsOur results demonstrate that targeted gene panel testing is an unbiased approach which overcomes the limitations imposed by limited existing knowledge for rare genes, reveals high heterogeneity, and provides high diagnostic yield. It is therefore a highly efficient and cost effective tool for achieving a genetic diagnosis for IPN.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0224-8) contains supplementary material, which is available to authorized users.

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“…CMT1X is caused by mutations in the GJB1 gene that encodes the gap junction protein connexin32 (Cx32) [108–110]. Studies have shown that CMT1X-linked Cx32 mutations impair gap junction formation through a combination of loss-of-function and gain-of-function effects [111], but how these mutations cause demyelinating CMT neuropathy is incompletely understood.…”

Section: Elevated Erbb Receptor Levels and Altered Erk And Akt Signalmentioning

confidence: 99%

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

Lee

Chin

2016

Mol Neurobiol

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Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy.

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A novel mutation in the nerve‐specific 5′UTR of the GJB1 gene causes X‐linked Charcot‐Marie‐Tooth disease

Cited by 29 publications

References 29 publications

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

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

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

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