Allelic variants in the 5` non-coding region of the connexin32 gene: possible pitfalls in the diagnosis of X linked Charcot-Marie-Tooth neuropathy (CMTX)

Bergmann, Carsten; Zerres, Klaus; Rudnik‐Schöneborn, Sabine; Eggermann, Thomas; Schröder, Johann Michael; Senderek, Jan

doi:10.1136/jmg.39.9.e58

Cited by 8 publications

(5 citation statements)

References 31 publications

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“…The −713G>A variant was reported to cosegregate with CMTX in Taiwan Chinese ( Wang et al, 2000 ) but this association was not replicated in Germans ( Wang et al, 2000; Bergmann et al, 2001; 2002 ) . Ethnic heterogeneity at this locus was proposed to be a possible reason for this discordance ( Bergmann et al, 2001 ) .…”

Section: Discussionmentioning

confidence: 99%

“…The effects of non‐coding variants may only impact upon biological processes such as transcription and translation, which can be difficult to quantify in vivo . At least four benign allelic variants in the P2 non‐coding region of GJB1 exist ( Bergmann et al, 2002 ) . The genotype‐phenotype correlation between GJB1 mutations and CMTX is still unclear, especially those in the promoter region ( Kleopa and Scherer, 2006 ) .…”

Section: Introductionmentioning

confidence: 99%

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−459C>T point mutation in 5′ non‐coding region of human GJB1 gene is linked to X‐linked Charcot‐Marie‐Tooth neuropathy

Li¹,

Cheng²,

Ho³

et al. 2009

J Peripheral Nervous Sys

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Charcot-Marie-Tooth (CMT) neuropathy is inherited with genetic and clinical heterogeneity. The X-linked form (CMTX) is linked to mutations in the GJB1 gene. However, the genotype-phenotype correlation between variants in the non-coding region of GJB1 gene and CMTX is unclear. We found two structural variants (-459C>T and -713G>A) in the 5' non-coding region of a transcript (Ref seq ID: NM_000166) of the GJB1 gene and explored its association with CMTX in two Chinese families. All family members who carried the -459C>T variant either were symptomatic or had abnormal electrophysiological studies compatible with CMTX, whereas all the non-symptomatic family members who had normal electrophysiological studies and 10 healthy unrelated controls did not have this variant. The other variant in the 5'-flanking region of the gene was found to be a benign polymorphism, although it had been earlier reported to be associated with CMTX in a Taiwanese family. Secondary structure prediction analysis of mutant mRNA using M fold and RNA structure softwares indicates that the -459C>T mutation may reduce translation efficiency of the GJB1 gene by changing its 5'-untranslated region secondary structure and abolishing the internal ribosome entry site at the initialization of its translation in Schwann cells. Our study can help clarify the causal mutations of CMTX in the non-protein coding region of GJB1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

−459C>T point mutation in 5′ non‐coding region of human GJB1 gene is linked to X‐linked Charcot‐Marie‐Tooth neuropathy

Li¹,

Cheng²,

Ho³

et al. 2009

J Peripheral Nervous Sys

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“…Of note, the c.-102G>A variant (reported as c.-458G>A), affecting the adjacent base, did not segregate in a large family with CMT, suggesting that not every variant of an IRES element is pathogenic. 29 …”

Section: Discussionmentioning

confidence: 99%

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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“…Most disease-causing GJB1 mutations occur in the coding region, however, mutations altering non-coding regions and genomic deletions have also been reported [14,15]. There was no consistent relationship between the site and type of connexin32 mutation and the severity of the phenotype [5].…”

Section: Geneticsmentioning

confidence: 66%