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Article: -459C>T point mutation in 5′ non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy
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Title-459C>T point mutation in 5′ non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy
 
AuthorsLi, M
Cheng, TS2
Ho, PWL2
Chan, KH2 1
Mak, W2
Cheung, RTF2 1
Ramsden, DB3
Sham, PC1
Song, Y
Ho, SL2 1
 
KeywordsCharcot-Marie-Tooth
GJB1 (Connexin32)
Mutation
Neuropathy
Non-coding region
 
Issue Date2009
 
CitationJournal Of The Peripheral Nervous System, 2009, v. 14 n. 1, p. 14-21 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1529-8027.2009.00201.x
 
AbstractCharcot-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 Mfold and RNAstructure 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. © 2009 Peripheral Nerve Society.
 
ISSN1085-9489
2013 Impact Factor: 2.504
 
DOIhttp://dx.doi.org/10.1111/j.1529-8027.2009.00201.x
 
ISI Accession Number IDWOS:000264635600002
Funding AgencyGrant Number
Council, Hong KongHKU7496/04M
Donation Fund
Henry G. Leong Professorship
University of Hong Kong
Funding Information:

This project was supported by Liu Po Shan/Dr. Vincent Liu Endowment Fund for Motor Neuron Disease (S.-L.H), Research Grants Council, Hong Kong (HKU7496/04M; YQS), Donation Fund for Neurology Research (S.-L.H.) and the Henry G. Leong Professorship in Neurology (S.-L.H.). P.W.-L.H. is supported by a Postdoctoral Fellowship. M.L. is supported by Postgraduate PhD Studentship from the University of Hong Kong.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorLi, M
 
dc.contributor.authorCheng, TS
 
dc.contributor.authorHo, PWL
 
dc.contributor.authorChan, KH
 
dc.contributor.authorMak, W
 
dc.contributor.authorCheung, RTF
 
dc.contributor.authorRamsden, DB
 
dc.contributor.authorSham, PC
 
dc.contributor.authorSong, Y
 
dc.contributor.authorHo, SL
 
dc.date.accessioned2012-05-29T06:04:51Z
 
dc.date.available2012-05-29T06:04:51Z
 
dc.date.issued2009
 
dc.description.abstractCharcot-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 Mfold and RNAstructure 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. © 2009 Peripheral Nerve Society.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of The Peripheral Nervous System, 2009, v. 14 n. 1, p. 14-21 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1529-8027.2009.00201.x
 
dc.identifier.citeulike4242324
 
dc.identifier.doihttp://dx.doi.org/10.1111/j.1529-8027.2009.00201.x
 
dc.identifier.epage21
 
dc.identifier.hkuros155728
 
dc.identifier.isiWOS:000264635600002
Funding AgencyGrant Number
Council, Hong KongHKU7496/04M
Donation Fund
Henry G. Leong Professorship
University of Hong Kong
Funding Information:

This project was supported by Liu Po Shan/Dr. Vincent Liu Endowment Fund for Motor Neuron Disease (S.-L.H), Research Grants Council, Hong Kong (HKU7496/04M; YQS), Donation Fund for Neurology Research (S.-L.H.) and the Henry G. Leong Professorship in Neurology (S.-L.H.). P.W.-L.H. is supported by a Postdoctoral Fellowship. M.L. is supported by Postgraduate PhD Studentship from the University of Hong Kong.

 
dc.identifier.issn1085-9489
2013 Impact Factor: 2.504
 
dc.identifier.issue1
 
dc.identifier.pmid19335535
 
dc.identifier.scopuseid_2-s2.0-62849106648
 
dc.identifier.spage14
 
dc.identifier.urihttp://hdl.handle.net/10722/147598
 
dc.identifier.volume14
 
dc.languageeng
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of the Peripheral Nervous System
 
dc.relation.referencesReferences in Scopus
 
dc.subject.mesh5' Untranslated Regions - Genetics
 
dc.subject.meshAdolescent
 
dc.subject.meshAdult
 
dc.subject.meshAged
 
dc.subject.meshAsian Continental Ancestry Group - Ethnology
 
dc.subject.meshCharcot-Marie-Tooth Disease - Genetics - Pathology - Physiopathology
 
dc.subject.meshChild
 
dc.subject.meshConnexins - Genetics
 
dc.subject.meshDNA Mutational Analysis
 
dc.subject.meshElectromyography
 
dc.subject.meshFamily Health
 
dc.subject.meshFemale
 
dc.subject.meshGenetic Diseases, X-Linked - Genetics
 
dc.subject.meshHumans
 
dc.subject.meshMale
 
dc.subject.meshMicroscopy, Electron, Transmission
 
dc.subject.meshMiddle Aged
 
dc.subject.meshNeural Conduction - Genetics - Physiology
 
dc.subject.meshPeripheral Nerves - Pathology - Physiopathology - Ultrastructure
 
dc.subject.meshPoint Mutation - Genetics
 
dc.subject.meshSequence Analysis
 
dc.subject.meshYoung Adult
 
dc.subjectCharcot-Marie-Tooth
 
dc.subjectGJB1 (Connexin32)
 
dc.subjectMutation
 
dc.subjectNeuropathy
 
dc.subjectNon-coding region
 
dc.title-459C>T point mutation in 5′ non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Division of Neurology
  3. University of Birmingham