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Article: Pathogenetic role of the deafness-related M34T mutation of Cx26

TitlePathogenetic role of the deafness-related M34T mutation of Cx26
Authors
KeywordsMolecular Sequence Numbers
Issue Date2006
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2006, v. 15 n. 17, p. 2569-2587 How to Cite?
AbstractMutations in the GJB2 gene, which encodes the gap junction protein connexin26 (Cx26), are the major cause of genetic non-syndromic hearing loss. The role of the allelic variant M34T in causing hereditary deafness remains controversial. By combining genetic, clinical, biochemical, electrophysiological and structural modeling studies, we have re-assessed the pathogenetic role of the M34T mutation. Genetic and audiological data indicate that the majority of heterozygous carriers and all five compound heterozygotes exhibited an impaired auditory function. Functional expression in transiently transfected HeLa cells showed that, although M34T was correctly synthesized and targeted to the plasma membrane, it inefficiently formed intercellular channels that displayed an abnormal electrical behavior and retained only 11% of the unitary conductance of the wild-type protein (HCx26wt). Moreover, M34T channels failed to support the intercellular diffusion of Lucifer Yellow and the spreading of mechanically induced intercellular Ca2+ waves. When co-expressed together with HCx26wt, M34T exerted dominant-negative effects on cell-cell coupling. Our findings are consistent with a structural model, predicting that the mutation leads to a constriction of the channel pore. These data support the view that M34T is a pathological variant of Cx26 associated with hearing impairment. © 2006 Oxford University Press.
Persistent Identifierhttp://hdl.handle.net/10722/132691
ISSN
2015 Impact Factor: 5.985
2015 SCImago Journal Rankings: 4.288
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorBicego, Men_HK
dc.contributor.authorBeltramello, Men_HK
dc.contributor.authorMelchionda, Sen_HK
dc.contributor.authorCarella, Men_HK
dc.contributor.authorPiazza, Ven_HK
dc.contributor.authorZelante, Len_HK
dc.contributor.authorBukauskas, FFen_HK
dc.contributor.authorArslan, Een_HK
dc.contributor.authorCama, Een_HK
dc.contributor.authorPantano, Sen_HK
dc.contributor.authorBruzzone, Ren_HK
dc.contributor.authorD'Andrea, Pen_HK
dc.contributor.authorMammano, Fen_HK
dc.date.accessioned2011-03-28T09:28:17Z-
dc.date.available2011-03-28T09:28:17Z-
dc.date.issued2006en_HK
dc.identifier.citationHuman Molecular Genetics, 2006, v. 15 n. 17, p. 2569-2587en_HK
dc.identifier.issn0964-6906en_HK
dc.identifier.urihttp://hdl.handle.net/10722/132691-
dc.description.abstractMutations in the GJB2 gene, which encodes the gap junction protein connexin26 (Cx26), are the major cause of genetic non-syndromic hearing loss. The role of the allelic variant M34T in causing hereditary deafness remains controversial. By combining genetic, clinical, biochemical, electrophysiological and structural modeling studies, we have re-assessed the pathogenetic role of the M34T mutation. Genetic and audiological data indicate that the majority of heterozygous carriers and all five compound heterozygotes exhibited an impaired auditory function. Functional expression in transiently transfected HeLa cells showed that, although M34T was correctly synthesized and targeted to the plasma membrane, it inefficiently formed intercellular channels that displayed an abnormal electrical behavior and retained only 11% of the unitary conductance of the wild-type protein (HCx26wt). Moreover, M34T channels failed to support the intercellular diffusion of Lucifer Yellow and the spreading of mechanically induced intercellular Ca2+ waves. When co-expressed together with HCx26wt, M34T exerted dominant-negative effects on cell-cell coupling. Our findings are consistent with a structural model, predicting that the mutation leads to a constriction of the channel pore. These data support the view that M34T is a pathological variant of Cx26 associated with hearing impairment. © 2006 Oxford University Press.en_HK
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_HK
dc.relation.ispartofHuman Molecular Geneticsen_HK
dc.subjectMolecular Sequence Numbersen_US
dc.titlePathogenetic role of the deafness-related M34T mutation of Cx26en_HK
dc.typeArticleen_HK
dc.identifier.emailBruzzone, R: bruzzone@hkucc.hku.hken_HK
dc.identifier.authorityBruzzone, R=rp01442en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1093/hmg/ddl184en_HK
dc.identifier.pmid16849369-
dc.identifier.pmcidPMC2829448-
dc.identifier.scopuseid_2-s2.0-33747880802en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33747880802&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume15en_HK
dc.identifier.issue17en_HK
dc.identifier.spage2569en_HK
dc.identifier.epage2587en_HK
dc.identifier.eissn1460-2083-
dc.identifier.isiWOS:000239901800004-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridBicego, M=7004711890en_HK
dc.identifier.scopusauthoridBeltramello, M=6508041363en_HK
dc.identifier.scopusauthoridMelchionda, S=6603966689en_HK
dc.identifier.scopusauthoridCarella, M=7006410698en_HK
dc.identifier.scopusauthoridPiazza, V=7007182411en_HK
dc.identifier.scopusauthoridZelante, L=7006328415en_HK
dc.identifier.scopusauthoridBukauskas, FF=7004944501en_HK
dc.identifier.scopusauthoridArslan, E=7004957334en_HK
dc.identifier.scopusauthoridCama, E=14319013200en_HK
dc.identifier.scopusauthoridPantano, S=8503991400en_HK
dc.identifier.scopusauthoridBruzzone, R=7006793327en_HK
dc.identifier.scopusauthoridD'Andrea, P=7005979859en_HK
dc.identifier.scopusauthoridMammano, F=7006987421en_HK

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