Human Molecular Genetics Advance Access originally published online on July 18, 2006
Human Molecular Genetics 2006 15(17):2569-2587; doi:10.1093/hmg/ddl184
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Pathogenetic role of the deafness-related M34T mutation of Cx26
1 Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, University of Trieste, 34127 Trieste, Italy, 2 Istituto Veneto di Medicina Molecolare (VIMM), Fondazione per la Ricerca Biomedica Avanzata, 35129 Padova, Italy, 3 Servizio di Genetica Medica, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, 4 Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA, 5 Servizio di Audiologia e Foniatria, University of Padova, 35128 Padova, Italy, 6 Département de Neuroscience, Institut Pasteur, 75015 Paris, France and 7 Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia (CNISM) and 8 Dipartimento di Fisica ‘G.Galilei’, Università di Padova, 35131 Padova, Italy
* To whom correspondence should be addressed at: Département de Neuroscience, Institut Pasteur, 25, rue du Dr Roux, 75015 Paris, France. Tel: +33 140613436; Fax: +33 140613421; Email: bruzzone{at}pasteur.fr
Received April 21, 2006; Revised July 5, 2006; Accepted July 12, 2006
Mutations 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.
These authors have contributed equally.
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