Human Molecular Genetics Advance Access published online on July 18, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl184
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1 Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, University of Trieste, 34127 Trieste, Italy
* To whom correspondence should be addressed. Mutations in the GJB2 gene, which encodes the gap junction protein connexin26 (Cx26), are the major cause of genetic nonsyndromic 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 audiologic data indicate that the majority (62.5%) 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.
Received April 21, 2006
Revised July 12, 2006
Accepted July 12, 2006
Article
Pathogenetic role of the deafness-related M34T mutation of Cx26
Massimiliano Bicego 1, Martina Beltramello 2, Salvatore Melchionda 3, Massimo Carella 3, Valeria Piazza 2, Leopoldo Zelante 3, Feliksas F. Bukauskas 4, Edoardo Arslan 5, Elona Cama 5, Sergio Pantano 6, Roberto Bruzzone 7 *, Paola D'Andrea 1, and Fabio Mammano 8
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 Istituto Veneto di Medicina Molecolare (VIMM), Fondazione per la Ricerca Biomedica Avanzata, 35129 Padova, Italy; Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia (CNISM)
7 Département de Neuroscience, Institut Pasteur, 25, rue du Dr Roux, 75015 Paris, France
8 Istituto Veneto di Medicina Molecolare (VIMM), Fondazione per la Ricerca Biomedica Avanzata, 35129 Padova, Italy; Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia (CNISM); Dipartimento di Fisica "G.Galilei", Università di Padova, 35131 Padova, Italy
Roberto Bruzzone, E-mail: bruzzone{at}pasteur.fr
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