Journal Article

Pathogenetic role of the deafness-related M34T mutation of Cx26

Massimiliano Bicego, Martina Beltramello, Salvatore Melchionda, Massimo Carella, Valeria Piazza, Leopoldo Zelante, Feliksas F. Bukauskas, Edoardo Arslan, Elona Cama, Sergio Pantano, Roberto Bruzzone, Paola D'Andrea and Fabio Mammano

in Human Molecular Genetics

Volume 15, issue 17, pages 2569-2587
Published in print September 2006 | ISSN: 0964-6906
Published online July 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl184
Pathogenetic role of the deafness-related M34T mutation of Cx26

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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.

Journal Article.  11527 words.  Illustrated.

Subjects: Genetics and Genomics

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