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, Fabio Mammano

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2569-2587
Number of pages19
JournalHuman Molecular Genetics
Volume15
Issue number17
DOIs
Publication statusPublished - Sep 1 2006

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ASJC Scopus subject areas

  • Genetics

Cite this

Bicego, M., Beltramello, M., Melchionda, S., Carella, M., Piazza, V., Zelante, L., Bukauskas, F. F., Arslan, E., Cama, E., Pantano, S., Bruzzone, R., D'Andrea, P., & Mammano, F. (2006). Pathogenetic role of the deafness-related M34T mutation of Cx26. Human Molecular Genetics, 15(17), 2569-2587. https://doi.org/10.1093/hmg/ddl184