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J. Biol. Chem., Vol. 279, Issue 18, 19157-19168, April 30, 2004

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Functional Domain Mapping and Selective Trans-dominant Effects Exhibited by Cx26 Disease-causing Mutations^*

Tamsin Thomas, Debra Telford, and Dale W. Laird

From the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada

Mutations in Cx26 are a major cause of autosomal dominant and recessive forms of sensorineural deafness. Some mutations in Cx26 are associated not only with deafness but also with skin disease. We examined the subcellular localization and function of two green fluorescent protein (GFP)-tagged Cx26 point mutants that exhibit both phenotypes, G59A-GFP and D66H-GFP. D66H-GFP was retained within the brefeldin A-insensitive trans-Golgi network, whereas a population of G59A-GFP was transported to the cell surface. Neither G59A nor D66H formed gap junctions that were permeable to small fluorescent dyes, suggesting they are loss-of-function mutations. When co-expressed with wild-type Cx26, both G59A and D66H exerted dominant-negative effects on Cx26 function. G59A also exerted a trans-dominant negative effect on co-expressed wild type Cx32 and Cx43, whereas D66H exerted a trans-dominant negative effect on Cx43 but not Cx32. We propose that the severity of the skin disease is dependent on the specific nature of the Cx26 mutation and the trans-dominant selectivity of the Cx26 mutants on co-expressed connexins. Additional systematic mutations at residue D66, in which the overall charge of this motif was altered, suggested that the first extracellular loop is critical for Cx26 transport to the cell surface as well as function of the resulting gap junction channels.

Received for publication, December 23, 2003

^* This work was supported by a grant from the Canadian Institutes of Health Research (to D. W. L.) and a studentship from the Natural Sciences and Engineering Research Council of Canada (to T. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dental Science Building, Rm 00077, London, Ontario N6A 5C1, Canada. Tel.: 519-661-2111 (ext. 86827); Fax: 519-850-2562; E-mail: dwlaird{at}uwo.ca.

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