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J. Biol. Chem., Vol. 280, Issue 12, 11458-11466, March 25, 2005

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Oculodentodigital Dysplasia-causing Connexin43 Mutants Are Non-functional and Exhibit Dominant Effects on Wild-type Connexin43^*

Wendi Roscoe, Gregory I. L. Veitch, Xiang-Qun Gong, Emily Pellegrino, Donglin Bai, Elizabeth McLachlan, Qing Shao, Gerald M. Kidder, and Dale W. Laird¶

From the Departments of Physiology and Pharmacology and Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada

Oculodentodigital dysplasia, a rare condition displaying congenital craniofacial deformities and limb abnormalities, has been associated with over 20 known human connexin43 (Cx43) mutations. The localization of two of these mutants, G21R and G138R, was examined in Cx43-positive normal rat kidney cells (NRK) and Cx43-negative gap junctional intercellular communication-deficient HeLa cells. Green fluorescent protein-tagged and untagged Cx43 G21R and G138R mutants were transported to the plasma membrane and formed punctate structures reminiscent of gap junction plaques in both NRK and HeLa cells. Further localization studies revealed no significant trafficking defects as subpopulations of Cx43 mutants were found in both the Golgi apparatus and lysosomes, not unlike wild-type Cx43. Dual patch clamp functional analysis of the mutants expressed in gap junctional intercellular communication-deficient N2A cells revealed that neither G21R nor G138R formed functional gap junction channels, although they successfully reached cell-cell interfaces between cell pairs. Importantly, when either mutant was expressed in NRK cells, dye coupling experiments revealed that both mutants inhibited endogenous Cx43 function. These studies suggest that, although patients suffering from oculodentodigital dysplasia possess one wild-type Cx43 allele, it is likely that Cx43-mediated gap junctional intercellular communication is reduced below 50% because of a dominant-negative effect of mutant Cx43 on wild-type Cx43.

Received for publication, August 19, 2004 , and in revised form, January 6, 2005.

^* This work was supported by grants from the Canadian Institutes of Health Research (to D. W. L. and D. B.). 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: Dept. of Anatomy and Cell Biology, The University of Western Ontario, Dental Science Bldg., Rm. 00077, London, Ontario N6A 5C1, Canada. Tel.: 519-661-2111 (ext. 86827); Fax: 519-850-2562; E-mail: dale.laird{at}fmd.uwo.ca.

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