Human Molecular Genetics Advance Access originally published online on November 13, 2007
Human Molecular Genetics 2008 17(4):539-554; doi:10.1093/hmg/ddm329
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The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans
1 Institute of Genetics 2 Institute of Physiology I, Life and Brain Center 3 Department of Medicine/Cardiology, University of Bonn, Germany 4 Division of Bone and Mineral Diseases, Washington University in St Louis, USA 5 Department of Pathology, University of Ulsan College of Medicine, Seoul, Korea 6 Department of Neuroscience, Albert Einstein College of Medicine, New York, USA
* To whom correspondence should be addressed at: Roemerstr. 164, 53117 Bonn, Germany. Tel: +49 228734210; Fax: +49 228734263; Email: genetik{at}uni-bonn.de
Received September 7, 2007; Revised October 19, 2007; Accepted November 9, 2007
Oculodentodigital dysplasia (ODDD) is a dominant negatively inherited disorder with variable but characteristic anomalies of the fingers and toes, eyes, face and teeth, which are caused by mutations in the connexin 43 (Cx43) gene. All mutations analyzed so far have a negative influence on the conductance through gap junctional channels and hemichannels, as well as trafficking of Cx43 protein in transfected cells. In this study, we inserted the human Cx43G138R point mutation into the mouse Cx43 gene and generated mice conditionally expressing this mutation. All ODDD phenotypic manifestations observed in humans, including syndactyly and enamel hypoplasia as well as craniofacial, bone and heart anomalies, were also observed with significant penetrance in Cx43G138R mice. When this mutation was specifically expressed in cardiomyocytes, characteristic alterations in the electrocardiogram and spontaneous arrhythmias were recorded. In vitro studies with Cx43G138R-expressing cells revealed loss of the Cx43 P2 phosphorylation state, which was also absent in the mutated hearts. This loss has previously been associated with gap junctional dysfunction and increased cellular ATP release. The Cx43G138R mutated mice show significantly increased arrhythmogeneity ex vivo in Langendorff experiments with explanted hearts and in vivo in particular under hypoxic conditions. Our results suggest that the increased activity of ATP-releasing channels in Cx43G138R mutated cardiomyocytes may further reduce the already decreased gap junctional communication and thus aggravate arrhythmogenesis in the mouse mutant.
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