Expression and function of the connexin43G138R mutation in mice causing oculodentodigital dyplasia (ODDD) in human

Abstract

<p>The Cx43G13R expressing mice present a new conditional mouse model for ODDD, carrying the human G138R point mutation. The main findings of this study are the occurrence of all common phenotypes of the human-inherited disease ODDD, like syndactylies, craniofacial anomalies, enamel hypoplasia, and the heart related mortality of Cx43G138R heterozygously mutated mice. The mortality of the mice is likely due to the strongly decreased gap junctional function, supporting the proarrhythmic action of the G138R-mutated Cx43 protein. This appears to be associated with a strongly diminished phosphorylation (P2 band) of this protein. The expression of the mutant Cx43 in HeLa and ES cell as well as the use of primary cardiomyocytes derived from mutant embryonic hearts revealed besides a strong decrease of Cx43 mediated gap junctional coupling and increased activity of ATP releasing channels. The physiological relevance of both effects could be ascertained in vivo. </p>