Abstract 573: Abnormal Impulse Propagation and Susceptibility to Ventricular Tachycardia in a Murine Model of Oculodentodigital Dysplasia

Abstract

Mutations in the gene encoding connexin43 (Cx43), have been identified in families with oculodentodigital dysplasia (ODDD), a dominantly inherited disorder with pleiotropic phenotypic manifestations. In one family with ODDD due to an isoleucine to threonine missense mutation at residue 130 (I130T), several individuals developed cardiac rhythm disturbances including ventricular tachycardia and sudden cardiac death. To explore the molecular pathology linking Cx43 mutations with arrhythmic behavior, we established a murine model of ODDD by introducing the disease causing I130T mutation into the Cx43 gene through homologous recombination. Approximately 20% of heterozygous Cx43-I130T mutant mice died in the immediate perinatal period, whereas the other 80% have survived for at least 5 months. Heterozygous mutant mice develop hindlimb syndactyly - a common phenotypic characteristic of humans with ODDD. The hearts of mutant mice did not display gross anatomical abnormalities and evaluation of left ventricular chamber size, wall thickness and contractile performance as assessed by echocardiography was not significantly different than wildtype littermates. Western blot analysis of heterozygous I130T mice demonstrated substantially less than 50% of wildtype levels of Cx43, whereas Cx43 transcript levels were normal, suggesting a dominant-negative effect of the mutation on Cx43 protein stability. Immunohistochemical stainining demonstrated less efficient trafficking of Cx43 to the intercaled disk in mutant hearts. Optical mapping studies of impulse propagation in Langendorff-perfused hearts demonstrated significant slowing (p<0.05) of conduction velocity in both the longitudinal (.61 ± .03 m/s vs .74 ± .04 m/s) and transverse (.30 ± .02 m/s vs .43 ± .02) directions in mutant hearts compared to wildtype littermates. Moreover 7/7 mutant hearts developed spontaneous and inducible sustained monomorphic ventricular tachycardia where 0/7 wildtype littermates developed sustained arrhythmias. In summary, Cx43-I130T mutant mice display phenotypic features of human ODDD including syndactyly and rhythm disturbances. Additional study of this novel mouse model will provide insights into aberrant function of Cx43 and pro-arrhythmic behavior.