Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 51; pp. 20512 - 20516
• Main Authors: Kalcheva, Nellie, Qu, Jiaxiang, Sandeep, Nefthi, Garcia, Luis, Zhang, Jie, Wang, Zhiyong, Lampe, Paul D, Suadicani, Sylvia O, Spray, David C, Fishman, Glenn I
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.12.2007; National Acad Sciences
• Subjects: Abnormalities, Multiple - genetics; Animals; Antibodies; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Biological Sciences; Cardiac arrhythmia; Cardiac Electrophysiology; Conduction; Connexin 43 - deficiency; Connexin 43 - genetics; Craniofacial Abnormalities - genetics; Disease Models, Animal; Dyes; Dysrhythmias; Electric potential; Gap junctions; Gap Junctions - genetics; Gap Junctions - metabolism; Genetic mutation; Genomics; Heart - physiopathology; Heart Conduction System - physiopathology; Isoquinolines - analysis; Isoquinolines - metabolism; Lower Extremity Deformities, Congenital - genetics; Mice; Mice, Knockout; Mutation; Myocytes, Cardiac - pathology; Phosphorylation; Renovations; Rodents; Syndrome
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0705472105

Gap junction channels are required for normal cardiac impulse propagation, and gap junction remodeling is associated with enhanced arrhythmic risk. Oculodentodigital dysplasia (ODDD) is a multisystem syndrome due to mutations in the connexin43 (Cx43) gap junction channel gene. To determine the effects of a human connexin channelopathy on cardiac electrophysiology and arrhythmogenesis, we generated a murine model of ODDD by introducing the disease-causing I130T mutant allele into the mouse genome. Cx43 abundance was markedly reduced in mutant hearts with preferential loss of phosphorylated forms that interfered with trafficking and assembly of gap junctions in the junctional membrane. Dual whole-cell patch-clamp studies showed significantly lower junctional conductance between neonatal cell pairs from mutant hearts, and optical mapping of isolated-perfused hearts with voltage-sensitive dyes demonstrated significant slowing of conduction velocity. Programmed electrical stimulation revealed a markedly increased susceptibility to spontaneous and inducible ventricular tachyarrhythmias. In summary, our data demonstrate that the I130T mutation interferes with Cx43 posttranslational processing, resulting in diminished cell-cell coupling, slowing of impulse propagation, and a proarrhythmic substrate.