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

Abstract

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.arrhythmia ͉ connexin43 ͉ transgenic ͉ channel ͉ mouse

Closing the Gap on Autosomal Dominant Connexin-26 and Connexin-43 Mutants Linked to Human Disease

“…Jrt/ϩ mouse, as well as molecular characteristics that included aberrant Cx43 phosphorylation and trafficking, leading to reduced intercellular junctional conductance (42). Consequently, both mouse models appeared to reliably mimic the human ODDD disease phenotype at least with regard to morphological features.…”

“…Consequently, both mouse models appeared to reliably mimic the human ODDD disease phenotype at least with regard to morphological features. However, although the Cx43 I130T mutant mice exhibited no obvious morphological defects of the heart, these animals showed a tendency toward spontaneous and inducible ventricular tachyarrhythmias (42), whereas incidents of bradycardia, bone weaknesses, and hematopoietic defects were seen in the Cx43 G60S mice (41). Interestingly, these latter defects are rarely reported in the small cohort of human ODDD patients, raising some concerns that these conditions may be more mouse-specific.…”

Oogenesis defects in a mutant mouse model of oculodentodigital dysplasia

“…However, the cardiac electrical waves described in the three mutant strains were not identical; the differences will need to be examined more carefully within a single laboratory to confirm that they represent different effects of the three mutant alleles. A reduction in litter size was reported for I130T and G138R females, but in both cases it was attributed to prenatal death; ovulation rate was not investigated (Kalcheva et al, 2007;Dobrowolski et al, 2008). It will be important to investigate whether defects in oogenesis, similar to those observed in G60S females, are also present in the I130T and G138R mutants.…”

“…Further experiments will be needed to explore the possibility that implantation failure contributes to the reduced litter sizes of Gja1 Jrt /+ females. To date, two mutant mouse models have been generated that carry human GJA1 mutations: I130T and G138R (Kalcheva et al, 2007;Dobrowolski et al, 2008); it is of interest to compare the phenotype of these two mutants with that of the Gja1 Jrt /+ phenotype. Overall, the G138R and I130T mutants demonstrated ODDD-like phenotypes that are similar to the Gja1 Jrt /+ mice (summarized in Table 2).…”

Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium

“…Changes in the localization and regulation of gap junctions during ischemic and non-ischemic heart disease are well documented (3)(4)(5)(6) and contribute to the arrhythmogenic substrate of slowed conduction, unidirectional block, and reentrant circuits (1,(7)(8)(9). The molecular mechanisms underlying gap junction remodeling remain largely unknown, but their elucidation is paramount to the development of therapies aimed at improving gap junction coupling during disease.…”