2007
DOI: 10.1073/pnas.0705472105
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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 abundanc… Show more

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Cited by 116 publications
(142 citation statements)
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“…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.…”
Section: Mouse Models Of Connexin Diseasementioning
confidence: 99%
See 1 more Smart Citation
“…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.…”
Section: Mouse Models Of Connexin Diseasementioning
confidence: 99%
“…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.…”
Section: Mouse Models Of Connexin Diseasementioning
confidence: 99%
“…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.…”
Section: Disease Models and Mechanisms 163mentioning
confidence: 99%
“…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).…”
Section: Disease Models and Mechanisms 163mentioning
confidence: 99%
“…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.…”
Section: Introductionmentioning
confidence: 99%