Slow ventricular conduction in mice heterozygous for a connexin43 null mutation.

Guerrero, Patricia A.; Schuessler, Richard B.; Davis, Lloyd M.; Beyer, Eric C.; Johnson, Carolyn M.; Yamada, Kiyomi; Saffitz, Jeffrey E.

doi:10.1172/jci119367

Cited by 292 publications

(212 citation statements)

References 26 publications

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“…Cx43 has long been known to be the principle conductor of the intercellular current in ventricular cardiomyocytes 39,40 . Since we identified Tmem65 as a protein that interacts with and regulates Cx43 expression/localization, we hypothesized that Tmem65 is functionally involved in regulating gap junction communication.…”

Section: Resultsmentioning

confidence: 99%

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

et al. 2015

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Membrane proteins are crucial to heart function and development. Here we combine cationic silica-bead coating with shotgun proteomics to enrich for and identify plasma membrane-associated proteins from primary mouse neonatal and human fetal ventricular cardiomyocytes. We identify Tmem65 as a cardiac-enriched, intercalated disc protein that increases during development in both mouse and human hearts. Functional analysis of Tmem65 both in vitro using lentiviral shRNA-mediated knockdown in mouse cardiomyocytes and in vivo using morpholino-based knockdown in zebrafish show marked alterations in gap junction function and cardiac morphology. Molecular analyses suggest that Tmem65 interaction with connexin 43 (Cx43) is required for correct localization of Cx43 to the intercalated disc, since Tmem65 deletion results in marked internalization of Cx43, a shorter half-life through increased degradation, and loss of Cx43 function. Our data demonstrate that the membrane protein Tmem65 is an intercalated disc protein that interacts with and functionally regulates ventricular Cx43.

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Section: Resultsmentioning

confidence: 99%

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

et al. 2015

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“…In addition to dysmorphogenesis of the heart leading to early neonatal death (31,38), offspring lacking Cx43 exhibit pathophysiological features in a variety of organs. These include slowed cardiac conduction and increased susceptibility to arrhythmias (8,14,22), precataractogenic lesions in the lenses (12), delayed ossification and osteoblast dysfunction (21), impaired hematopoiesis (27), reduced germ cell numbers in the fetal gonads (17), and disrupted gametogenesis in both sexes (1,32). It is the latter consequence of the loss of Cx43 that is the focus of the present report.…”

mentioning

confidence: 94%

Functional analysis of gap junctions in ovarian granulosa cells: distinct role for connexin43 in early stages of folliculogenesis

Gittens

Mhawi

Lidington

et al. 2003

American Journal of Physiology-Cell Physiology

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Ovarian granulosa cells are coupled via gap junctions containing connexin43 (Cx43 or α-1 connexin). In the absence of Cx43, granulosa cells stop growing in an early preantral stage. However, the fact that granulosa cells of mature follicles express multiple connexins complicated interpretation of this finding. The present experiments were designed to clarify the role of Cx43 vs. these other connexins in the earliest stages of folliculogenesis. Dye injection experiments revealed that granulosa cells from Cx43 knockout follicles are not coupled, and this was confirmed by ionic current injections. Furthermore, electron microscopy revealed that gap junctions are extremely rare in mutant granulosa cells. In contrast, mutant granulosa cells were able to form gap junctions with wild-type granulosa cells in a dye preloading assay. It was concluded that mutant granulosa cells contain a population of connexons, composed of an unidentified connexin, that do not normally contribute to gap junctions. Therefore, although Cx43 is not the only gap junction protein present in granulosa cells of early preantral follicles, it is the only one that makes a significant contribution to intercellular coupling.

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“…Subsequent studies delineate the abnormal cardiac morphogenetic process and changes in blood pressure and heart rate [Guerrero et al, 1997;Ya et al, 1998;Liao et al, 2001]. Mice with a homozygous lack of the carboxyl-terminal portion of Cx43 (K258X) [Maass et al, 2004] die shortly after birth (o3% survival to adulthood) due to a defect of the epidermal barrier resulting from lack of terminal keratinocyte differentiation brought about by the prolonged half life of mutant Cx43 gap junction channels in the upper layers of the epidermis.…”

Section: Introductionmentioning

confidence: 99%

GJA1mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype

et al. 2009

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The predominantly autosomal dominant disorder, oculodentodigital dysplasia (ODDD) has high penetrance with intra-and interfamilial phenotypic variability. Abnormalities observed in ODDD affect the eye, dentition, and digits of the hands and feet. Patients present with a characteristic facial appearance, narrow nose, and hypoplastic alae nasi. Neurological problems, including dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, are known to occur as well as conductive hearing loss, cardiac defects, and anomalies of the skin, hair, and nails. In 2003, our analysis of 17 ODDD families revealed that each had a different mutation within the human gap junction alpha 1 (GJA1) gene which encodes the protein connexin 43 (Cx43). Since then at least 17 publications have identified an additional 26 GJA1 mutations and in this study, we present 28 new cases with 18 novel GJA1 mutations. We include tables summarizing the 62 known GJA1 nucleotide changes leading to Cx43 protein alterations and the phenotypic information available on 177 affected individuals from 54 genotyped families. Mutations resulting in ODDD occur in each of the nine domains of the Cx43 protein, and we review our functional experiments and those in the literature, examining the effects of 13 different Cx43 mutations upon gap junction activity.

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Slow ventricular conduction in mice heterozygous for a connexin43 null mutation.

Cited by 292 publications

References 26 publications

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

Functional analysis of gap junctions in ovarian granulosa cells: distinct role for connexin43 in early stages of folliculogenesis

GJA1mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype

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