title: Cardiac morphogenetic defects and conduction abnormalities in mice homozygously deficient for connexin40 and heterozygously deficient for connexin45.
abstract: Connexin40 (Cx40) and connexin45 (Cx45) are involved in both cardiac morphogenesis and propagation of electrical activity. We found that Cx40/Cx45 double deficiency (Cx40(-/-)/Cx45(+/-)) causes a variety of cardiac defects leading to high mortality during embryonic development and at birth. The majority of Cx40(-/-)/Cx45(+/-) embryos and postnatal mice suffered from atrioventricular septal defects. Additional cardiac abnormalities, e.g., ventricular septal defects and abnormal myocardial arrangement, occurred at lower abundance. Electrocardiograms of Cx40(-/-)/Cx45(+/+) and Cx40(-/-)/Cx45(+/-) mice revealed prolongation of P-wave, PQ interval and QRS duration compared to controls. Interestingly, in Cx40(-/-)/Cx45(+/-) mice, PQ interval and QRS duration were significantly prolonged compared to Cx40(-/-)/Cx45(+/+) mice. We conclude that the gap junctional proteins Cx40 and Cx45 have overlapping and partially compensatory functions with regard to heart morphogenesis and cardiac conduction. Cx45 might be one of the genetic modifiers that can cause variations in the phenotype of connexin40-deficient animals. Our findings may be particularly relevant for understanding molecular factors contributing to human congenital cardiac diseases.
authors.affiliation: Institute of Genetics, Division of Molecular Genetics, University of Bonn, Roemerstr. 164, 53117 Bonn, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Krüger
authors.forename: Stephan
authors.initials: S
authors.lastname: Maxeiner
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Dominik
authors.initials: D
authors.lastname: Eckardt
authors.forename: Klaus
authors.initials: K
authors.lastname: Tiemann
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lewalter
authors.forename: Alexander
authors.initials: A
authors.lastname: Ghanem
authors.forename: Bernd
authors.initials: B
authors.lastname: Lüderitz
authors.forename: Klaus
authors.initials: K
authors.lastname: Willecke
mesh_terms: D000818:Animals; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005318:Fetal Heart / Q000002:abnormalities* / Q000503:physiopathology; D005328:Fetal Viability; D006329:Heart Conduction System / Q000002:abnormalities*; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D000097003:Gap Junction alpha-5 Protein; C082920:connexin 45