title: Mouse Model of Human Congenital Heart Disease: Progressive Atrioventricular Block Induced by a Heterozygous Nkx2-5 Homeodomain Missense Mutation.
abstract: BACKGROUND
  Heterozygous human NKX2-5 homeodomain (DNA-binding domain) missense mutations are highly penetrant for varied congenital heart defects, including progressive atrioventricular (AV) block requiring pacemaker implantation. We recently replicated this genetic defect in a murine knockin model, in which we demonstrated highly penetrant, pleiotropic cardiac anomalies. In this study, we examined postnatal AV conduction in the knockin mice.
  
  
  RESULTS
  A murine knockin model (Arg52Gly, Nkx2-5(+/R52G)) in a 129/Sv background was analyzed by histopathology, surface, and telemetry ECG, and in vivo electrophysiology studies, comparing with control Nkx2-5(+/+) mice at diverse postnatal stages, ranging from postnatal day 1 (P1) to 17 months. PR prolongation (first degree AV block) was present at 4 weeks, 7 months, and 17 months of age, but not at P1 in the mutant mice. Advanced AV block was also occasionally demonstrated in the mutant mice. Electrophysiology studies showed that AV nodal function and right ventricular effective refractory period were impaired in the mutant mice, whereas sinus nodal function was not affected. AV nodal size was significantly smaller in the mutant mice than their controls at 4 weeks of age, corresponding to the presence of PR prolongation, but not P1, suggesting, at least in part, that the conduction abnormalities are the result of a morphologically atrophic AV node.
  
  
  CONCLUSIONS
  The highly penetrant and progressive AV block phenotype seen in human heterozygous missense mutations in NKX2-5 homeodomain was replicated in mice by knocking in a comparable missense mutation.
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: Rajib
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashraf
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Melanson
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: Yohei
authors.initials: Y
authors.lastname: Tanada
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: Michael
authors.initials: M
authors.lastname: Silberbach
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.).
authors.forename: Robert H
authors.initials: RH
authors.lastname: Anderson
authors.affiliation: From the Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (R.C., H.A., M.M., Y.T., M.N., H.K.); Department of Pediatrics, Oregon Health Science School, Portland (M.S.); Department of Genetics, Harvard Medical School, Boston, MA (H.W.); Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee (D.W.B.); and Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom (R.H.A.). hkasahar@ufl.edu.
authors.forename: Hideko
authors.initials: H
authors.lastname: Kasahara
mesh_terms: D000818:Animals; D054537:Atrioventricular Block / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D006330:Heart Defects, Congenital / Q000503:physiopathology*; D006579:Heterozygote; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D014157:Transcription Factors
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors
keywords: animal models; atrioventricular block; congenital heart defects; genetics; human