title: A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation.
abstract: BACKGROUND
  Heterozygous human mutations of NKX2-5 are highly penetrant and associated with varied congenital heart defects. The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy between human and mouse genetics. Because missense mutations in the NKX2-5 homeodomain (DNA-binding domain) are the most frequently reported type of human mutation, we replicated this genetic defect in a murine knockin model.
  
  
  RESULTS
  We generated a murine model in a 129/Sv genetic background by knocking-in an Nkx2-5 homeodomain missense mutation previously identified in humans. The mutation was located at homeodomain position 52Arg→Gly (R52G). All the heterozygous neonatal Nkx2-5(+/R52G) mice demonstrated a prominent trabecular layer in the ventricular wall, so called noncompaction, along with diverse cardiac anomalies, including atrioventricular septal defects, Ebstein malformation of the tricuspid valve, and perimembranous and muscular ventricular septal defects. In addition, P10 Nkx2-5(+/R52G) mice demonstrated atrial sepal anomalies, with significant increase in the size of the interatrial communication and fossa ovalis, and decrease in the length of the flap valve compared with control Nkx2-5(+/+) or Nkx2-5(+/-) mice.
  
  
  CONCLUSIONS
  The results of our study demonstrate that heterozygous missense mutation in the murine Nkx2-5 homeodomain (R52G) is highly penetrant and result in pleiotropic cardiac effects. Thus, in contrast to heterozygous Nkx2-5 knockout mice, the effects of the heterozygous knockin mimic findings in humans with heterozygous missense mutation in NKX2-5 homeodomain.
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashraf
authors.affiliation: Department of Bioengineering, University of Texas at Dallas, TX 75080.
authors.forename: Lagnajeet
authors.initials: L
authors.lastname: Pradhan
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Eileen I
authors.initials: EI
authors.lastname: Chang
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Ryota
authors.initials: R
authors.lastname: Terada
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Ryan
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Briggs
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Rajib
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Zárate
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sugi
authors.affiliation: Department of Bioengineering, University of Texas at Dallas, TX 75080.
authors.forename: Hyun-Joo
authors.initials: HJ
authors.lastname: Nam
authors.affiliation: Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Anderson
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Hideko
authors.initials: H
authors.lastname: Kasahara
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology; D006579:Heterozygote; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors
keywords: congenital; genetics