Developmentally modulated cardiac conduction failure in transgenic mice with fetal or postnatal overexpression of DNA nonbinding mutant Nkx2.5.
BACKGROUND
Nkx2.5 is a conserved homeodomain (HD) containing transcription factor essential for early cardiac development. We generated a DNA nonbinding missense mutation, I183P in the HD, similar to the missense HD mutation found in patients. Transgenic mice expressing this mutation under beta-MHC promoter [beta-MHC(I183P)] showed a postnatal lethal phenotype with heart failure. In contrast, mice expressing the mutation under alpha-MHC promoter [alpha-MHC(I183P)] survive, with later onset heart failure. The aim of this study was to investigate the interrelationship between lethal cardiac failure and the electrophysiologic (EP) phenotypes using cardiac-specific promoters with mutant gene expression at different stages of development and maturation.


RESULTS
In beta-MHC(I183P) and wild-type littermates, six-lead ECG and in vivo endocardial EP studies were performed at 2.5, 3, 4, and 5 weeks of age. In alpha-MHC(I183P) and their wild-type controls, ECGs were acquired at 3, 19, 31, and 64 weeks and in vivo EP studies assessed at 19 +/- 4 weeks of age. Beta-MHC(I183P) mice display AV nodal, atrial, and ventricular EP dysfunction by 3 weeks of age. Bradycardia and PR prolongation were evident on telemetered ambulatory ECG of beta-MHC(I183P) mice. In contrast, alpha-MHC(I183P) mice had no abnormalities on serial ECG through 31 weeks or EP findings at 19 weeks, except increased myocardial tissue refractoriness. However, by 64 weeks, PR intervals lengthened in alpha-MHC(I183P) mice.


CONCLUSIONS
Both prenatal and postnatal overexpression of DNA nonbinding mutant Nkx2.5 are associated with AV conduction malfunction and heart failure; however, more profound progressive EP defects are seen when this mutation expresses during fetal and neonatal periods. These conduction abnormalities may contribute to the lethal heart failure and early mortality evident in DNA nonbinding mutant Nkx2.5 mice.
Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
Hiroko
H
Wakimoto
Hideko
H
Kasahara
Colin T
CT
Maguire
Seigo
S
Izumo
Charles I
CI
Berul
D000818:Animals; D017630:Connexins / Q000378:metabolism; D015536:Down-Regulation; D015716:Electrocardiography, Ambulatory; D004594:Electrophysiology; D015870:Gene Expression; D006329:Heart Conduction System / Q000002:abnormalities* / Q000196:embryology* / Q000254:growth & development; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000502:physiology; D014157:Transcription Factors; D024723:Ventricular Myosins / Q000502:physiology; D029867:Xenopus Proteins
D017630:Connexins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D029867:Xenopus Proteins; D024723:Ventricular Myosins