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Circ Cardiovasc Genet. 2014 Aug;7(4):423-433. doi: 10.1161/CIRCGENETICS.113.000281. Epub 2014 Jul 15.

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.

Author information

1
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610.
2
Department of Bioengineering, University of Texas at Dallas, TX 75080.
3
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425.
4
Department of Pediatrics, Herma Heart Center, Medical College of Wisconsin, Milwaukee, WI 53226.
5
Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
#
Contributed equally

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.

METHODS AND 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.

KEYWORDS:

congenital; genetics

PMID:
25028484
PMCID:
PMC4140955
DOI:
10.1161/CIRCGENETICS.113.000281
[Indexed for MEDLINE]
Free PMC Article
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