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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

Lookup NU author(s): Professor Bob Anderson


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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.

Publication metadata

Author(s): Ashraf H, Pradhan L, Chang EI, Terada R, Ryan NJ, Briggs LE, Chowdhury R, Zarate MA, Sugi Y, Nam HJ, Benson DW, Anderson RH, Kasahara H

Publication type: Article

Publication status: Published

Journal: Circulation: Cardiovascular Genetics

Year: 2014

Volume: 7

Issue: 4

Pages: 423-433

Print publication date: 01/08/2014

Online publication date: 15/07/2014

Acceptance date: 29/05/2014

ISSN (print): 1942-325X

ISSN (electronic): 1942-3268

Publisher: Lippincott Williams & Wilkins


DOI: 10.1161/CIRCGENETICS.113.000281


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Funder referenceFunder name
13BGIA13960001American Heart Association
HL081577-05S1National Institutes of Health Recovery Act Grant