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. Circ Cardiovasc Genet 2014 Aug;7(4):423-433
Date
07/17/2014Pubmed ID
25028484Pubmed Central ID
PMC4140955DOI
10.1161/CIRCGENETICS.113.000281Scopus ID
2-s2.0-84925969711 (requires institutional sign-in at Scopus site) 39 CitationsAbstract
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.
Author List
Ashraf H, Pradhan L, Chang EI, Terada R, Ryan NJ, Briggs LE, Chowdhury R, Zárate MA, Sugi Y, Nam HJ, Benson DW, Anderson RH, Kasahara HMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Disease Models, Animal
Gene Knock-In Techniques
Heart Defects, Congenital
Heart Ventricles
Heterozygote
Homeobox Protein Nkx-2.5
Homeodomain Proteins
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Molecular Sequence Data
Mutation, Missense
Phenotype
Protein Structure, Tertiary
Transcription Factors