Cardiac Septal and Valvular Dysmorphogenesis in Mice Heterozygous for Mutations in the Homeobox Gene Nkx2-5
- 10 November 2000
- journal article
- other
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 87 (10), 888-895
- https://doi.org/10.1161/01.res.87.10.888
Abstract
—Heterozygous mutations in the cardiac homeobox gene, NKX2-5, underlie familial cases of atrial septal defect (ASD) with severe atrioventricular conduction block. In this study, mice heterozygous for Nkx2-5–null alleles were assessed for analogous defects. Although ASD occurred only rarely, atrial septal dysmorphogenesis was evident as increased frequencies of patent foramen ovale and septal aneurysm, and decreased length of the septum primum flap valve. These parameters were compounded by genetic background effects, and in the 129/Sv strain, septal dysmorphogenesis bordered on ASD in 17% of Nkx2-5 heterozygotes. In a proportion of neonatal heterozygotes, as well as in adults with ASD, we found that the size of the foramen ovale was significantly enlarged and altered in shape, potentially exposing the normally thin septum primum to excessive hemodynamic forces. Therefore, defective morphogenesis of the septum secundum may be one contributing factor in the generation of patent foramen ovale, septal aneurysm, and certain ASDs. Mild prolongation of P-R interval in females and an increased frequency of stenotic bicuspid aortic valves were also features of the Nkx2-5 heterozygous phenotype. Our data demonstrate that the complex effects of Nkx2-5 haploinsufficiency in mice are weaker but convergent with those in humans. As in the mouse, the phenotype of human NKX2-5 mutations may be modulated by interacting alleles.Keywords
This publication has 20 references indexed in Scilit:
- Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart diseaseJCI Insight, 2000
- Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathwaysJCI Insight, 1999
- Congenital Heart Disease Caused by Mutations in the Transcription Factor NKX2-5Science, 1998
- Expression of NK-2 class homeobox gene Nkx2–6 in foregut endoderm and heartMechanisms of Development, 1998
- An Enhanced Green Fluorescent Protein Allows Sensitive Detection of Gene Transfer in Mammalian CellsBiochemical and Biophysical Research Communications, 1996
- Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findingsThe American Journal of Cardiology, 1996
- Echocardiographic and cardiac doppler assessment of miceJournal of the American Society of Echocardiography, 1995
- Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5.Genes & Development, 1995
- Saline contrast and colour Doppler transoesophageal echocardiography in detecting a patent foramen ovale and right‐to‐left shunts in stroke patientsClinical Physiology and Functional Imaging, 1995
- Acre-transgenic mouse strain for the ubiquitous deletion ofloxP-flanked gene segments including deletion in germ cellsNucleic Acids Research, 1995