Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5

Heterozygous mutations in the cardiac homeobox gene, NKX2-5, underlie famil ial cases of atrial septal defect (ASD) with severe atrioventricular conduc tion block. In this study, mice heterozygous for Nkx2-5-null alleles were a ssessed for analogous defects. Although ASD occurred only rarely, atrial se ptal dysmorphogenesis was evident as increased frequencies of patent forame n ovale and septal aneurysm, and decreased length of the septum primum flap valve. These parameters were compounded by genetic background effects, and in the 139/Sv strain, septal dysmorphogenesis bordered on ASD in 17% of Nk x2-5 heterozygotes. In a proportion of neonatal heterozygotes, as well as i n adults with ASD, we found that the size of the foramen ovale was signific antly enlarged and altered in shape, potentially exposing the normally thin septum primum to excessive hemodynamic forces. Therefore, defective morpho genesis of the septum secundum may be one contributing factor in the genera tion of patent foramen ovale, septal aneurysm, and certain ASDs. Mild prolo ngation of P-R interval in females and an increased frequency of stenotic b icuspid aortic valves were also features of the Nkx2-5 heterozygous phenoty pe. Our data demonstrate that the complex effects of Nkx2-5 haploinsufficie ncy 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 a lleles.