Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5
Details
Publication Year 2000-11-10, Volume 87, Issue #10, Page 888-895
Journal Title
CIRCULATION RESEARCH
Publication Type
Journal Article
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 139/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.
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Keywords
PATENT FORAMEN OVALE; TINMAN-RELATED GENES; HEART DEVELOPMENT; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; EXPRESSION; DEFECTS; MOUSE; CELLS
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Creation Date: 2000-11-10 12:00:00
Last Modified: 0001-01-01 12:00:00
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