Congenital heart disease (CHD) is the most common birth defect. However, the majority
of CHD cases have unknown etiology. Here we report the identification of ASXL2 and
ASXL1, two homologous chromatin factors, as novel regulators of heart development.
Asxl2(-/-) fetuses have reduced body weight and display congenital heart malformations
including thickened compact myocardium in the left ventricle, membranous ventricular
septal defect, and atrioventricular valval stenosis. Although most Asxl2(-/-) animals
survive to term, the neonates have patent ductus arteriosus and consequent lung hemorrhage
and die soon after birth. Asxl1(-/-) fetuses have reduced body weight and display
cleft palate, anophthalmia as well as ventricular septal defects and a failure in
lung maturation. From these results, we conclude that normal heart development requires
both ASXL proteins. In particular, ASXL2 plays an important role in heart morphogenesis
and the transition from fetal to postnatal circulation.