Poster abstracts

Poster number 49 submitted by Sheng-Wei Chang

Genetic abnormalities in FOXP1 are associated with congenital heart defects

Sheng-Wei Chang (Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Childrens Hospital), Mona Mislankar (Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Childrens Hospital), Chaitali Misra (Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Childrens Hospital), Nianyuan Huang (Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Childrens Hospital), Daniel G. DaJusta (Department of Urology, University of Texas Southwestern Medical Center), Steven M. Harrison (Department of Urology, University of Texas Southwestern Medical Center)

Abstract:
The etiology for the majority of congenital heart defects (CHD) is unknown but genetic contributors are implicated. A 0.3Mb monoallelic deletion on chromosome 3p14.1, encompassing the first 4 exons of FOXP1, was identified using chromosomal microarray in a patient with unbalanced atrioventricular septal defect (AVSD) and hypoplastic left ventricle. FOXP1, a member of Forkhead box family of transcription factors, is critical for normal heart development and represses cardiomyocyte proliferation and expression of NKX2.5, a gene implicated in human CHD. To determine if FOXP1 mutations are found in patients with CHD, we sequenced FOXP1 in 82 patients with AVSD or hypoplastic left heart syndrome. We discovered two patients who harbored a heterozygous C1702T variant that predicted the amino acid substitution, P568S. The proline at position 568 is highly conserved and is predicted to result in functional deficits. This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The FOXP1 P568S mutant protein displayed a reduced ability to repress Nkx2.5 in luciferase reporter assays and expression in HL-1 cardiomyocytes resulted in increased proliferation and Nkx2.5 expression. Our data suggest that FOXP1 mutations are associated with human CHD and that FOXP1 P568S is a loss-of-function mutant.

Keywords: congenital heart defect, FOXP1, cardiomyocyte proliferation