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Case Reports
. 2013 Sep;34(9):1226-30.
doi: 10.1002/humu.22366. Epub 2013 Jul 11.

Genetic abnormalities in FOXP1 are associated with congenital heart defects

Sheng-Wei Chang  1 , Mona Mislankar, Chaitali Misra, Nianyuan Huang, Daniel G Dajusta, Steven M Harrison, Kim L McBride, Linda A Baker, Vidu Garg
Affiliations
Case Reports

Genetic abnormalities in FOXP1 are associated with congenital heart defects

Sheng-Wei Chang et al. Hum Mutat. 2013 Sep.

Abstract

The etiology for the majority of congenital heart defects (CHD) is unknown. We identified a patient with unbalanced atrioventricular septal defect (AVSD) and hypoplastic left ventricle who harbored an ~0.3 Mb monoallelic deletion on chromosome 3p14.1. The deletion encompassed the first four exons of FOXP1, a gene critical for normal heart development that represses cardiomyocyte proliferation and expression of Nkx2.5. To determine whether 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 c.1702C>T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p.Pro568Ser). This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The orthologous murine Foxp1 p.Pro596Ser mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and Nkx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD.

Keywords: FOXP1; atrioventricular septal defect; cardiomyocyte; hypoplastic left heart syndrome.

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Figures

Figure 1
Figure 1. Deletion of FOXP1 on chromosome 3 and Foxp1 expression in human and mouse
(A) Schematic of chromosome 3. Dashed line indicates location of microdeletion of FOXP1 in region of chromosome 3p14.1. ◇, miR-1284 locus. (B) FOXP1 mRNA is expressed at higher levels in the human fetal heart as compared to other fetal tissues by qRT-PCR. FOXP1 mRNA is expressed at higher levels in the human fetal and adult ovary than the fetal and adult testis by qRT-PCR. (C) Expression of Foxp1 protein in murine atria and ventricles at various embryonic and postnatal timepoints. β-actin is shown as loading control. *, p value<0.05.
Figure 2
Figure 2. Identification of FOXP1 c.1702C>T variation (p.Pro568Ser) in individual with CHD and functional analysis of murine Foxp1 P596S protein
(A) Sequence chromatogram showing heterozygous C to T transition at nucleotide position 1702 in affected subject as compared to control individual. Asterisk (*) indicates the location of c.1702C>T transition as +1 corresponds to the A of the ATG of FOXP1 (GenBank accession number NM_032682.5). (B) Summary of non-synonymous FOXP1 p.Pro568Ser variation identified in children with CHD. (C) Luciferase reporter assays using the 3kb mouse Nkx2.5 promoter/enhancer demonstrates that the murine Foxp1 p.P596S mutant protein without wildtype Foxp1 does not repress the Nkx2.5-luciferase reporter as compared to wildtype Foxp1. The addition of Foxp1 p.P596S mutant did not affect the ability of wildtype Foxp1 to repress reporter activation. *, p<0.05 comparison between empty vector and Foxp1; #, p<0.05 comparison between wildtype Foxp1 and Foxp1 p.P596S. Luciferase activity is normalized to β-gal. (D) Expression of CyclinD1, CyclinD2, CyclinA2 and Nkx2.5 mRNA was increased with transfection of Foxp1 p.P596S plasmid alone as compared to wildtype Foxp1 in H9C2 cardiomyoblasts as measured by qRT-PCR. (E) Transient transfection of Foxp1 p.P596S mutation without wildtype Foxp1 is unable to repress proliferation of H9C2 cardiomyoblasts as compared to wildtype Foxp1 as measured by immunofluorescent staining for Ki67 and quantified in (F). DAPI is shown in blue. *, p<0.05. Scale bar indicates 100μm.
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