title: Genetic abnormalities in FOXP1 are associated with congenital heart defects.
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.
authors.affiliation: Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Sheng-Wei
authors.initials: SW
authors.lastname: Chang
authors.forename: Mona
authors.initials: M
authors.lastname: Mislankar
authors.forename: Chaitali
authors.initials: C
authors.lastname: Misra
authors.forename: Nianyuan
authors.initials: N
authors.lastname: Huang
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Dajusta
authors.forename: Steven M
authors.initials: SM
authors.lastname: Harrison
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.forename: Linda A
authors.initials: LA
authors.lastname: Baker
authors.forename: Vidu
authors.initials: V
authors.lastname: Garg
mesh_terms: D000818:Animals; D001483:Base Sequence; D002893:Chromosomes, Human, Pair 3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D005787:Gene Frequency; D056726:Genetic Association Studies; D014644:Genetic Variation; D057895:Haploinsufficiency; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism; D006343:Heart Septal Defects / Q000235:genetics*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics*; D007231:Infant, Newborn; D051379:Mice; D008969:Molecular Sequence Data; D032386:Myoblasts, Cardiac / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors
keywords: FOXP1; atrioventricular septal defect; cardiomyocyte; hypoplastic left heart syndrome