title: MESP1 Mutations in Patients with Congenital Heart Defects.
abstract: Identifying the genetic etiology of congenital heart disease (CHD) has been challenging despite being one of the most common congenital malformations in humans. We previously identified a microdeletion in a patient with a ventricular septal defect containing over 40 genes including MESP1 (mesoderm posterior basic helix-loop-helix transcription factor 1). Because of the importance of MESP1 as an early regulator of cardiac development in both in vivo and in vitro studies, we tested for MESP1 mutations in 647 patients with congenital conotruncal and related heart defects. We identified six rare, nonsynonymous variants not seen in ethnically matched controls and one likely race-specific nonsynonymous variant. Functional analyses revealed that three of these variants altered activation of transcription by MESP1. Two of the deleterious variants are located within the conserved HLH domain and thus impair the protein-protein interaction of MESP1 and E47. The third deleterious variant was a loss-of-function frameshift mutation. Our results suggest that pathologic variants in MESP1 may contribute to the development of CHD and that additional protein partners and downstream targets could likewise contribute to the wide range of causes for CHD.
authors.affiliation: Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.
authors.forename: Petra
authors.initials: P
authors.lastname: Werner
authors.affiliation: Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.
authors.forename: Brande
authors.initials: B
authors.lastname: Latney
authors.affiliation: Division of Genetics, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, 19104.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.affiliation: Division of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, 19104.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D004285:Dogs; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C000589015:MESP1 protein, human
keywords: Conotruncal heart defects; MESP1; congenital heart disease; mesoderm posterior bHLH transcription factor 1