The basic helix-loop-helix (bHLH) transcription factor Hey2 (gridlock) is an important determinant of mammalian heart development, but its role in human ventricular septal defects is unknown. Hey2 functions as a repressor through the bHLH domain. By direct sequencing, we analyzed the sequences encoding the bHLH domain of the human HEY2 in 52 explanted hearts of unrelated patients with complex cardiac malformations, notably ventricular (VSD) and atrioventricular septal defects (AVSD). We found three nonsynonymous mutations, namely, c.286A>G (p.Thr96Ala), c.293A>C (p.Asp98Ala), and c.299T>C (p.Leu100Ser) affecting the second helix of HEY2 in the diseased cardiac tissues of two patients with AVSD. This result suggests a possible role of HEY2 in the regulation of ventricular septation in humans. Since the two AVSD patients carried also binding domain mutations in other cardiac-specific transcription factors, e.g. NKX2-5, TBX5, and GATA4, breakdown of combinatorial interactions of transcription factors may have contributed to the complexity of their cardiac malformations.
2005 Wiley-Liss, Inc.