Gene for Cardiac Septal Defects Identified

Researchers have found that a mutation in the gene GATA4 causes congenital cardiac septal defects, which occur when the walls separating the heart's four chambers do not form properly.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) performed genetic linkage analyses on members of two families, one in the United States that spanned five generations and included 16 members suffering from congenital heart defects, and the other from Japan that spanned four generations and included eight members with defects. Analyses were also performed on more than 3,000 unrelated individuals.

The results, published July 6, 2003, in the online edition of Nature, showed that cardiac septal defects were linked to chromosome 8p22-23. A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation, was found in all available affected family members but not in any unaffected family members or in control individuals. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of GATA4. Furthermore, the GATA4 mutation abrogated a physical interaction between GATA4 and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal defects.

"This discovery could one day help doctors prevent congenital heart defects, the most common developmental anomaly, by fixing the problem before a baby is born,” said senior author Dr. Deepak Srivastava, associate professor of pediatrics and molecular biology at University of Texas Southwestern Medical Center. "We cannot change the fact that parents are going to pass along the mutation, but we might be able to develop a way to keep the disease from occurring.”