Garg Vidu, Kathiriya Irfan S, Barnes Robert, Schluterman Marie K, King Isabelle N, Butler Cheryl A, Rothrock Caryn R, Eapen Reenu S, Hirayama-Yamada Kayoko, Joo Kunitaka, Matsuoka Rumiko, Cohen Jonathan C, Srivastava Deepak
Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Rm. NA8.124, Dallas, Texas 75390-9148, USA.
Nature. 2003 Jul 24;424(6947):443-7. doi: 10.1038/nature01827. Epub 2003 Jul 6.
Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs. Here, we show that isolated cardiac septal defects in a large pedigree 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 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. Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. In a second family, we identified a frame-shift mutation of GATA4 (E359del) that was transcriptionally inactive and segregated with cardiac septal defects. These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.
先天性心脏病（CHD）是最常见的发育异常，也是新生儿非感染性死亡的主要原因。通过对非综合征性CHD家系进行遗传连锁分析，仅鉴定出一个致病基因NKX2-5。在此，我们表明一个大家系中的孤立性心脏间隔缺损与8号染色体p22-23区域连锁。在所有可用的患病家庭成员中发现了心脏形成所必需的转录因子GATA4的一个杂合G296S错义突变，而在任何对照个体中均未发现。该突变导致Gata4的DNA结合亲和力和转录活性降低。此外，Gata4突变消除了Gata4与TBX5之间的物理相互作用，TBX5是一种T盒蛋白，与一部分综合征性心脏间隔缺损有关。相反，Gata4与TBX5的相互作用被导致类似心脏间隔缺损的特定人类TBX5错义突变所破坏。在第二个家系中，我们鉴定出GATA4的一个移码突变（E359del），该突变无转录活性，并与心脏间隔缺损共分离。这些结果表明GATA4可能是人类心脏间隔缺损的一个遗传原因，可能是通过其与TBX5的相互作用。
