Wang Jun, Chen Li, Wen Shu, Zhu Huiping, Yu Wei, Moskowitz Ivan P, Shaw Gary M, Finnell Richard H, Schwartz Robert J
Center for Stem Cell Engineering, Texas Heart Institute, Houston, TX 77030, USA.
Birth Defects Res A Clin Mol Teratol. 2011 Jun;91(6):468-76. doi: 10.1002/bdra.20816. Epub 2011 May 11.
Congenital heart defects (CHDs) are the most common of all birth defects, yet molecular mechanism(s) underlying highly prevalent atrial septal defects (ASDs) and ventricular septal defects (VSDs) have remained elusive. We demonstrate the indispensability of "balanced" posttranslational small ubiquitin-like modifier (SUMO) conjugation-deconjugation pathway for normal cardiac development. Both hetero- and homozygous SUMO-1 knockout mice exhibited ASDs and VSDs with high mortality rates, which were rescued by cardiac reexpression of the SUMO-1 transgene. Because SUMO-1 was also involved in cleft lip/palate in human patients, the previous findings provided a powerful rationale to question whether SUMO-1 was mutated in infants born with cleft palates and ASDs. Sequence analysis of DNA from newborn screening blood spots revealed a single 16 bp substitution in the SUMO-1 regulatory promoter of a patient displaying both oral-facial clefts and ASDs. Diminished sumoylation activity whether by genetics, environmental toxins, and/or pharmaceuticals may significantly contribute to susceptibility to the induction of congenital heart disease worldwide. Birth Defects Research (Part A) 2011. © 2011 Wiley-Liss, Inc.
先天性心脏缺陷（CHD）是所有出生缺陷中最常见的，但高度普遍的房间隔缺损（ASD）和室间隔缺损（VSD）的分子机制仍然难以捉摸。我们证明了“平衡”的翻译后小泛素样修饰物（SUMO）缀合-去缀合途径对于正常心脏发育的不可或缺性。杂合和纯合SUMO-1基因敲除小鼠均表现出ASD和VSD，死亡率很高，而SUMO-1转基因的心脏重新表达可挽救这些情况。由于SUMO-1也与人类患者的唇腭裂有关，先前的发现为质疑患有腭裂和ASD的婴儿中SUMO-1是否发生突变提供了有力的依据。对新生儿筛查血斑中的DNA进行序列分析发现，一名同时患有口腔面部裂隙和ASD的患者的SUMO-1调控启动子中有一个16 bp的单碱基替换。无论是通过遗传学、环境毒素和/或药物导致的SUMO化活性降低，都可能在全球范围内显著增加先天性心脏病的易感性。《出生缺陷研究（A部分）》2011年。©2011威利-利斯公司。
