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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling
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GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

机译：GATA6突变通过破坏信号量-plexin信号传导导致人类心脏流出道缺陷

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摘要

Congenital heart diseases (CHD) occur in nearly 1 % of all live births and are the major cause of infant mortality and morbidity. Although an improved understanding of the genetic causes of CHD would provide insight into the underlying pathobiology, the genetic etiology of most CHD remains unknown. Here we show that mutations in the gene encoding the transcription factor GATA6 cause CHD characteristic of a severe form of cardiac outflow tract (OFT) defect, namely persistent truncus arteriosus (PTA). Two different GATA6 mutations were identified by systematic genetic analysis using DNA from patients with PTA. Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis further suggests that, in the developing heart, the expression of SEMA3C in the OFT/subpul-monary myocardium and PLXNA2 in the cardiac neural crest contributing to the OFT is dependent on GATA transcription factors. Together, our data implicate mutations in GATA6 as genetic causes of CHD involving OFT development, as a result of the disruption of the direct regulation of semaphorin-plexin signaling.
机译：先天性心脏病（CHD）占所有活产婴儿的近1％，是婴儿死亡率和发病率的主要原因。尽管对冠心病的遗传原因有了更好的了解，可以深入了解潜在的病理生物学，但是大多数冠心病的遗传病因仍然未知。在这里，我们表明，编码转录因子GATA6的基因中的突变导致严重形式的心脏流出道（OFT）缺陷，即持续性动脉干（PTA）的冠心病特征。通过使用来自PTA患者的DNA进行系统的遗传分析，鉴定出两个不同的GATA6突变。编码神经血管引导分子信号蛋白3C（SEMA3C）及其受体plexin A2（PLXNA2）的基因似乎直接受到GATA6的调控，并且两种GATA6突变蛋白均未能激活这些基因。转基因分析进一步表明，在发育中的心脏中，OFTA /亚肺下心肌中SEMA3C的表达以及对OFT起作用的心脏神经neural中PLXNA2的表达依赖于GATA转录因子。在一起，我们的数据表明GATA6中的突变是CHD涉及OFT发展的遗传原因，这是对信号量-plexin信号直接调节的破坏。

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  • 作者

    Kazuki Kodo; Tsutomu Nishizawa; Michiko Furutani; Shoichi Arai; Eiji Yamamura; Kunitaka Joo; Takao Takahashi; Rumiko Matsuoka; Hiroyuki Yamagishi;

  • 作者单位

    Department of Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan;

    International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan;

    International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan Division of Pediatric Cardiology, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan;

    International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan;

    Division of Pediatric Cardiology, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan;

    Department of Pediatrics, Kyushu Koseinenkin Hospital, 1-8-1 Kishinoura Yahatanishi-ku, Kitakyushu 806-8501, Japan;

    Department of Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan;

    International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan Division of Pediatric Cardiology, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan;

    Department of Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1, Kawadacho, Shinjyuku-ku, Tokyo 162-8666, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    congenital heart disease; persistent truncus arteriosus; cardiac neural crest;

    机译：先天性心脏病;持续性动脉瘤心脏神经rest;

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