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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation
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Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation

机译：Noonan综合征的心脏缺陷是由PTPN11在心内膜中起作用以增强心内膜-间质转化引起的

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摘要

Noonan syndrome (NS), the most common single-gene cause of congenital heart disease, is an autosomal dominant disorder that also features proportionate short stature, facial abnormalities, and an increased risk of myeloproliferative disease. Germline-activat-ing mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, cause about half of NS cases; other causative alleles include KRAS, SOS1, and RAF1 mutants. We showed previously that knock-in mice bearing the NS mutant Ptpn11~(D61G) on a mixed 129S4/SvJae X C57BL6/J background exhibit all major NS features, including a variety of cardiac defects, with variable penetrance. However, the cellular and molecular mechanisms underlying NS cardiac defects and whether genetic background and/or the specific NS mutation contribute to the NS phenotype remained unclear. Here, using an inducible knock-in approach, we show that all cardiac defects in NS result from mutant Shp2 expression in the endocardium, not in the myocardium or neural crest. Furthermore, the penetrance of NS defects is affected by genetic background and the specific Ptpn11 allele. Finally, ex vivo assays and pharmacological approaches show that NS mutants cause cardiac valve defects by increasing Erk MAPK activation, probably downstream of ErbB family receptor tyrosine kinases, extending the interval during which cardiac endocardial cells undergo endocardial-mesenchymal transformation. Our data provide a mechanistic underpinning for the cardiac defects in this disorder.
机译：先天性心脏病最常见的单基因病因是Noonan综合征（NS），是一种常染色体显性遗传疾病，其特征还在于矮小的身材，面部畸形和骨髓增生性疾病的风险增加。编码蛋白质酪氨酸磷酸酶SHP2的PTPN11中的种系激活突变引起大约一半的NS病例。其他致病等位基因包括KRAS，SOS1和RAF1突变体。先前我们已经证明，在混合的129S4 / SvJae X C57BL6 / J背景下带有NS突变体Ptpn11〜（D61G）的敲入小鼠表现出所有主要的NS功能，包括各种心脏缺陷和不同的渗透性。然而，尚不清楚NS心脏缺陷的潜在细胞和分子机制，以及遗传背景和/或特定的NS突变是否有助于NS表型。在这里，我们使用诱导性敲入方法，表明NS中的所有心脏缺陷均由心内膜而不是心肌或神经rest中的突变Shp2表达引起。此外，NS缺陷的渗透性受遗传背景和特定的Ptpn11等位基因影响。最后，离体测定和药理学方法表明，NS突变体可能通过增加Erk MAPK激活（可能在ErbB家族受体酪氨酸激酶的下游），延长心脏心内膜细胞进行心内膜间质转化的间隔而引起心脏瓣膜缺陷。我们的数据为这种疾病的心脏缺陷提供了机械基础。

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    Toshiyuki Araki; Gordon Chan; Susan Newbigging; Lily Morikawa; Roderick T. Bronson; Benjamin G. Neel;

  • 作者单位

    Division of Hematology/Oncology and Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115 Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, 101 College Street, TMDT8-355, Toronto, ON, Canada M5G1L7;

    Division of Hematology/Oncology and Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115 Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, 101 College Street, TMDT8-355, Toronto, ON, Canada M5G1L7;

    Pathology Core, Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, Toronto, ON, Canada M5T 3H7;

    Pathology Core, Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, Toronto, ON, Canada M5T 3H7;

    Rodent Histopathology Core, Harvard Medical School, Goldenson 141, Boston, MA 02115;

    Division of Hematology/Oncology and Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115 Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, 101 College Street, TMDT8-355, Toronto, ON, Canada M5G1L7;

  • 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
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  • 关键词

    cardiac development; human disease; signal transduction; protein tyrosine phosphatase; cardiac valves;

    机译：心脏发育;人类疾病;信号转导;蛋白酪氨酸磷酸酶;心脏瓣膜;

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