Araki Toshiyuki, Chan Gordon, Newbigging Susan, Morikawa Lily, Bronson Roderick T, Neel Benjamin G
Division of Hematology/Oncology and Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4736-41. doi: 10.1073/pnas.0810053106. Epub 2009 Feb 27.
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-activating 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.
努南综合征（NS）是先天性心脏病最常见的单基因病因，是一种常染色体显性疾病，其特征还包括身材比例矮小、面部异常以及骨髓增殖性疾病风险增加。编码蛋白酪氨酸磷酸酶SHP2的PTPN11基因中的种系激活突变导致约一半的NS病例；其他致病等位基因包括KRAS、SOS1和RAF1突变体。我们之前表明，在129S4/SvJae X C57BL6/J混合背景下携带NS突变体Ptpn11（D61G）的基因敲入小鼠表现出所有主要的NS特征，包括各种心脏缺陷，且外显率可变。然而，NS心脏缺陷背后的细胞和分子机制以及遗传背景和/或特定的NS突变是否对NS表型有影响仍不清楚。在这里，我们使用诱导性基因敲入方法表明，NS中的所有心脏缺陷都是由心内膜而非心肌或神经嵴中的突变型Shp2表达引起的。此外，NS缺陷的外显率受遗传背景和特定的Ptpn11等位基因影响。最后，体外试验和药理学方法表明，NS突变体通过增加Erk MAPK激活导致心脏瓣膜缺陷，可能是在ErbB家族受体酪氨酸激酶下游，延长了心脏心内膜细胞经历心内膜-间充质转化的时间间隔。我们的数据为这种疾病中的心脏缺陷提供了机制基础。
