Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation
Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation
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DOI：
10.1038/nm1084
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发表时间：
2004-08-01
期刊：
影响因子：
82.9
通讯作者：
Neel, BG
中科院分区：
文献类型：
--
作者：
Araki, T;Mohi, MG;Neel, BG
努南综合征是一种常见的人类常染色体显性出生缺陷，其特征是身材矮小、面部异常、心脏缺陷以及可能增加患白血病的风险。编码蛋白酪氨酸磷酸酶 Shp2 的 Ptpn11（也称为 Shp2）突变发生在大约 50% 的努南综合征个体中，但其分子、细胞和发育影响以及努南综合征和白血病之间的关系尚不清楚。我们培育了表达努南综合征相关突变体 D61G 的小鼠。当纯合子时，D61G 突变体是胚胎致死的，而杂合子则活力降低。存活的 Ptpn11(D61G/+) 胚胎（约 50%）具有身材矮小、颅面部异常（类似于努南综合征）和骨髓增生性疾病。严重受影响的 Ptpn11(D61G/+) 胚胎（大约 50%）具有多种心脏缺陷，与缺乏 Ras-GAP 蛋白神经纤维蛋白的小鼠相似。它们的心内膜垫增加了 Erk 激活，但 Erk 过度激活是细胞和通路特异性的。我们的结果阐明了努南综合征和白血病之间的关系，并表明单个 Ptpn11 功能获得性突变通过以基因剂量依赖性和途径选择性的方式作用于多个发育谱系，从而诱发努南综合征的所有主要特征。
Noonan syndrome is a common human autosomal dominant birth defect, characterized by short stature, facial abnormalities, heart defects and possibly increased risk of leukemia. Mutations of Ptpn11 ( also known as Shp2), which encodes the protein-tyrosine phosphatase Shp2, occur in similar to50% of individuals with Noonan syndrome, but their molecular, cellular and developmental effects, and the relationship between Noonan syndrome and leukemia, are unclear. We generated mice expressing the Noonan syndrome - associated mutant D61G. When homozygous, the D61G mutant is embryonic lethal, whereas heterozygotes have decreased viability. Surviving Ptpn11(D61G/+) embryos (similar to 50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11(D61G/+) embryos (similar to50%) have multiple cardiac defects similar to those in mice lacking the Ras-GAP protein neurofibromin. Their endocardial cushions have increased Erk activation, but Erk hyperactivation is cell and pathway specific. Our results clarify the relationship between Noonan syndrome and leukemia and show that a single Ptpn11 gain-of-function mutation evokes all major features of Noonan syndrome by acting on multiple developmental lineages in a gene dosage - dependent and pathway-selective manner.