Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
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DOI：
10.1038/ng772
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发表时间：
2001-12-01
期刊：
影响因子：
30.8
通讯作者：
Gelb, BD
中科院分区：
文献类型：
--
作者：
Tartaglia, M;Mehler, EL;Gelb, BD
努南综合征 (MIM 163950) 是一种常染色体显性遗传疾病，其特征是面部特征畸形、身材矮小和心脏病（最常见的是肺动脉瓣狭窄和肥厚性心肌病）(1,2)。颈蹼、胸部畸形、隐睾、智力低下和出血素质也常与本病相关。这种综合征相对常见，估计发病率为 1,000-2,500 名活产儿中就有 1 人发病。它已被定位到染色体 12q24.1 上的 5-cM 区域 (N-SH2)，并且遗传异质性也已被记录(3-6)。在这里，我们发现 PTPN11 (MIM 176876)（编码非受体蛋白酪氨酸磷酸酶 SHP-2 的基因，包含两个 Src 同源 2 (SH2) 结构域）的错义突变会导致努南综合征，并占我们检查病例的 50% 以上。所有 PTPN11 错义突变都聚集在氨基 N-SH2 结构域和磷酸酪氨酸磷酸酶结构域的相互作用部分，这些结构域参与蛋白质在非活性和活性构象之间的转换。对两个 N-SH2 突变体进行的基于能量学的结构分析表明，在这些突变体中，平衡可能发生显着的有利于活性构象的转变。这意味着它们是功能获得性变化，并且努南综合征的发病机制源于过度的 SHP-2 活性。
Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy)(1,2). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. it has been mapped to a 5-cM region (N-SH2) on chromosome 12q24.1, and genetic heterogeneity has also been documented(3-6). Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.