, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome

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作者：

M Tartaglia，EL Mehler，R Goldberg，G Zampino，GB Han，H Kremer，IVD Burgt，AH Crosby，A Ion，S Jeffery

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摘要：

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). 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. Here we show that missense mutations in(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. Allmissense 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.

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关键词：

Chromosomes, Human, Pair 12 Humans Noonan Syndrome Intracellular Signaling Peptides and Proteins Protein Conformation Genetic Heterogeneity Mutation, Missense Models, Molecular Molecular Sequence Data Protein Tyrosine Phosphatases