Nature Genetics
29, 465 - 468 (2001)
Published online: 12 November 2001; | doi:10.1038/ng772
There is a Correction (December 2001) associated with this Letter.
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndromeMarco Tartaglia1, 4, Ernest L. Mehler2, Rosalie Goldberg5, Giuseppe Zampino6, Han G. Brunner7, Hannie Kremer7, Ineke van der Burgt7, Andrew H. Crosby8, Andra Ion8, Steve Jeffery8, Kamini Kalidas8, Michael A. Patton8, Raju S. Kucherlapati5
& Bruce D. Gelb1, 31
Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA. 2
Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029, USA. 3
Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA. 4
Laboratorio di Metabolismo e Biochimica Patologica, Istituto Superiore di Sanità, Rome, Italy. 5
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA. 6
Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy. 7
Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands. 8
Department of Medical Genetics, St George's Hospital Medical School, London, UK.
Correspondence should be addressed to Marco Tartaglia tartam02@doc.mssm.eduNoonan 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 documented3,
4,
5,
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.
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