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Titolo:
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
Autore:
Tartaglia, M; Mehler, EL; Goldberg, R; Zampino, G; Brunner, HG; Kremer, H; van der Burgt, I; Crosby, AH; Ion, A; Jeffery, S; Kalidas, K; Patton, MA; Kucherlapati, RS; Gelb, BD;
Indirizzi:
Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA Mt Sinai Sch Med New York NY USA 10029 ept Pediat, New York, NY 10029 USA Mt Sinai Sch Med, Dept Physiol & Biophys, New York, NY 10029 USA Mt Sinai Sch Med New York NY USA 10029 & Biophys, New York, NY 10029 USA Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA Mt Sinai Sch Med New York NY USA 10029 uman Genet, New York, NY 10029 USA Ist Super Sanita, Lab Metab & Biochim Patol, I-00161 Rome, Italy Ist SuperSanita Rome Italy I-00161 & Biochim Patol, I-00161 Rome, Italy Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA Albert Einstein Coll Med Bronx NY USA 10461 ol Genet, Bronx, NY 10461 USA Univ Cattolica Sacro Cuore, Ist Clin Pediat, Rome, Italy Univ Cattolica Sacro Cuore Rome Italy ore, Ist Clin Pediat, Rome, Italy Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands Univ Nijmegen Nijmegen Netherlands t Human Genet, Nijmegen, Netherlands Univ London St Georges Hosp, Sch Med, Dept Med Genet, London SW17 0RE, England Univ London St Georges Hosp London England SW17 0RE on SW17 0RE, England
Titolo Testata:
NATURE GENETICS
fascicolo: 4, volume: 29, anno: 2001,
pagine: 465 - 468
SICI:
1061-4036(200112)29:4<465:MIPETP>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
SH-PTP2; MUTANT; KINASE; MICE; CONFORMATIONS; ACTIVATION; CELL; SYP;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Tartaglia, M Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA Mt Sinai Sch Med New York NY USA 10029 ew York, NY 10029 USA
Citazione:
M. Tartaglia et al., "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome", NAT GENET, 29(4), 2001, pp. 465-468

Abstract

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.

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Documento generato il 10/07/20 alle ore 12:54:05