title: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.
abstract: Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.
authors: Department of Pediatrics, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors: Marco
authors: M
authors: Tartaglia
authors: Kamini
authors: K
authors: Kalidas
authors: Adam
authors: A
authors: Shaw
authors: Xiaoling
authors: X
authors: Song
authors: Dan L
authors: DL
authors: Musat
authors: Ineke
authors: I
authors: van der Burgt
authors: Han G
authors: HG
authors: Brunner
authors: Débora R
authors: DR
authors: Bertola
authors: Andrew
authors: A
authors: Crosby
authors: Andra
authors: A
authors: Ion
authors: Raju S
authors: RS
authors: Kucherlapati
authors: Steve
authors: S
authors: Jeffery
authors: Michael A
authors: MA
authors: Patton
authors: Bruce D
authors: BD
authors: Gelb
mesh_terms: D002021:Buffers; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009634:Noonan Syndrome / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011487:Protein Conformation; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics*; D013696:Temperature
chemical_list: D002021:Buffers; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases