PTPN11 Mutations in Noonan Syndrome: Molecular Spectrum, Genotype-Phenotype Correlation, and Phenotypic Heterogeneity
| Autor: | Bruce D. Gelb, Han G. Brunner, Andra Ion, Ineke van der Burgt, Dan L. Musat, Michael A. Patton, Steve Jeffery, Marco Tartaglia, Andrew H. Crosby, Kamini Kalidas, Débora Romeo Bertola, Adam Shaw, Xiaoling Song, Raju Kucherlapati |
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| Rok vydání: | 2002 |
| Předmět: |
Male
Models Molecular medicine.medical_specialty Genotype Protein Conformation Heart malformation Elucidation of hereditary disorders and their molecular diagnosis DNA Mutational Analysis Buffers Biology Polymorphism Single Nucleotide LEOPARD Syndrome Cohort Studies Genetic Heterogeneity 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Genetics Humans Missense mutation Genetics(clinical) Protein Phosphatase 2 Genetics (clinical) 030304 developmental biology 0303 health sciences Genetic heterogeneity Noonan Syndrome PTPN11 Gene Mutation Temperature Genetic Variation Exons Articles medicine.disease Introns Pedigree PTPN11 Phenotype Endocrinology Mutation Noonan syndrome Female Protein Tyrosine Phosphatases Opheldering van erfelijke ziekten en hun moleculaire diagnostiek 030217 neurology & neurosurgery Noonan Syndrome with Multiple Lentigines |
| Zdroj: | American Journal of Human Genetics, 70, 6, pp. 1555-63 American Journal of Human Genetics, 70, 1555-63 |
| ISSN: | 0002-9297 |
| DOI: | 10.1086/340847 |
| Popis: | Item does not contain fulltext 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 |
| Databáze: | OpenAIRE |
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