PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.

TitlePTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.
Publication TypeJournal Article
Year of Publication2002
AuthorsMaheshwari, M, Belmont, J, Fernbach, S, Ho, T, Molinari, L, Yakub, I, Yu, F, Combes, A, Towbin, J, Craigen, WJ, Gibbs, RA
JournalHum Mutat
Volume20
Issue4
Pagination298-304
Date Published2002 Oct
ISSN1098-1004
KeywordsCatalytic Domain, DNA Mutational Analysis, Exons, Female, Humans, Intracellular Signaling Peptides and Proteins, Isoenzymes, Male, Mutation, Noonan Syndrome, Phenotype, Protein Structure, Quaternary, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatases, Recurrence, SH2 Domain-Containing Protein Tyrosine Phosphatases, src Homology Domains
Abstract

We surveyed 16 subjects with the clinical diagnosis of Noonan Syndrome (NS1) from 12 families and their relevant family members for mutations in PTPN11/SHP2 using direct DNA sequencing. We found three different mutations among five families. Two unrelated subjects shared the same de novo missense substitution in exon 13 (S502T); an additional two unrelated families had a mutation in exon 3 (Y63C); and one subject had the amino acid substitution Y62D, also in exon 3. None of the three mutations were present in ethnically matched controls. In the mature protein model, the exon 3 mutants and the exon 13 mutant amino acids cluster at the interface between the N' SH2 domain and the phosphatase catalytic domain. Six of eight subjects with PTPN11/SHP2 mutations had pulmonary valve stenosis while no mutations were identified in those subjects (N = 4) with hypertrophic cardiomyopathy. An additional four subjects with possible Noonan syndrome were evaluated, but no mutations in PTPN11/SHP2 were identified. These results confirm that mutations in PTPN11/SHP2 underlie a common form of Noonan syndrome, and that the disease exhibits both allelic and locus heterogeneity. The observation of recurrent mutations supports the hypothesis that a special class of gain-of-function mutations in SHP2 give rise to Noonan syndrome.

DOI10.1002/humu.10129
Alternate JournalHum. Mutat.
PubMed ID12325025
Grant List5U5HG002051 / HG / NHGRI NIH HHS / United States
HD39056 / HD / NICHD NIH HHS / United States
P01 HL67155 / HL / NHLBI NIH HHS / United States