PTPN11(Protein-Tyrosine Phosphatase, Nonreceptor-Type 11) Mutations in Seven Japanese Patients with Noonan Syndrome

Abstract

Noonan syndrome is an autosomal dominant disorder defined by short stature, delayed puberty, and characteristic dysmorphic features. Tartaglia et al. (Nature Genetics, 29:465-468) have recently shown that gain-of-function mutations in the gene PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) cause Noonan syndrome in roughly half of patients that they examined. To further explore the relevance of PTPN11 mutations to the pathogenesis of Noonan syndrome, we analyzed the PTPN11 gene in 21 Japanese patients. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed six different heterozygous missense mutations (Asp61Gly, Tyr63Cys, Ala72Ser, Thr73Ile, Phe285Ser, and Asn308Asp) in seven cases (six sporadic and one familial). The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. The results provide further support to the notion that PTPN11 mutations are responsible for the development of Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11.

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“…11,12 A total of 100 ng of genomic DNA was amplified in a 20 ml reaction buffer containing 2.5 mM of each primer, 0.2 mM of deoxynucleotide triphosphate, 1.5 mM of MgCl 2 and 1.0 U of AmpliTaq Gold DNA Polymerase (Perkin-Elmer Corp., Foster City, CA). For PCR of PTPN11, the samples were denatured at 951C for 10 min, then subjected to 30 cycles at 951C for 1 min, at 581C for 1 min, and at 721C for 1 min with a final 10 min of extension at 721C.…”