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.

Clinically aggressive central giant cell granulomas in two patients with neurofibromatosis 1

“…Possible origins of these mononuclear cells include endothelial cells 30 , myofibroblasts 31 with Noonan syndrome. 34,35 Missense mutations in the gene PTPN11 37 , which encodes the non-receptor tyrosine phosphatase protein SHP-2 38 and is responsible for Noonan syndrome, were identified in two siblings inheriting Noonan-like/ multiple giant cell lesions syndrome 39 and in one patient who progressed from Noonan syndrome to multiple lentigines/LEOPARD syndrome and ultimately to Noonan-like/ multiple giant cell lesions syndrome. 40 Moreover, there has been one report of a patient with NF1-Noonan-like phenotype with a solitary CGCG of the jaws.…”

Association between serum pepsinogens and polymorphismof PTPN11 encoding SHP‐2 among Helicobacter pylori seropositive Japanese

“…15,16 It is widely expressed in both embryonic and adult tissues and is required in several developmental processes, including gastrulation and mesodermal patterning. 17,18 Germline mutations in PTPN11, the gene encoding SHP-2, play a major role in the pathogenesis of Noonan syndrome, 19,20 juvenile myelomonocytic Leukemia 21 and Leopard syndrome. 22 All mutations were missense changes and clustered at the interacting portions of the amino terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase domains.…”

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

“…Upon binding of phosphotyrosyl peptides, the self‐locking conformation is disrupted, freeing the PTP domain for catalysis (active state) 23. Most PTPN11 mutations in NS are clustered in exons 3, 4, 7, 8, 12, and 13, which mainly affect residues involved in the interface between N‐SH2 and PTP domains, leading to gain‐of‐function 5, 12, 24…”

“…To the best of our knowledge, 22 patients with NS with p.Thr42Ala have been reported in literature (Table 1). 12, 13, 15, 17, 21, 25, 26, 27, 28, 29, 30, 31, 32 However, data were limited because of the lack of a detailed description of their clinical features (Table 1). Among these reported patients with NS with p.Thr42Ala mutation in PTPN11 , ASD or atrioventricular canal defect (AVCD) were reported in six patients (Table 1).…”

“…Pulmonary stenosis (PS) (57%) is the most common type of CHD in individuals with NS, followed by atrial septal defect (ASD; 32%), and HCM (16%) 10, 1110, 11, 12, 13. HCM is associated with mutations in exons 7 and 12 of PTPN11 14, 15.…”