Alternative titles; symbols
HGNC Approved Gene Symbol: PTPN11
SNOMEDCT: 205481009, 205684007, 205824006; ICD10CM: Q87.19;
Cytogenetic location: 12q24.13 Genomic coordinates (GRCh38): 12:112,418,947-112,509,918 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.13 | LEOPARD syndrome 1 | 151100 | Autosomal dominant | 3 |
| Leukemia, juvenile myelomonocytic, somatic | 607785 | 3 | ||
| Metachondromatosis | 156250 | Autosomal dominant | 3 | |
| Noonan syndrome 1 | 163950 | Autosomal dominant | 3 |
The protein-tyrosine phosphatases are a highly pleomorphic set of molecules that have a role in regulating the responses of eukaryotic cells to extracellular signals (Dechert et al., 1995). They achieve this by regulating the phosphotyrosine content of specific intracellular proteins. The PTPases have been grouped by virtue of the characteristic catalytic domain sequence similarities that define this family. Dechert et al. (1995) noted that the noncatalytic domain shows a striking degree of sequence heterogeneity. In general, however, mammalian PTPases can be subdivided into 1 of 2 broad categories: (1) transmembrane receptor PTPases that contain linked cytoplasmic catalytic domains, and (2) intracellular PTPases. Included within the latter category are 2 closely related mammalian intracellular PTPases whose sequences encode 2 tandem SRC homology 2 (SH2) domains that are located at the amino-terminal side of a single PTPase catalytic domain. SH2 domains enable the binding of these SH2 domain-containing PTPases to specific phosphotyrosine residues within protein sequences. The first mammalian SH2 domain-containing PTPase identified was PTP1C (PTPN6; 176883). The second mammalian SH2 domain-containing PTPase identified is encoded by the PTPN11 gene.
Ahmad et al. (1993) isolated a cDNA encoding a nontransmembrane protein-tyrosine phosphatase (PTP; EC 3.1.3.48), termed PTP2C, from a human umbilical cord cDNA library. The open reading frame consists of 1,779 nucleotides potentially encoding a protein of 593 amino acids with a predicted molecular mass of 68 kD. The identity between the 2 SH2 domains of PTP2C (PTPN11) and PTP1C (PTPN6) is 50 to 60%, higher than the identity between the 2 SH2 domains within the same molecule. Unlike PTP1C, which is restricted to hematopoietic and epithelial cells, PTP2C is widely expressed in human tissues and is particularly abundant in heart, brain, and skeletal muscle. Ahmad et al. (1993) also identified a variant of PTP2C, termed PTP2Ci by them, which had an in-frame insertion of 12 basepairs within the catalytic domain.
By fluorescence in situ hybridization, Isobe et al. (1994) mapped the PTP2C gene to 12q24.1. It is noteworthy that the PTP1C gene maps to the short arm of chromosome 12, whereas PTP2C maps to the long arm. Dechert et al. (1995) used a 2.1-kb SH-PTP2 cDNA clone (Bastien et al., 1993) to localize the PTPN11 gene to 12q24.1-q24.3 by isotopic in situ hybridization. The presence of cross-hybridizing sequences located on a number of other chromosomes suggested that latent genes or pseudogenes are present in the human genome.
Crystal Structure
Hof et al. (1998) described the crystal structure of amino acid residues 1 to 527 of the PTPN11 protein at 2.0-angstrom resolution. The crystal structure showed how its catalytic activity is regulated by its two SH2 domains. In the absence of a tyrosine-phosphorylated binding partner, the N-terminal SH2 domain binds the phosphatase domain and directly blocks its active site. This interaction alters the structure of the N-SH2 domain, disrupting its phosphopeptide-binding cleft. Conversely, interaction of the N-SH2 domain with phosphopeptide disrupts its phosphatase recognition surface. Thus, the N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-terminal SH2 domain contributes binding energy and specificity, but does not have a direct role in activation.
Reduction of SHP2 activity suppresses tumor cell growth and is a potential target of cancer therapy. Chen et al. (2016) reported the discovery of a highly potent (IC50 = 0.071 micromolar), selective, and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an autoinhibited conformation. The crystal structure of SHP099 in complex with to SHP2 at 1.7-angstrom resolution showed that SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppressed RAS-ERK signaling to inhibit the proliferation of receptor tyrosine kinase-driven human cancer cells in vitro and was efficacious in mouse tumor xenograft models. Chen et al. (2016) concluded that pharmacologic inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
Zhao and Zhao (1998) presented evidence indicating that MPZL1 (604376) and PTPNS1 (602461) are substrates for PTPN11.
Using wildtype and Shp2 -/- mouse embryonic fibroblasts, Zannettino et al. (2003) found that full-length human PZR (MPZL1), which contains 2 intracellular Shp2-binding immunoreceptor tyrosine-based inhibitory motifs (ITIMs), promoted Shp2-dependent migration over a fibronectin (FN1; 135600) substrate. PZR isoforms lacking the intracellular ITIMs did not promote Shp2-dependent cell migration.
Helicobacter pylori CagA protein is injected from the attached H. pylori into host cells in the stomach and undergoes tyrosine phosphorylation. Higashi et al. (2002) demonstrated that wildtype but not phosphorylation-resistant CagA induces a growth factor-like response in gastric epithelial cells by forming a physical complex with SHP2 in a phosphorylation-dependent manner and stimulating the phosphatase activity. Disruption of the CagA-SHP2 complex abolishes the CagA-dependent cellular response. Conversely, the CagA effect on cells was reproduced by constitutively active SHP2. Thus, Higashi et al. (2002) concluded that upon translocation, CagA perturbs cellular functions by deregulating SHP2.
Kwon et al. (2005) showed that activation of T-cell antigen receptor (see 186880) in human Jurkat T cells and in mouse T-cell blasts induced transient inactivation of SHP2 by the oxidation of the SHP2 active site cysteine. SHP2 was recruited to the LAT (602354)-GADS (GRAP2; 604518)-SLP76 (LCP2; 601603) complex and regulated the phosphorylation of VAV1 (164875) and ADAP (FYB; 602731). The association of ADAP with the SLP76 complex was regulated by SHP2 in a redox-dependent manner. Kwon et al. (2005) concluded that TCR-mediated ROS generation leads to SHP2 oxidation, which promotes T-cell adhesion through effects on SLP76-dependent signaling.
Kikkawa et al. (2010) identified a putative microRNA-489 (MIR489; 614523) target site in the 3-prime UTR of PTPN11, which encodes a protein tyrosine phosphatase that can activate RAS (HRAS; 190020)-MAP kinase (see 176948) signaling in response to growth factors and cytokines. Overexpression of MIR489 in a human squamous cell carcinoma cell line reduced PTPN11 mRNA and protein expression and inhibited expression of a reporter gene containing a partial PTPN11 3-prime UTR. PTPN11 mRNA expression was significantly higher in hypopharyngeal squamous cell carcinomas compared with adjacent normal tissue from 16 patients. In contrast, MIR489 was downregulated in hypopharyngeal squamous cell carcinomas.
Using RNA pull-down assays and mass spectrometric analysis, Zheng et al. (2016) found that the long intergenic noncoding RNA LINC00673 (617079) interacted with PTPN11, which promotes cell growth and proliferation by activating SRC (190090)-ERK (see 176948) signaling and inhibiting STAT1 (600555) signaling. RNA immunoprecipitation assays confirmed interaction of PTPN11 with LINC00673, which promoted ubiquitination and degradation of PTPN11. LINC00673 interacted with the E3 ubiquitin ligase PRPF19 (608330) and appeared to mediate and strengthen the interaction between PTPN11 and PRPF19, enhancing PRPF19-mediated ubiquitination and degradation of PTPN11. Zheng et al. (2016) concluded that LINC00673 plays a role in maintenance of cellular homeostasis by regulating PTPN11.
Dong et al. (2016) reported that Ptpn11 activating mutations in the mouse bone marrow microenvironment promoted the development and progression of myeloproliferative neoplasm (MPN) through profound detrimental effects on hematopoietic stem cells. Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, caused excessive production of the CC chemokine CCL3 (182283), which recruited monocytes to the area in which hematopoietic stem cells also resided. Consequently, hematopoietic stem cells were hyperactivated by interleukin-1-beta (IL1B; 147720) and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reversed MPN development induced by the Ptpn11-mutated bone marrow microenvironment. Dong et al. (2016) concluded that their study revealed the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukemogenesis and identified CCL3 as a potential therapeutic target for controlling leukemic progression in Noonan syndrome (163950) and for improving stem cell transplantation therapy in Noonan syndrome-associated leukemias.
Noonan Syndrome 1
In more than 50% of patients with Noonan syndrome (see NS1, 163950), Tartaglia et al. (2001) identified mutations in the PTPN11 gene (see, e.g., 176876.0001-176876.0003). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP-2 activity underlie the pathogenesis of Noonan syndrome.
Tartaglia et al. (2002) identified a PTPN11 mutation (176876.0004) in a family inheriting Noonan syndrome with multiple giant cell lesions in bone.
Using direct DNA sequencing, Maheshwari et al. (2002) surveyed 16 subjects with the clinical diagnosis of Noonan syndrome from 12 families and their relevant family members for mutations in the PTPN11/SHP2 gene, and found 3 different mutations among 5 families. Two unrelated subjects shared a de novo ser502-to-thr (S502T; 176876.0007) substitution in exon 13; 2 additional unrelated families had a tyr63-to-cys (Y63C; 176876.0008) mutation in exon 3; and 1 subject had a tyr62-to-asp (Y62D; 176876.0009) substitution, also in exon 3. In the mature protein model, the exon 3 mutants and the exon 13 mutant amino acids cluster at the interface between the N-terminal SH2 domain and the phosphatase catalytic domain. Six of 8 subjects with mutations had pulmonary valve stenosis, while no mutations were identified in 4 subjects with hypertrophic cardiomyopathy. An additional 4 subjects with possible Noonan syndrome were evaluated, but no mutations in PTPN11 were identified. These results confirmed that mutations in PTPN11 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 gives rise to Noonan syndrome.
Kosaki et al. (2002) analyzed the PTPN11 gene in 21 Japanese patients with Noonan syndrome. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed 6 different heterozygous missense mutations in 7 cases. 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.
Musante et al. (2003) screened the PTPN11 gene for mutations in 96 familial or sporadic Noonan syndrome patients. They identified 15 mutations, all of which were missense mutations; 11 of them were located in exon 3, which encodes the N-SH2 domain. No obvious clinical differences were detected between subgroups of patients with mutations in different PTPN11 domains. Analysis of the clinical features of the patients revealed that several patients with facial abnormalities thought to be pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely varying phenotypes among the group of 64 patients without PTPN11 mutations suggested further genetic heterogeneity.
Tartaglia et al. (2004) investigated the parental origin of de novo PTPN11 lesions and explored the effect of paternal age in Noonan syndrome. By analyzing intronic positions that flank the exonic PTPN11 lesions in 49 sporadic Noonan syndrome cases, they traced the parental origin of mutations in 14 families. All mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. They also found advanced paternal age among cohorts of sporadic Noonan syndrome cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic Noonan syndrome caused by PTPN11 mutations, as well as in families inheriting the disorder. They favored sex-specific developmental effects as the explanation for the sex-ratio distortion in PTPN11-associated Noonan syndrome, because fetal lethality has been documented in this disorder.
Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. Sequence analysis of the coding exons 1 through 15 of PTPN11 revealed a novel 3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18 patients.
Becker et al. (2007) reported what they stated was the first known case of compound heterozygosity for NS-causing mutations in the PTPN11 gene (see 176876.0004 and 176876.0008), resulting in early fetal death.
Shchelochkov et al. (2008) and Graham et al. (2009) reported 2 unrelated patients with a Noonan syndrome phenotype associated with respective 10-Mb and 8.98-Mb duplications on chromosome 12q24.13, encompassing the PTPN11 gene. Graham et al. (2009) did not identify additional duplications in a screening of more than 250 Noonan syndrome cases without mutations in known disease-causing genes. Graham et al. (2009) concluded that duplication of PTPN11 represents an uncommon cause of Noonan syndrome. However, the rare observation of NS in individuals with duplications involving the PTPN11 locus suggested that increased dosage of this gene may have dysregulating effects on intracellular signaling.
Patients affected with cardiofaciocutaneous syndrome (CFC; 115150) present with symptoms that some considered to represent a more severe expression of Noonan syndrome, namely, congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and severe psychomotor developmental delay. Because mutations in PTPN11 are responsible for Noonan syndrome, Ion et al. (2002) investigated the possibility that this gene may be involved in CFC syndrome. A cohort of 28 CFC subjects rigorously assessed as having CFC 'based on OMIM diagnostic criteria' was examined for mutations in the PTPN11 coding sequence by means of denaturing high-performance liquid chromatography (DHPLC). No abnormalities in the coding region of the gene were found in any patient, nor any evidence of major deletions within the gene. Musante et al. (2003) screened for mutations in the PTPN11 gene in 5 sporadic patients with CFC syndrome and found none.
In 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, Schollen et al. (2003) identified a missense mutation in the PTPN11 gene (176876.0018). The mutation was not found in 7 unaffected relatives or 3 spouses. The authors noted that in D. melanogaster and C. elegans, the Ptpn11 gene has been implicated in oogenesis. In this family, there were 3 sets of dizygotic twins among the offspring of 2 affected females, suggesting that PTPN11 might also be involved in oogenesis and twinning in humans.
Bertola et al. (2004) described a young woman with clinical features of Noonan syndrome but with some characteristics of CFC as well, including prominent ectodermal involvement, developmental delay, and mental retardation. They identified a T411M mutation in the PTPN11 gene (176876.0019); the same mutation was found in her mother and older sister, not initially considered to be affected but who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies.
LEOPARD Syndrome 1
LEOPARD syndrome (LPRD1; 151100) is an autosomal dominant disorder characterized by lentigines and cafe-au-lait spots, facial anomalies, and cardiac defects, sharing several clinical features with Noonan syndrome. Digilio et al. (2002) screened 9 patients with LEOPARD syndrome (including a mother-daughter pair), and 2 children with Noonan syndrome who had multiple cafe-au-lait spots, for mutations in the PTPN11 gene. In 10 of the 11 patients, they found 1 of 2 novel missense mutations: Y27C (176876.0005) in exon 7 or T468M (176876.0006) in exon 12. Both mutations affected the PTPN11 phosphotyrosine phosphatase domain, which is involved in less than 30% of the Noonan syndrome PTPN11 mutations. This study demonstrated that LEOPARD syndrome and Noonan syndrome are allelic disorders. The detected mutations suggested that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the LEOPARD syndrome subtype of Noonan syndrome.
Kontaridis et al. (2006) examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see 176948)-mediated signaling. Molecular modeling and biochemical studies suggested that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. Kontaridis et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation.
In 4 of 6 Japanese patients with LEOPARD syndrome, Yoshida et al. (2004) identified 1 of 3 heterozygous missense mutations: tyr279 to cys (Y279C), ala461 to thr (A461T; 176876.0020), or gly464 to ala (G464A; 176876.0021).
In a Saudi father and his 2 sons with LEOPARD syndrome and variable phenotypes, Alfurayh et al. (2020) identified heterozygosity for the Y279C mutation (176876.0005) in the PTPN11 gene. The mutation was identified by next-generation sequencing. The father had normal stature, hypertelorism, lentigines, pectus excavatum, atrial septal defect, cryptorchidism, and motor delay as a child. His children had lentigines, normal stature, hypertelorism, and motor delays. The oldest son had pectus excavatum and cryptorchidism. The younger son had a history of an atrial septal defect and small posterior muscular ventricular septal defect.
Juvenile Myelomonocytic Leukemia
Juvenile myelomonocytic leukemia (JMML; 607785), a disorder with excessive proliferation of myelomonocytic cells, constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. JMML is observed occasionally in patients with Noonan syndrome, leading Tartaglia et al. (2003) to consider whether defects in PTPN11 are present in myeloid disorders. In 5 unrelated children with Noonan syndrome and JMML, they found heterozygosity with respect to a mutation in exon 3 of PTPN11. Four of the children shared the same mutation (218C-T; 176876.0011). In 2 unrelated individuals with growth retardation, pulmonic stenosis, and JMML, they found missense defects in PTPN11: the 218C-T transition, and a defect in exon 13 affecting the protein tyrosine phosphatase domain. Analysis of germline and parental DNAs for these 6 cases indicated that the mutations were de novo germline events.
Tartaglia et al. (2003) also identified somatic missense mutations in PTPN11 in 21 of 62 individuals with JMML but without Noonan syndrome, with 9 different molecular defects in exon 3 and 1 in exon 13. Nonhematologic DNAs were available for 9 individuals with a mutation in PTPN11 in their leukemic cells, and none harbored the defect.
Tartaglia et al. (2003) identified no mutation in PTPN11 among 8 individuals with JMML and neurofibromatosis type I (162200). Molecular screening for mutations in exons 1 and 2 of NRAS (164790) and KRAS2 (190070) identified defects in 5 and 7 individuals with isolated cases of JMML, respectively, none of whom harbored a mutation in PTPN11. This indicated that defects in RAS, neurofibromin, and SHP2, all involved in regulation of the MAPK cascade, are mutually exclusive in JMML. Comparison of phenotypes and karyotypes did not identify differences between individuals with JMML who did or did not have mutations in PTPN11.
Other Malignancies
Tartaglia et al. (2003) investigated the prevalence of somatic mutations in PTPN11 among 50 children with myelodysplastic syndrome. They identified no mutation among 23 children with refractory anemia, but observed missense mutations in exon 3 in 5 of 27 children with an excess of blasts. Three of these mutations were also associated with JMML in other patients. Among 24 children with de novo AML (601626), they identified a novel trinucleotide substitution in an infant with acute monoblastic leukemia.
Bentires-Alj et al. (2004) demonstrated that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma (256700) and AML.
Metachondromatosis
Using whole-genome sequencing in 1 affected individual from a 5-generation family with metachondromatosis (METCDS; 156250), Sobreira et al. (2010) identified a heterozygous 11-bp deletion in the PTPN11 gene (176876.0025) that segregated with the disease. Sequencing of PTPN11 in another family with metachondromatosis revealed a heterozygous nonsense mutation (176876.0026) in affected individuals. Neither mutation was detected in 469 controls.
Bowen et al. (2011) used a targeted array to capture exons and promoter sequences from an 8.6-Mb linked interval in 16 participants from 11 metachondromatosis families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. By this method, they identified heterozygous putative loss-of-function mutations in the PTPN11 gene in 4 of the 11 families (176876.0028-176876.0031). Sanger sequence analysis of PTPN11 coding regions in the 7 remaining families and in 6 additional metachondromatosis families identified novel heterozygous mutations in 4 families (176876.0032-176876.0035). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an METCDS patient with a 15-kb deletion spanning exon 7 of PTPN11 (176876.0036). In total, of 17 METCDS families, Bowen et al. (2011) identified mutations in 11 (5 frameshift, 2 nonsense, 3 splice site, and 1 large deletion). Each family had a different mutation, and the mutations were scattered across the gene. Microdissected METCDS lesions from 2 patients with PTPN11 mutations demonstrated loss of heterozygosity for the wildtype allele. Bowen et al. (2011) suggested that metachondromatosis may be genetically heterogeneous because 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations.
Tartaglia et al. (2002) reported the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. They found mutations 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. 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 less than 0.01); hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations: 5.9% vs 26.2%; (P less than 0.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the 2 groups. A PTPN11 mutation was identified in a family inheriting Noonan syndrome with multiple giant cell lesions in bone, extending the phenotypic range of disease associated with this gene (see 176876.0004).
Sarkozy et al. (2003) analyzed the PTPN11 gene in 71 Italian patients with Noonan syndrome and 13 with multiple lentigines/LEOPARD syndrome (ML/LS) and identified 14 different missense mutations in 34 patients, 23 with Noonan syndrome and 11 with ML/LS. The distribution of congenital heart defects was markedly different between the 2 groups. Pulmonary valve stenosis, the most common congenital heart defect in Noonan syndrome, was related to an exon 8 mutation hotspot at residue asn308 (see, e.g., 176876.0003 and 176876.0004), whereas hypertrophic cardiomyopathy, predominant in patients with ML/LS, was associated with mutations in exon 7 (see, e.g., Y279C, 176876.0005) and exon 12 (see, e.g., T468M, 176876.0006). Atrial septal defects were related to exon 3 mutations (see, e.g., Y62D, 176876.0009), whereas atrioventricular canal defects and mitral valve anomalies were found in association with different exon mutations.
Niihori et al. (2005) identified PTPN11 mutations in 16 of 41 patients with Noonan syndrome and 3 of 29 patients with childhood leukemia. Immune complex tyrosine phosphatase assays showed that all the mutations resulted in increased phosphatase activity compared to wildtype. Several mutations in the N-SH2 domain, including T73I (176876.0011), showed a 6- to 12-fold increase in activity. Other N-SH2 mutations (Y63C; 176876.0008 and Q79R; 176876.0018) and PTP-domain mutations (N308D; 176876.0003 and S502T; 176876.0007) showed a 2- to 4-fold increase in activity. These results and a review of previously reported cases indicated that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis. Two mutations associated with Noonan syndrome failed to promote the RAS/MAPK downstream signaling pathway.
Tartaglia et al. (2006) proposed a model that splits Noonan syndrome- and leukemia-associated PTPN11 mutations in the 2 major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, they investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP2 proteins recurring in Noonan syndrome, LEOPARD syndrome, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. The results documented a strict correlation between the identity of the lesion and disease, and demonstrated that Noonan syndrome-causative mutations have less potency for promoting SHP2 gain of function than do leukemia-associated ones. Furthermore, they showed that the recurrent LEOPARD syndrome-causing Y279C (176876.0005) and T468M (176876.0006) amino acid substitutions engender loss of SHP2 catalytic activity, identifying a previously unrecognized behavior of this class of missense PTPN11 mutations. By molecular modeling and biochemical studies, Kontaridis et al. (2006) showed that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. They concluded that pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation.
Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. They identified 11 mutations in 18 patients. Clinical assessment showed that the growth pattern was similar in mutation-positive and mutation-negative patients. Pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients, as was atrial septal defect, whereas hypertrophic cardiomyopathy was present in 5 mutation-negative patients only. Hematologic abnormalities such as bleeding diathesis and juvenile myelomonocytic leukemia were exclusively present in mutation-positive patients.
Limongelli et al. (2008) studied 24 LEOPARD syndrome patients, 16 with mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene (164760), and 6 in whom no mutation had been found. Patients without PTPN11 mutations showed a significantly higher frequency of family history of sudden death, increased left atrial dimensions, and cardiac arrhythmias, and seemed to be at higher risk for adverse cardiac events. Three patients with mutations in exon 13 of the PTPN11 gene had a severe form of biventricular obstructive LVH with early onset of heart failure symptoms, consistent with previous observations.
Atrioventricular and semilunar valve abnormalities are common birth defects. During studies of genetic interaction between Egr2 and Ptpn11, encoding the protein-tyrosine phosphatase Shp2, Chen et al. (2000) found that Egfr (131550) is required for semilunar, but not atrioventricular, valve development. Although unnoticed in earlier studies, mice homozygous for the hypomorphic Egfr allele 'waved-2' exhibited semilunar valve enlargement resulting from overabundant mesenchymal cells. Egfr -/- mice (on CD1 background) had similar defects. The penetrance and severity of the defects in the homozygous 'waved-2' mice were enhanced by heterozygosity for targeted mutation of exon 2 of Ptpn11. Compound mutant mice also showed premature lethality. Electrocardiography, echocardiography, and hemodynamic analyses showed that affected mice developed aortic stenosis and regurgitation. The results identified Egfr and Shp2 as components of a growth-factor signaling pathway required specifically for semilunar valvulogenesis, supported the hypothesis that Shp2 is required for Egfr signaling in vivo, and provided an animal model for aortic valve disease.
Shp2 can potentiate signaling for the MAP kinase pathway (see 602425) and is required during early mouse development for gastrulation. Chimeric analysis can identify, by study of phenotypically normal embryos, tissues that tolerate mutant cells, and therefore do not require the mutated gene, or lack mutant cells and presumably require the mutated gene during the developmental history. Saxton et al. (2000) therefore generated chimeric mouse embryos to explore the cellular requirements for Shp2. This analysis revealed an obligatory role for Shp2 during outgrowth of the limb. Shp2 is specifically required in mesenchyme cells of the progress zone, directly beneath the distal ectoderm of the limb bud. Comparison of Ptpn11 mutant and Fgfr1 (136350) mutant chimeric limbs indicated that in both cases mutant cells failed to contribute to the progress zone of phenotypically normal chimeras, leading to the hypothesis that a signal transduction pathway, initiated by Fgfr1 and acting through Shp2, is essential within progress zone cells. Rather than integrating proliferative signals, Shp2 probably exerts its effects on limb development by influencing cell shape, movement, or adhesion. Furthermore, the branchial arches, which also use Fgfs during bud outgrowth, similarly require Shp2. Thus, Shp2 regulates phosphotyrosine-signaling events during the complex ectodermal-mesenchymal interactions that regulate mammalian budding morphogenesis.
Saxton et al. (1997) generated mice deficient in Shp2 by targeted disruption. Homozygous Shp2 -/- mice die at midgestation with multiple defects in mesodermal patterning, while heterozygous mutants appear normal. Qu et al. (1998) aggregated homozygous mutant embryonic stem (ES) cells and wildtype embryos to create Shp2 -/- wildtype chimeric animals. They reported an essential role of Shp2 in the control of blood cell development. Despite the widespread contribution of mutant cells to various tissues, no Shp2 -/- progenitors for erythroid or myeloid cells were detected in the fetal liver or bone marrow of chimeric animals by using the in vitro colony forming unit (CFU) assay. Furthermore, hematopoiesis was defective in Shp2 -/- yolk sacs. In addition, the Shp2 mutant caused multiple developmental defects in chimeric mice, characterized by short hind legs, aberrant limb features, split lumbar vertebrae, abnormal rib patterning, and pathologic changes in the lungs, intestines, and skin. Qu et al. (1998) concluded that Shp2 is involved in the differentiation of multiple tissue-specific cells and in body organization. They suggested that the requirement for Shp2 appears to be more stringent in hematopoiesis than in other systems.
Using mouse and zebrafish models, Paardekooper Overman et al. (2014) found that both Shp2 activating mutations associated with Noonan syndrome and Shp2 inactivating mutations associated with LEOPARD syndrome caused tyrosine hyperphosphorylation of Pzr. Immunoprecipitation analysis indicated that the mutations, which result in an open Shp2 conformation, increased association of the tyrosine kinase Src (190090) with Shp2 and Pzr, suggesting a pathway for Pzr hyperphosphorylation.
Zhang et al. (2004) selectively deleted Shp2 in postmitotic forebrain neurons of mice and observed the development of early-onset obesity with increased serum levels of leptin (164160), insulin (176730), glucose, and triglycerides, although the mutant mice were not hyperphagic. In wildtype mice, the authors found that Shp2 downregulation of Jak2 (147796)/Stat3 (102582) activation by leptin in the hypothalamus was offset by a dominant Shp2 promotion of the leptin-stimulated Erk (see 601795) pathway; thus, Shp2 deletion in the brain results in induction rather than suppression of leptin resistance. Zhang et al. (2004) suggested that a primary function of SHP2 in the postmitotic forebrain is to control energy balance and metabolism, and that SHP2 is a critical signaling component of the leptin receptor (601007) in the hypothalamus.
Using a constitutively active mouse Shp2 mutant, He et al. (2012) found that Shp2 integrated leptin and estrogen signaling in transgenic female mice. Transgenic females, but not males, were resistant to high-fat diet-induced obesity and liver steatosis via enhanced leptin and insulin sensitivity and downstream ERK activation. SHP2 and estrogen receptor-alpha (ESR1; 133430) interacted directly in MCF-7 cells and female mouse tissues, and the interaction was enhanced by estrogen stimulation. Ovariectomy of transgenic mice reversed their resistance to high-fat diet-induced obesity.
Nakamura et al. (2007) generated Q79R (176876.0018) transgenic mice in which the mutated protein was expressed in cardiomyocytes either during gestation or following birth. Q79R Shp2 embryonic hearts showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects, whereas in the postnatal cardiomyocyte, Q79R Shp2 expression was benign. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway (see 176948), and breeding Q79R transgenics into Erk1/2-null backgrounds confirmed that the pathway was necessary and sufficient for mediating the effects of mutant Shp2. Nakamura et al. (2007) concluded that there are developmental stage-specific effects of Q79R cardiac expression in Noonan syndrome, and that ablation of subsequent ERK1/2 activation prevents the development of cardiac abnormalities.
In cultured mouse embryonic cortical precursor cells, Gauthier et al. (2007) found that Shp2 enhanced neurogenesis and inhibited cytokine-mediated astrocytosis. Inhibition of Shp2 resulted in decreased neurogenesis, aberrant migration of neurons, and premature gliogenesis. Expression of a Noonan syndrome-associated Shp2 mutant with enhanced activity promoted neurogenesis and inhibited astrogenesis in vitro and in vivo. Further studies showed that Shp2 promotes neurogenesis via activation of the MEK-ERK pathway, and inhibits gliogenesis by suppressing the gp130 (IL6ST; 600694)-JAK-STAT pathway. Gauthier et al. (2007) suggesting that the cognitive impairment observed in some patients with Noonan syndrome may result from aberrant neuron cell-fate and a perturbation in the relative ratios of these brain cell types during development.
To study the developmental effects of the Y279C and T468M mutations in the PTPN11 gene, Oishi et al. (2009) generated the equivalent mutations in the orthologous Drosophila corkscrew (csw) gene. Ubiquitous expression of the mutant csw alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were gain-of-function phenotypes mediated by increased RAS/MAPK signaling and requiring the residual phosphatase activity of the mutant Y279C and T468M alleles.
Princen et al. (2009) created mice with deletion of Shp2 directed to striated muscle. Homozygous mutant mice were born at the expected frequency, but developed severe dilated cardiomyopathy, resulting in heart failure and death within 2 weeks of birth. Development of cardiomyopathy was associated with insulin resistance, glucose intolerance, and impaired insulin-stimulated glucose uptake in striated muscle. No significant abnormalities were observed in other tissues and organs, including skeletal muscle.
Xu et al. (2010) found that mice with a germline heterozygous D61G mutation (176876.0010) developed a JMML-like myeloproliferative disorder with excessive myeloid expansion in the bone marrow and spleen. Homozygous mutant mice were embryonic lethal due to cardiac developmental defects. Heterozygous mutant mice had higher levels of short- and long-term hematopoietic stem cells in the bone marrow and spleen compared to wildtype mice. Stem cells from heterozygous mutant mice showed enhanced entry of quiescent stem cells (G0 phase) into the cell cycle, as well as decreased apoptosis, and showed a greater long-term repopulating ability in transplanted mice compared to wildtype cells. Primary and secondary recipient mice transplanted with D61G-mutant bone marrow cells or purified lineage-negative Sca1+/Kit+ (LSK) cells developed a myeloproliferative disorder, suggesting that the pathogenic effects of the Ptpn11 mutation are cell autonomous and occur at the level of the hematopoietic stem cell. D61G-mutant cells also showed an enhanced response to stimulation with IL3 (147740). Studies with heterozygous D61G/Gab2 (606203)-null mice and cells showed attenuation of the increased number of stem cells, indicating that Gab2 is an important mediator of the myeloproliferative disorder induced by the D61G mutation. Gab2 is a prominent PTPN11-interacting protein with a role in cell signaling.
Sharma et al. (2012) generated mast cell-specific Shp2-knockout mice and found that Shp2 was required for peritoneal mast cell homeostasis. Examination of other tissues revealed reduced mature mast cells in skin, but not mucosa, of mutant mice. The results suggested that the deficit in mast cells in connective tissues was likely due to growth or survival defects within mature connective tissue mast cells (CTMCs) and not due to defects in mast cell progenitors that retained Shp2 function and allowed normal mucosal mast cell (MMC) development. Shp2 mutant mice failed to mount a mast cell IgE-mediated late-phase cutaneous reaction, unlike wildtype mice. Knockout of Shp2 in bone marrow-derived mast cells (BMMCs) showed that Shp2 promoted Scf/Kit signaling to ERK kinases and suppression of proapoptotic Bim (603827) in mast cells, thereby promoting BMMC survival. Further analysis revealed a significant defect in the ability of Shp2-knockout BMMCs to repopulate peritoneal mast cells and skin mast cells compared with wildtype BMMCs, demonstrating that Shp2 plays an essential role in promoting CTMC survival and homeostasis in vivo. Bim silencing in Shp2-knockout BMMCs rescued their survival defects.
To investigate the pathogenesis of metachondromatosis (156250), Yang et al. (2013) used a conditional knockout (floxed) Ptpn11 allele (Ptpn11(fl)) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages, and osteoclasts (lysozyme (153450) M-Cre; LysMCre) or in cathepsin K (Ctsk; 601105)-expressing cells, theretofore thought to be osteoclasts. The LysMCre;Ptpn11(fl/fl) mice had mild osteopetrosis. However, CtskCre;Ptpn11(fl/fl) mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors (Ctsk+ chondroid progenitors, or CCPs). Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh; 600726) and parathyroid hormone-related protein (Pthrp; 168470) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor (FGF)-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR; see 136350) or mitogen-activated protein kinase kinase (MEK; see 176872) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened (601500) inhibitor treatment ameliorated metachondromatosis features in the CtskCre;Ptpn11(fl/fl) mice. Yang et al. (2013) concluded that thus, in contrast to its prooncogenic role in hematopoietic and epithelial cells, Ptpn11 is a tumor suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.
Coulombe et al. (2013) found that mice homozygous for Shp2 knockout in intestinal epithelial cells (IECs) had similar body weight to wildtype mice at birth but subsequently exhibited growth retardation. Mutant mice had diarrhea and rectal bleeding with higher mortality than wildtype mice, and macroscopic examination revealed severe colitis affecting all parts of the colon. Histologic analysis of mutant colon showed immune cell infiltration, longer crypts, and apparent reduction of goblet cells. Cytokines and chemokines were significantly upregulated in mutant mice. IEC-specific Shp2 loss deregulated intestinal permeability and decreased expression of barrier component proteins. SHP2 silencing in human Caco-2/15 cells also compromised barrier function, supporting the cell-intrinsic effect of SHP2 ablation on permeability. Western blot analysis demonstrated that IEC-specific loss of Shp2 deregulated epithelial ERK, Stat3, and NF-kappa-B (see 164011) signaling pathways. Antibiotic treatment significantly inhibited development of colitis in mutant mice.
Tajan et al. (2018) found that mice heterozygous for the NS mutation D61G in SHP2 showed homogeneous postnatal growth retardation without bone deformity compared with wildtype mice. Histologic analysis revealed reduced epiphyseal growth plate length in NS mice, mostly due to shortening of the hypertrophic zone. Quantitative RT-PCR showed that the Shp2 mutant impaired chondrocyte differentiation during endochondral ossification. Further analysis demonstrated that the Shp2 mutant enhanced Ras/ERK activation in chondrocytes in vivo and in vitro. The Shp2 mutant impaired production of insulin-like growth factor-1 (IGF1; 147440) through hyperactivation of the Ras/ERK signalling pathway, and inhibition of Ras/ERK activation was associated with significant growth improvement in NS mice. However, Igf1 supplementation only partially corrected growth retardation of NS mice, and histologic analysis of the growth plate revealed that Igf1 treatment increased the length of the proliferating zone without correcting the decreased hypertrophic zone. Statin treatment significantly improved endochondral bone growth and restored the length of the hypertrophic zone growth plate in NS mice. Moreover, statin treatment also restored alkaline phosphatase (ALPL; 171760) expression and differentiation activity in NS mouse primary chondrocytes in vitro.
In a family with Noonan syndrome (NS1; 163950), Tartaglia et al. (2001) found that affected members had a G-to-T transversion at position 214 in exon 3 of the PTPN11 gene, predicting an ala72-to-ser (A72S) substitution in the N-SH2 domain. This mutation was also identified by Kosaki et al. (2002).
In a family with Noonan syndrome (NS1; 163950), Tartaglia et al. (2001) found that affected members had a C-to-G transversion at nucleotide 215 in exon 3 of the PTPN11 gene, predicting an ala72-to-gly (A72G) amino acid substitution.
In affected members of 3 families and in a sporadic case of Noonan syndrome (NS1; 163950), Tartaglia et al. (2001) found a 922A-G transition in exon 8 of the PTPN11 gene, predicting an asn308-to-asp (N308D) amino acid change. This missense mutation affected the phosphotyrosine phosphatase (PTP) domain.
In a comprehensive study of Tartaglia et al. (2002), about one-third of the patients who had mutations in the PTPN11 gene had this mutation, which was by far the most common. This was the mutation present in the large 3-generation family that was used originally to establish linkage to the locus on 12q. That codon 308 is a hotspot for Noonan syndrome was further indicated by the finding of an asn308-to-ser (176876.0004) missense mutation in 2 families (Tartaglia et al., 2002). In the cohort of Noonan syndrome patients studied by Tartaglia et al. (2002) noted that in their cohort, no patient carrying the N308D mutation was enrolled in special education.
Kosaki et al. (2002) found this mutation in a Japanese patient.
In 13 (23%) of 56 patients with Noonan syndrome, Jongmans et al. (2005) identified the N308D mutation, confirming the reputation of nucleotide 922 as a mutation hotspot. Among these 13 patients only 3 attended special school. Except for this suspected correlation with normal education, the phenotype observed in patients with the mutation at nucleotide 922 did not differ from the phenotype in patients with other mutations.
Yoon et al. (2013) calculated that the de novo mutation frequency of the 922A-G (N308D) mutation exceeds the genome average A-G mutation frequency by more than 2,400-fold. Yoon et al. (2013) examined the spacial distribution of the mutation in testes of 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be the expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2, the protein encoded by PTPN11, interacts with the transcriptional activator STAT3 (102582). Given STAT3's function in mouse spermatogonial stem cells, Yoon et al. (2013) suggested that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of STAT3 activity by cyclin D1 (168461) might also play a role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome (101200) and MEN2B (162300).
In affected members of 2 families with Noonan syndrome (NS1; 163950), Tartaglia et al. (2002) identified an 923A-G transition in the PTPN11 gene, resulting in an asn308-to-ser (N308S) substitution. This mutation occurs in the same codon as the common N308D mutation (176876.0003); thus, codon 308 is a hotspot for Noonan syndrome. One of the 2 families in which the N308S mutation was observed had typical features of Noonan syndrome associated with multiple giant cell lesions in bone.
In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007) identified compound heterozygosity for the N308S and Y63C (176876.0008) mutations in the PTPN11 gene. The mother and father, who exhibited facial features of Noonan syndrome and had both undergone surgical correction of pulmonary valve stenosis, were heterozygous for N308S and Y63C, respectively. A second pregnancy resulted in the birth of a boy with Noonan syndrome carrying the paternal Y63C mutation.
In 3 patients with LEOPARD syndrome-1 (LPRD1; 151100), Digilio et al. (2002) found an A-to-G transition at nucleotide 836 in exon 7 of the PTPN11 gene resulting in a tyr279-to-cys (Y279C) mutation.
Yoshida et al. (2004) identified heterozygosity for the Y279C mutation in 2 Japanese patients with LEOPARD syndrome.
In a Saudi father and his 2 sons with LEOPARD syndrome and variable phenotypes, Alfurayh et al. (2020) identified the Y279C mutation. The mutation was identified by next-generation sequencing. All 3 patients had normal stature. The father had hypertelorism, lentigines, pectus excavatum, atrial septal defect, cryptorchidism, and motor delay as a child. His children had lentigines, hypertelorism, and motor delays. The oldest son had pectus excavatum and cryptorchidism. The younger son had a history of an atrial septal defect and small posterior muscular ventricular septal defect.
Edouard et al. (2010) found that the Y279C mutation caused elevated EGF (131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation and activation in LEOPARD syndrome patient fibroblasts and transfected HEK293 cells compared with normal controls. This upregulation was due to impaired dephosphorylation of GAB1 (604439), which resulted in enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (see PIK3R1; 171833). PI3 kinase hyperactivation in Y279C mutant cells also enhanced myocardin (MYOCD; 606127)/SRF (600589) activity.
In 5 unrelated patients and in a mother-daughter pair with LEOPARD syndrome-1 (LPRD1; 151100), Digilio et al. (2002) found a thr468-to-met (T468M) mutation resulting from a C-to-T transition at nucleotide 1403 in exon 12 of the PTPN11 gene.
Carvajal-Vergara et al. (2010) generated induced pluripotent stem cells (iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous for the T468M mutation in the PTPN11 gene. The iPSCs were extensively characterized and produced multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. Carvajal-Vergara et al. (2010) showed that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization, and have preferential localization of NFATC4 (602699) in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlated with a potential hypertrophic state. Carvajal-Vergara et al. (2010) also provided molecular insights into signaling pathways that may promote the disease phenotype. Carvajal-Vergara et al. (2010) showed that basic fibroblast growth factor treatment increased the phosphorylation of ERK1/2 levels over time in several cell lines but did not have a similar effect in the LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in the LEOPARD syndrome iPSCs compared with the other cell lines.
Edouard et al. (2010) found that the T468M mutation caused elevated EGF (131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation and activation in LEOPARD syndrome patient fibroblasts and transfected HEK293 cells compared with normal controls. This upregulation was due to impaired dephosphorylation of GAB1 (604439), which resulted in enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (see PIK3R1; 171833). PI3 kinase hyperactivation in T468M mutant cells also enhanced myocardin (MYOCD; 606127)/SRF (600589) activity and promoted hypertrophic growth in cultured chicken embryo myocardial cushions and primary human cardiomyocytes.
In a Chinese boy (patient 3) with cafe-au-lait spots and freckles over the face and trunk, who also had dysmorphic facial features including hypertelorism, and pectus excavatum, Zhang et al. (2016) identified heterozygosity for the PTPN11 T468M mutation, which was not found in unaffected family members or in 100 controls.
Maheshwari et al. (2002) found a de novo ser502-to-thr (S502T) substitution in exon 13 in 2 unrelated subjects with Noonan syndrome (NS1; 163950).
Kondoh et al. (2003) described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a Japanese infant with Noonan syndrome and the S502T mutation.
In 2 unrelated families, Maheshwari et al. (2002) found that probands with Noonan syndrome (NS1; 163950) had a tyr63-to-cys (Y63C) mutation in exon 3. This same mutation was identified by Tartaglia et al. (2001). This mutation was also identified by Kosaki et al. (2002) in 2 patients.
See 176876.0004 and Becker et al. (2007).
In a subject with Noonan syndrome (NS1; 163950), Maheshwari et al. (2002) found a tyr62-to-asp (Y62D) substitution in exon 3 of the PTPN11 gene. This same mutation was identified by Tartaglia et al. (2002).
In a Japanese patient with sporadic Noonan syndrome (NS1; 163950), Kosaki et al. (2002) found an A-to-G transition at nucleotide 182 in exon 3 of the PTPN11 gene, which resulted in an asp61-to-gly (D61G) amino acid substitution.
In a Japanese patient with sporadic Noonan syndrome (NS1; 163950), Kosaki et al. (2002) identified a 218C-T transition in exon 3 of the PTPN11 gene, resulting in a thr73-to-ile (T73I) substitution.
In 4 children with Noonan syndrome who developed juvenile myelomonocytic leukemia, Tartaglia et al. (2003) observed a heterozygous germline T73I mutation, which alters the N-terminal Src homology 2 (SH2) domain. The T73I mutation was also identified in an individual with growth retardation, pulmonic stenosis, and JMML. Analysis of germline and parental DNAs indicated that the mutations were de novo germline events.
Jongmans et al. (2005) described a patient with Noonan syndrome and mild JMML who carried the T73I mutation.
In a Japanese patient with sporadic Noonan syndrome (NS1; 163950), Kosaki et al. (2002) found a T-to-C transition at nucleotide 854 in exon 8 of the PTPN11 gene, resulting in a phe285-to-ser (F285S) amino acid substitution.
Tartaglia et al. (2003) identified somatic missense mutations in PTPN11 in 21 of 62 individuals with JMML (607785) but without Noonan syndrome. A 226G-A transition predicting a glu76-to-lys (E76K) substitution within the N-SH2 domain accounted for 25% of the total number of mutations. Codon 76 was a mutation hotspot for JMML, with 4 different amino acid substitutions predicted among 8 individuals: in addition to E76K, which was present in 5 cases, E76V (176876.0015), E76G (176876.0016), and E76A (176876.0017) were each present in 1 case.
See 176876.0014 and Tartaglia et al. (2003).
See 176876.0014 and Tartaglia et al. (2003).
See 176876.0014 and Tartaglia et al. (2003).
In 10 affected members from a large 4-generation Belgian family with Noonan syndrome (NS1; 163950) and some features suggestive of cardiofaciocutaneous syndrome (115150), Schollen et al. (2003) identified a 236A-G transition in exon 3 of the PTPN11 gene, resulting in a gln79-to-arg (Q79R) mutation. The mutation was not found in 7 unaffected relatives or 3 spouses.
In a 24-year-old female with clinical features of Noonan syndrome (NS1; 163950) but with some characteristics of cardiofaciocutaneous syndrome (CFC; 115150) as well, including prominent ectodermal involvement (sparse and very coarse hair, and sparse eyebrows and eyelashes), developmental delay, and mental retardation, Bertola et al. (2004) identified a T-to-C transition in exon 11 of the PTPN11 gene, resulting in a thr411-to-met (T411M) substitution. Molecular dynamic studies indicated that this mutation favors a more active protein conformation. The mutation was also found in the patient's mother and older sister, who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies.
In a Japanese patient with LEOPARD syndrome (LPRD1; 151100), Yoshida et al. (2004) identified heterozygosity for a 1381G-A transition in exon 12 of the PTPN11 gene, resulting in an ala461-to-thr (A461T) substitution.
In a Japanese patient with LEOPARD syndrome (LPRD1; 151100), Yoshida et al. (2004) identified heterozygosity for a 1391G-C transversion in exon 12 of the PTPN11 gene, resulting in a gly464-to-ala (G464A) substitution.
In the proband of a family with 3 individuals with LEOPARD syndrome (LPRD1; 151100), Kalidas et al. (2005) found a 1529A-C transversion in exon 13 of the PTPN11 gene resulting in a gln510-to-pro (Q510P) substitution.
Edouard et al. (2010) found that PTPN11 with the Q510P mutation elevated EGF (131530)-induced PI3 kinase (see 601232)/AKT (164730) phosphorylation and activation in transfected HEK293 cells compared with wildtype PTPN11. This upregulation was due to impaired dephosphorylation of GAB1 (604439), which enhanced binding between GAB1 and the PI3 kinase regulatory subunit p85 (PIK3R1; 171833).
Bertola et al. (2005) described a girl with both neurofibromatosis I (162200) and Noonan syndrome (NS1; 163950) who had a de novo mutation in the NF1 gene (613113.0043) and a mutation in the PTPN11 gene inherited from her father who was mildly affected with Noonan syndrome. The PTPN11 mutation was a 1909A-G transition, resulting in a gln510-to-arg substitution.
In a Japanese patient with Noonan syndrome (NS1; 163950), Yoshida et al. (2004) identified a 3-bp deletion in exon 3 of the PTPN11 gene, 181delGTG, that resulted in deletion of the gly60 codon in the N-SH2 domain of the protein. Because gly60 is directly involved in the N-SH2/PTP interaction, loss of this residue was predicted to disrupt N-SH2/PTP binding, activating the phosphatase function. Yoshida et al. (2004) stated that 181delGTG was the sole deletion mutation identified in the PTPN11 gene to that time.
In affected members of a 5-generation family segregating autosomal dominant metachondromatosis (METCDS; 156250), Sobreira et al. (2010) identified heterozygosity for an 11-bp deletion (514del11) in exon 4 of the PTPN11 gene, predicted to cause a frameshift leading to a new sequence of 12 codons followed by a premature stop codon. Two apparently unaffected individuals who carried the deletion were found upon examination to have manifestations of the disease. The mutation was not found in 469 controls, 60% of whom were ethnically matched.
In affected members of a 3-generation family segregating autosomal dominant metachondromatosis (METCDS; 156250), Sobreira et al. (2010) identified heterozygosity for a C-to-T transition in exon 4 of the PTPN11 gene, resulting in an arg138-to-ter (R138X) substitution. A brother and sister, both parents of affected children, were unaffected carriers of the mutation, indicating incomplete penetrance. The mutation was not found in 469 controls, 60% of whom were ethnically matched.
In a girl with both Noonan syndrome (NS1; 163950) and neurofibromatosis I (162200), Thiel et al. (2009) found compound heterozygosity for 2 mutations: a de novo 5C-T transition in the PTPN11 gene, resulting in a thr2-to-ile (T2I) substitution, and a splice site mutation in the NF1 gene (613113.0044). The PTPN11 mutation was predicted to destabilize the inactive form of PTPN11, resulting in increased basal activity and a gain of function. The proband had hypertelorism, low-set ears, short stature, delayed development, sternal abnormalities, and valvular pulmonary stenosis. The NF1 mutation was inherited from her mother who had mild features of neurofibromatosis I. The proband's brother, who carried the heterozygous NF1 mutation, also had mild features of neurofibromatosis I. Neither the mother nor the brother had optic gliomas. However, the girl developed bilateral optic gliomas before age 2 years, suggesting an additive effect of the 2 mutations on the Ras pathway. Compound heterozygosity for mutations in NF1 and PTPN11 were also reported by Bertola et al. (2005) in a patient with a combination of neurofibromatosis I and Noonan syndrome.
In 2 affected members of a family (family A) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 5-bp deletion in exon 4 of the PTPN11 gene (409_413del5) resulting in a frameshift (Val137ArgfsTer17). The mutation was not found in an unaffected family member.
In 2 affected members of a family (family B) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous complex deletion/insertion mutation in exon 4 of the PTPN11 gene (458_468del11ins24), resulting in a frameshift (Thr153LysfsTer8). The mutation was not found in an unaffected family member.
In affected members of a family (family C) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 2-bp deletion in exon 4 of the PTPN11 gene (353_354del2), resulting in a frameshift (Ser118TrpfsTer10).
In affected members of a family (family E) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 1516C-T transition in exon 13 of the PTPN11 gene, resulting in a gln506-to-ter (Q506X) nonsense mutation.
In affected members of a family (family D) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 1-bp deletion in exon 11 of the PTPN11 gene (1315del1), resulting in a frameshift (Leu439TrpfsTer33).
In 2 affected sibs in a family (family F) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous acceptor splice site mutation in intron 5 of the PTPN11 gene (643-2A-C). The mutation was not found in either parent, including the affected mother. Bowen et al. (2011) suggested that the mother was mosaic for a PTPN11 mutation.
In affected members of a family (family I) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous 295A-T transversion in exon 3 of the PTPN11 gene, resulting in a lys99-to-ter (K99X) nonsense mutation.
In an affected member of a family (family G) segregating metachondromatosis (METCDS; 156250), Bowen et al. (2011) identified a heterozygous acceptor splice site mutation in intron 9 of the PTPN11 gene (1093-1G-T).
Using copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene, Bowen et al. (2011) identified heterozygosity for a 15-kb deletion spanning exon 7 of the PTPN11 gene (Thr253LeufsTer54) in a patient (patient S) with metachondromatosis (METCDS; 156250).
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