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Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11 , SOS1 and KRAS mutations causes ∼60% of Noonan syndrome cases 1 , 2 , 3 , 4 , 5 , 6 , and PTPN11 mutations cause 90% of LEOPARD syndrome cases 7 . Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1 , which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non–HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.

LEOPARD syndrome (LS) is an autosomal dominant \"RASopathy\" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11(Y279C/+) (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.

Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant \"RASopathy\" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist-induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+) littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+) mice. In addition, we observed an increase in fractional shortening (FS%) in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel therapy for treatment of hypertrophy in NSML patients.

Background Noonan Syndrome with Multiple Lentigines (NSML) and Noonan Syndrome (NS) can be difficult to differentiate clinically in early childhood. This study aims to describe characteristics of the ventricular septum that may differentiate NSML from NS. We hypothesize that the shape of the ventricular septum determined by echocardiography correlates with genotype and may distinguish patients with NSML from those with NS. Methods We analyzed data from 17 NSML and 67 NS patients. Forty normal and 30 sarcomeric hypertrophic cardiomyopathy (HCM) patients were included as controls. Septal morphology was qualitatively evaluated, and septal angle was measured quantitatively at end diastole. We recorded the presence of a ventricular septal bulge (VSB) and reviewed genetic testing results for each patient. Results The most important findings were a sigmoid septum (71%) and VSB (71%) in NSML. NSML septal angle was decreased compared to the normal and sarcomeric HCM control groups, respectively (149 ± 13 vs. 177 ± 3, p  < 0.001; 149 ± 13 vs. 172 ± 7, p  < 0.001). NS septal angle was similar to the controls (176 ± 6 vs. 177 ± 3, p  > 0.5; 176 ± 6 vs. 172 ± 7, p  > 0.5). NSML-linked pathogenic variants were associated with sigmoid septum and VSB. Conclusions These findings provide novel phenotypic evidence to clinicians that may offer incremental diagnostic value in counseling families in ambiguous NSML/NS cases. Impact Characteristics of the ventricular septum are linked to specific gene variants that cause NSML and NS. Sigmoid septum and VSB are associated with NSML. This novel echocardiographic association may help clinicians distinguish NSML from NS in ambiguous cases. Early distinction between the two may be important, as syndrome-specific therapies may become available in the near future. This study may encourage further research into genotype–phenotype associations in other forms of HCM.

Background Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are neurodevelopmental conditions caused by genetic variants leading to upregulated signaling in the RAS-MAPK pathway. While previous research has focused on genetic variability in cognitive and cardiac phenotypes, behavioral phenotypes, and their correlations across genetic variants and within the PTPN11 gene remain poorly characterized. Methods This study included 121 individuals with NS ( PTPN11 : 88, SOS1 : 18, RAF1 : 6, KRAS : 2, RIT1 : 3, NRAS : 2, LZTR1 : 2, SOS2 : 1) and seven individuals with NSML ( PTPN11 ), compared to age- and sex-matched typically developing (TD) (N = 71). Behavioral questionnaires assessed social responsiveness and ASD-related traits (using SRS-2), and emotional problems (using CBCL) to identify genetic variant-specific behavioral profiles. Biochemical profiling of SHP2 activity in PTPN11 -associated NS variants examined genotype–phenotype relationships. Results Compared to TD individuals, those with PTPN11 -associated NS, NSML, and SOS1 -associated NS exhibited clinically elevated scores, indicating increased ASD-related behaviors, poorer social functioning, and heightened emotional problems. Genetic variant comparisons revealed that individuals with PTPN11 -associated NS and NSML exhibited greater ASD-related challenges than those with RAF1 . Individuals with NSML exhibit elevated attention problems compared to all other genetic groups. Logistic regression results suggested each one-unit increase in SHP2 fold activation for PTPN11 -associated NS corresponded to a 64% higher likelihood of markedly elevated restricted and repetitive behaviors, suggesting genotype–phenotype links. Limitations Small sample sizes for rarer variants, leading to unequal group sizes across subgroups, with PTPN11 variants comprising most of the NS group. Future research should address these sampling constraints and conduct functional studies to clarify variant impacts. Longitudinal assessments could elucidate behavioral phenotype trajectories. Conclusions This study underscores the importance of genetic variant-specific research to understand unique behavioral phenotypes in NS and NSML. Our findings indicate a higher risk for ASD-related symptoms in PTPN11 -associated NS and NSML compared to other variants. Additionally, individuals with PTPN11 -associated NS and higher SHP2 fold activation exhibited greater impairments in restricted and repetitive behaviors, suggesting SHP2 activation variations may contribute to phenotypic variability. By linking ASD-related symptoms to biochemical predictors in PTPN11 -associated NS, this study may inform future targeted treatment approaches.

Diverse cellular processes are regulated by tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). De-regulated tyrosyl phosphorylation, evoked by gain-of-function mutations and/or over-expression of PTKs, contributes to the pathogenesis of many cancers and other human diseases. PTPs, because they oppose the action of PTKs, had been considered to be prime suspects for potential tumor suppressor genes. Surprisingly, few, if any, tumor suppressor PTPs have been identified. However, the Src homology-2 domain-containing phosphatase Shp2 (encoded by PTPN11 ) is a bona fide proto-oncogene. Germline mutations in PTPN11 cause Noonan and LEOPARD syndromes, whereas somatic PTPN11 mutations occur in several types of hematologic malignancies, most notably juvenile myelomonocytic leukemia and, more rarely, in solid tumors. Shp2 also is an essential component in several other oncogene signaling pathways. Elucidation of the events underlying Shp2-evoked transformation may provide new insights into oncogenic mechanisms and novel targets for anti-cancer therapy.

Noonan Syndrome with Multiple Lentigines (NSML-formerly known as LEOPARD syndrome) is a rare autosomal dominant condition that usually exhibits cardiac involvement with hypertrophic cardiomyopathy (HCM). Here we present a case of a NSML patient with an unusual and patchy cardiac hypertrophy distribution.

Shp2 is a positive regulator for Erk activation downstream of receptor tyrosine kinases for growth factors. It has been controversial how Shp2 induces Erk activation. We here demonstrate that EphA2 is responsible for Shp2-mediated Erk activation by phosphorylating Tyr542 and Tyr580 of Shp2 in the cells stimulated with growth factors. In NMuMG mammary epithelial cells stimulated with hepatocyte growth factor (HGF), HGF-dependent Erk phosphorylation was prolonged only in the presence of EphA2. This Erk activation paralleled the phosphorylation of Tyr542/580 of Shp2 and the association of Grb2 with Shp2, suggesting the positive signal involving Grb2 signal to activate Ras-Erk pathway. Immunohistochemical studies of mammary cancer specimens revealed that the cancer progression was associated with both Tyr580 phosphorylation of Shp2 and increased expression of EphA2, which were also correlated with increased Erk phosphorylation. Overexpression of either Shp2Thr468Met (a phosphatase-defective mutant found in L entigines, E lectrocardiographic abnormalities, O cular hypertelorism, P ulmonary stenosis, A bnormal genitalia, R etardation of growth and sensorineural D eafness (LEOPARD) syndrome) or Shp2Asn308Asp (a phosphatase-active mutant found in Noonan syndrome) with EphA2 exhibited comparable activation of Erk and stronger activation than wild-type Shp2, suggesting the phosphatase-independent Erk activation. Expression of Shp2Thr468Met with Tyr542/580Phe mutations resulted in the suppression of Erk activation. Phosphatase-active and -inactive, and wild-type Shp2s bound equally to Grb2, suggesting that phosphorylation of Tyr542/580 of Shp2 was essential but not sufficient for Shp2-mediated Erk activation. We found that Gab1 (Grb2-associated binder 1) was involved in the mutant Shp2-mediated Erk activation. Zebrafish injected with Shp2Thr468Met mRNA showed cardiac edema, whereas those depleted of EphA2b showed less phenotype, suggesting that EphA2 might partly account for the phenotype of LEOPARD syndrome. Collectively, tyrosine phosphorylation of Shp2 by EphA2 contributes to the phosphatase-independent Shp2-mediated activation of Erk and might be involved in Shp2-associated diseases.

BackgroundNoonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is an autosomal-dominant disorder characterised by lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation and deafness. There is significant clinical overlap between NSML and other disorders that result from dysregulated rat sarcoma/mitogen-activated protein kinase pathway (RASopathies). Except for neurofibromatosis type 1, other RASopathies are not known to be typically associated with neurogenic tumours.Methods and resultsWe evaluated patients from three families with pigmentary skin lesions, progressive neuropathy, enlarged nerves, massive burden of paraspinal tumours (neurofibroma was confirmed in one patient) and a clinical diagnosis of NSML. All patients had a mutation in the protein tyrosine phosphatase catalytic domain of the PTPN11 gene; two unrelated patients had the p.Thr468Met mutation, while the family consisting of two affected individuals harboured the p.Thr279Cys mutation. Molecular analysis performed on hypertrophic nerve tissue did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes.ConclusionsNeurogenic tumours and hypertrophic neuropathy are unusual complications of NSML and may be an under-recognised manifestation that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation.