63 results on '"Noonan Syndrome with Multiple Lentigines"'
Search Results
2. Hypertrophic cardiomyopathy in an adult patient with Noonan syndrome with multiple lentigines.
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Rivero‐García, Pamela, Campuzano‐Estrada, Isabel del Carmen, and Hernandez‐Felix, Jorge Humberto
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NOONAN syndrome , *HYPERTROPHIC cardiomyopathy , *APICAL hypertrophic cardiomyopathy , *LENTIGO , *SHORT stature , *TAKOTSUBO cardiomyopathy , *PECTUS excavatum - Abstract
Key Clinical Message: Noonan syndrome with multiple lentigines (NSML) is a rare RASopathy caused by pathogenic variants (PV) predominantly in PTPN11 gene. We report a 54‐year‐old male with apical hypertrophic cardiomyopathy, who was diagnosed with NSML due to his short stature, multiple lentigines, winged neck, pectus excavatum, and a heterozygous PV in PTPN11 c.836A > ¡G. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Hypertrophic cardiomyopathy in an adult patient with Noonan syndrome with multiple lentigines
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Pamela Rivero‐García, Isabel del Carmen Campuzano‐Estrada, and Jorge Humberto Hernandez‐Felix
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LEOPARD syndrome ,Mexico ,Noonan syndrome with multiple lentigines ,PTPN11 ,RASopathy ,Medicine ,Medicine (General) ,R5-920 - Abstract
Key Clinical Message Noonan syndrome with multiple lentigines (NSML) is a rare RASopathy caused by pathogenic variants (PV) predominantly in PTPN11 gene. We report a 54‐year‐old male with apical hypertrophic cardiomyopathy, who was diagnosed with NSML due to his short stature, multiple lentigines, winged neck, pectus excavatum, and a heterozygous PV in PTPN11 c.836A > ¡G.
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- 2023
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4. PTPN11 Gen Mutasyonu Saptanan Olguların Genotip/Fenotip İlişkisi: Doğu Karadeniz Deneyimi .
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Altıner, Şule, Çebi, Alper Han, Çelik, Said, and Gökcü, Mehmet
- Abstract
Copyright of Journal of Ankara University Faculty of Medicine / Ankara Üniversitesi Tip Fakültesi Mecmuasi is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2022
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5. Compound heterozygosity for <scp>PTPN11</scp> variants in a subject with Noonan syndrome provides insights into the mechanism of <scp>SHP2</scp> ‐related disorders
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Marco Tartaglia, Simone Martinelli, Elías Cuesta-Llavona, Gianfranco Bocchinfuso, Luca Pannone, Julián Rodríguez-Reguero, Eliecer Coto, Inés Hernando, Rebeca Lorca, Giovanna Carpentieri, Juan Gómez, and Elisabetta Flex
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LEOPARD syndrome ,Noonan syndrome ,phosphatase assay ,PTPN11 ,SHP2 ,Male ,Models, Molecular ,musculoskeletal diseases ,0301 basic medicine ,Heterozygote ,Protein Conformation ,Mutation, Missense ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,030105 genetics & heredity ,RASopathy ,Biology ,Compound heterozygosity ,LEOPARD Syndrome ,03 medical and health sciences ,Settore CHIM/02 ,Genetics ,medicine ,Humans ,Allele ,skin and connective tissue diseases ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Noonan Syndrome ,Genetic Variation ,Middle Aged ,medicine.disease ,Pedigree ,030104 developmental biology ,Amino Acid Substitution ,Mutation ,Noonan Syndrome with Multiple Lentigines - Abstract
The RASopathies are a family of clinically related disorders caused by mutations affecting genes participating in the RAS-MAPK signaling cascade. Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in PTPN11, which encodes the nonreceptor SH2 domain-containing protein tyrosine phosphatase SHP2. Individual PTPN11 mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in PTPN11. While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that PTPN11 mutations causing this condition act through an alternative dominant mechanism.
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- 2021
6. Noonan Syndrome with Multiple Lentigines and PTPN11 Mutation: A Case with Intracerebral Hemorrhage
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Carlos Martin-Restrepo, Alberto Velez-van-Meerbeke, and Eduardo Orrego-González
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Intracerebral hemorrhage ,0303 health sciences ,medicine.medical_specialty ,business.industry ,030305 genetics & heredity ,medicine.disease ,LEOPARD Syndrome ,Dermatology ,PTPN11 ,03 medical and health sciences ,Dysmetria ,Genetics ,medicine ,Noonan syndrome ,Missense mutation ,Craniofacial ,business ,Genetics (clinical) ,Noonan Syndrome with Multiple Lentigines ,030304 developmental biology - Abstract
Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome, is a rare autosomal dominant disorder with an unknown prevalence. Characteristics of this disease include cutaneous, neurologic, and cardiologic abnormalities. In this case report, we present a 12-year-old girl who was admitted to the emergency department for acute-onset left weakness, unsteady gait, nausea, and vomiting. Her physical exam notably showed left side upper motor neuron signs and dysmetria. CT scan revealed an acute hemorrhage of the right thalamus. Physical exam exhibited several craniofacial dysmorphisms and lentigines. The genetic test revealed a heterozygous missense mutation in the protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene and a variant of unknown significance of the MYH11 gene. To the best of our knowledge, this is the first case of a patient with NSML presenting an intracerebral hemorrhage.
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- 2021
7. Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11.
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van Nierop, Josephine W.I., van Trier, Dorothée C., van der Burgt, Ineke, Draaisma, Jos M.T., Mylanus, Emmanuel A.M., Snik, Ad F., Admiraal, Ronald J.C., and Kunst, Henricus P.M.
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NOONAN syndrome , *TREATMENT of deafness , *COCHLEAR implants , *GENETIC mutation , *AUDIOLOGY , *LENTIGO , *THERAPEUTICS - Abstract
Existing literature only reports a few patients with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) who underwent cochlear implantation (CI). The present study describes four NS patients and one NSML patient with a PTPN11 mutation. They all had severe to profound hearing loss, and they received a CI. The age at which the CI surgery occurred ranged from 1 to 13 years old, and the audiological results in all five patients improved after the CI. Otological and audiological examinations in NS and NSML are important, and for those with severe hearing loss, the CI surgery improved the audiological outcome regardless of age. [ABSTRACT FROM AUTHOR]
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- 2017
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8. Congenital sensorineural hearing loss as the initial presentation ofPTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms
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Wei-Qian Wang, Jin-Cao Xu, Shi-Wei Qiu, Dongyang Kang, Hui-Yan Xu, Shasha Huang, Xue Gao, Pu Dai, Yu Su, and Yongyi Yuan
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musculoskeletal diseases ,0301 basic medicine ,Proband ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,business.industry ,Hearing loss ,030105 genetics & heredity ,medicine.disease ,Congenital hearing loss ,PTPN11 ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,otorhinolaryngologic diseases ,Genetics ,medicine ,Medical genetics ,Noonan syndrome ,medicine.symptom ,business ,Genetics (clinical) ,Noonan Syndrome with Multiple Lentigines ,Spiral ganglion - Abstract
BackgroundGermline variants inPTPN11are the primary cause of Noonan syndrome with multiple lentigines (NSML) and Noonan syndrome (NS), which share common skin and facial symptoms, cardiac anomalies and retardation of growth. Hearing loss is considered an infrequent feature in patients with NSML/NS. However, in our cohort, we identified a group of patients withPTPN11pathogenic variants that were primarily manifested in congenital sensorineural hearing loss (SNHL). This study evaluated the incidence ofPTPN11-related NSML or NS in patients with congenital SNHL and explored the expression ofPTPN11and the underlying mechanisms in the auditory system.MethodsA total of 1502 patients with congenital SNHL were enrolled. Detailed phenotype-genotype correlations were analysed in patients withPTPN11variants. Immunolabelling of Ptpn11 was performed in P35 mice. Zebrafish withPtpn11knockdown/mutant overexpression were constructed to further explore mechanism underlying the phenotypes.ResultsTen NSML/NS probands were diagnosed via the identification of pathogenic variants ofPTPN11, which accounted for ~0.67% of the congenital SNHL cases. In mice cochlea, Shp2, which is encoded byPtpn11, is distributed in the spiral ganglion neurons, hair cells and supporting cells of the inner ear. In zebrafish, knockdown ofptpn11aand overexpression of mutantPTPN11were associated with a significant decrease in hair cells and supporting cells. We concluded that congenital SNHL could be a major symptom inPTPN11-associated NSML or NS. Other features may be mild, especially in children.ConclusionScreening forPTPN11in patients with congenital hearing loss and variant-based diagnoses are recommended.
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- 2020
9. Occurrence of DNET and Other Brain Tumors in Noonan Syndrome Warrants Caution with Growth Hormone Therapy.
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McWilliams, Geoffrey D., SantaCruz, Karen, Hart, Blaine, and Clericuzio, Carol
- Abstract
Noonan syndrome (NS) is an autosomal dominant developmental disorder caused by mutations in the RAS-MAPK signaling pathway that is well known for its relationship with oncogenesis. An 8.1-fold increased risk of cancer in Noonan syndrome has been reported, including childhood leukemia and solid tumors. The same study found a patient with a dysembryoplastic neuroepithelial tumor (DNET) and suggested that DNET tumors are associated with NS. Herein we report an 8-year-old boy with genetically confirmed NS and a DNET. Literature review identified eight other reports, supporting the association between NS and DNETs. The review also ascertained 13 non-DNET brain tumors in individuals with NS, bringing to 22 the total number of NS patients with brain tumors. Tumor growth while receiving growth hormone (GH) occurred in our patient and one other patient. It is unknown whether the development or progression of tumors is augmented byGHtherapy, however there is concern based on epidemiological, animal and in vitro studies. This issue was addressed in a 2015 Pediatric Endocrine Society report noting there is not enough data available to assess the safety of GH therapy in children with neoplasia-predisposition syndromes. The authors recommend that GH use in children with such disorders, including NS, be undertaken with appropriate surveillance for malignancies. Our case report and literature review underscore the association of NS with CNS tumors, particularly DNET, and call attention to the recommendation that clinicians treating NS patients with GH do so with awareness of the possibility of increased neoplasia risk. [ABSTRACT FROM AUTHOR]
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- 2016
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10. SHP2 sails from physiology to pathology.
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Tajan, Mylène, de Rocca Serra, Audrey, Valet, Philippe, Edouard, Thomas, and Yart, Armelle
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PROTEIN-tyrosine kinases , *GENETIC mutation , *GENETIC code , *LENTIGO , *MITOGEN-activated protein kinases - Abstract
Over the two past decades, mutations of the PTPN11 gene, encoding the ubiquitous protein tyrosine phosphatase SHP2 (SH2 domain-containing tyrosine phosphatase 2), have been identified as the causal factor of several developmental diseases (Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), and metachondromatosis), and malignancies (juvenile myelomonocytic leukemia). SHP2 plays essential physiological functions in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a wide range of growth factors and hormones, notably the pleiotropic Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide-3 Kinase (PI3K)/AKT cascades. Analysis of the biochemical impacts of PTPN11 mutations first identified both loss-of-function and gain-of-function mutations, as well as more subtle defects, highlighting the major pathophysiological consequences of SHP2 dysregulation. Then, functional genetic studies provided insights into the molecular dysregulations that link SHP2 mutants to the development of specific traits of the diseases, paving the way for the design of specific therapies for affected patients. In this review, we first provide an overview of SHP2's structure and regulation, then describe its molecular roles, notably its functions in modulating the Ras/MAPK and PI3K/AKT signaling pathways, and its physiological roles in organism development and homeostasis. In the second part, we describe the different PTPN11 mutation-associated pathologies and their clinical manifestations, with particular focus on the biochemical and signaling outcomes of NS and NS-ML-associated mutations, and on the recent advances regarding the pathophysiology of these diseases. [ABSTRACT FROM AUTHOR]
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- 2015
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11. Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines
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Kana Mizuno, Sravan K. Perla, Jae Sung Yi, Anton M. Bennett, Alexander A. Vinks, Frank J. Giordano, and Yan Huang
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0301 basic medicine ,Cardiac fibrosis ,medicine.drug_class ,Dasatinib ,030204 cardiovascular system & hematology ,Pharmacology ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pharmacokinetics ,hemic and lymphatic diseases ,medicine ,LEOPARD Syndrome ,Animals ,Pharmacology (medical) ,business.industry ,Hypertrophic cardiomyopathy ,General Medicine ,Cardiomyopathy, Hypertrophic ,medicine.disease ,PTPN11 ,Disease Models, Animal ,030104 developmental biology ,Mutation ,Cardiology and Cardiovascular Medicine ,business ,Noonan Syndrome with Multiple Lentigines ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug - Abstract
Purpose Noonan syndrome with multiple lentigines (NSML) is an autosomal dominant disorder presenting with hypertrophic cardiomyopathy (HCM). Up to 85% of NSML cases are caused by mutations in the PTPN11 gene that encodes for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2). We previously showed that low-dose dasatinib protects from the development of cardiac fibrosis in a mouse model of NSML harboring a Ptpn11Y279C mutation. This study is performed to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a low-dose of dasatinib in NSML mice and to determine its effectiveness in ameliorating the development of HCM. Methods Dasatinib was administered intraperitoneally into NSML mice with doses ranging from 0.05 to 0.5 mg/kg. PK parameters of dasatinib in NSML mice were determined. PD parameters were obtained for biochemical analyses from heart tissue. Dasatinib-treated NSML mice (0.1 mg/kg) were subjected to echocardiography and assessment of markers of HCM by qRT-PCR. Transcriptome analysis was performed from the heart tissue of low-dose dasatinib-treated mice. Results Low-dose dasatinib exhibited PK properties that were linear across doses in NSML mice. Dasatinib treatment of between 0.05 and 0.5 mg/kg in NSML mice yielded an exposure-dependent inhibition of c-Src and PZR tyrosyl phosphorylation and inhibited AKT phosphorylation. We found that doses as low as 0.1 mg/kg of dasatinib prevented HCM in NSML mice. Transcriptome analysis identified differentially expressed HCM-associated genes in the heart of NSML mice that were reverted to wild type levels by low-dose dasatinib administration. Conclusion These data demonstrate that low-dose dasatinib exhibits desirable therapeutic PK properties that is sufficient for effective target engagement to ameliorate HCM progression in NSML mice. These data demonstrate that low-dose dasatinib treatment may be an effective therapy against HCM in NSML patients.
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- 2021
12. Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: Palliative treatment with a rapamycin analog.
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Hahn, Andreas, Lauriol, Jessica, Thul, Josef, Behnke‐Hall, Kachina, Logeswaran, Tushiha, Schänzer, Anne, Böğürcü, Nuray, Garvalov, Boyan K., Zenker, Martin, Gelb, Bruce D., von Gerlach, Susanne, Kandolf, Reinhard, Kontaridis, Maria I., and Schranz, Dietmar
- Abstract
Noonan syndrome with multiple lentigines (NSML) frequently manifests with hypertrophic cardiomyopathy (HCM). Recently, it was demonstrated that mTOR inhibition reverses HCM in NSML mice. We report for the first time on the effects of treatment with a rapamycin analog in an infant with LS and malignant HCM. In the boy, progressive HCM was diagnosed during the first week of life and a diagnosis of NSML was established at age 20 weeks by showing a heterozygous Q510E mutation in PTPN11. Immunoblotting with antibodies against pERK, pAkt, and pS6RP in fibroblasts demonstrated enhanced Akt/mTOR pathway activity. Because of the patient's critical condition, everolimus therapy was started at age 24 weeks and continued until heart transplantation at age 36 weeks. Prior to surgery, heart failure improved from NYHA stage IV to II and brain natriuretic peptide values decreased from 9,600 to <1,000 pg/ml, but no reversal of cardiac hypertrophy was observed. Examination of the explanted heart revealed severe hypertrophy and myofiber disarray with extensive perivascular fibrosis. These findings provide evidence that Akt/mTOR activity is enhanced in NSML with HCM and suggest that rapamycin treatment could principally be feasible for infantile NSML. The preliminary experiences made in this single patient indicate that therapy should start early to prevent irreversible cardiac remodelling. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2015
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13. The Q510E mutation in Shp2 perturbs heart valve development by increasing cell migration.
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Edwards, Michelle A., Crombie, Kathryn, Schramm, Christine, and Krenz, Maike
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HEART valves ,CELL migration ,CELLULAR control mechanisms ,PROTEIN-tyrosine kinases ,NOONAN syndrome - Abstract
Tightly regulated cellular signaling is critical for correct heart valve development, but how and why signaling is dysregulated in congenital heart disease is not very well known. We focused on protein tyrosine phosphatase Shp2, because mutations in this signaling modulator frequently cause valve malformations associated with Noonan syndrome or Noonan syndrome with multiple lentigines (NSML). To model NSML-asso-ciated valve disease, we targeted overexpression of Q510E-Shp2 to mouse endocardial cushions (ECs) using a Tie2-Cre-based approach. At midgestation, Q510E-Shp2 expression increased the size of atrio-ventricular ECs by 80%. To dissect the underlying cellular mechanisms, we explanted ECs from chick embryonic hearts and induced Q510E-Shp2 expression using adenoviral vectors. Valve cell outgrowth from cultured EC explants into surrounding matrix was significantly increased by Q510E-Shp2 expression. Because focal adhesion kinase (FAK) is a critical regulator of cell migration, we tested whether FAK inhibition counteracts the Q510E-Shp2-induced effects in explanted ECs. The FAK/src inhibitor PP2 normalized valve cell outgrowth from Q510E-Shp2-expressing ECs. Next, chick ECs were further dissociated to assess cell proliferation and migration. Valve cell proliferation was not increased by Q510E-Shp2 as determined by label incorporation. In contrast, valve cell migration as reflected in a wound-healing assay was increased by Q510E-Shp2 expression, indicating that increased migration is the predominant effect of Q510E-Shp2 expression in ECs. In conclusion, PP2-sensitive signaling mediates the pathogenic effects of Q510E-Shp2 on cell migration in EC explant cultures. This suggests a central role for FAK and provides new mechanistic insight into the molecular basis of valve defects in NSML. [ABSTRACT FROM AUTHOR]
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- 2015
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14. Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines
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Liz Enyenihi, Anton M. Bennett, Sravan K. Perla, and Jae Sung Yi
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Male ,0301 basic medicine ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Mice ,03 medical and health sciences ,0302 clinical medicine ,LEOPARD Syndrome ,medicine ,Animals ,Myocytes, Cardiac ,Phosphorylation ,Kinase activity ,Protein kinase B ,Mice, Knockout ,Chemistry ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Cardiomyopathy, Hypertrophic ,Phosphoproteins ,medicine.disease ,Molecular biology ,Mice, Inbred C57BL ,PTPN11 ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Tyrosine ,Female ,Signal transduction ,Noonan Syndrome with Multiple Lentigines ,Research Article ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder that presents with cardio-cutaneous-craniofacial defects. Hypertrophic cardiomyopathy (HCM) represents the major life-threatening presentation in NSML. Mutations in the PTPN11 gene that encodes for the protein tyrosine phosphatase (PTP), SHP2, represents the predominant cause of HCM in NSML. NSML-associated PTPN11 mutations render SHP2 catalytically inactive with an “open” conformation. NSML-associated PTPN11 mutations cause hypertyrosyl phosphorylation of the transmembrane glycoprotein, protein zero-related (PZR), resulting in increased SHP2 binding. Here we show that NSML mice harboring a tyrosyl phosphorylation–defective mutant of PZR (NSML/PZR(Y242F)) that is defective for SHP2 binding fail to develop HCM. Enhanced AKT/S6 kinase signaling in heart lysates of NSML mice was reversed in NSML/PZR(Y242F) mice, demonstrating that PZR/SHP2 interactions promote aberrant AKT/S6 kinase activity in NSML. Enhanced PZR tyrosyl phosphorylation in the hearts of NSML mice was found to drive myocardial fibrosis by engaging an Src/NF-κB pathway, resulting in increased activation of IL-6. Increased expression of IL-6 in the hearts of NSML mice was reversed in NSML/PZR(Y242F) mice, and PZR(Y242F) mutant fibroblasts were defective for IL-6 secretion and STAT3-mediated fibrogenesis. These results demonstrate that NSML-associated PTPN11 mutations that induce PZR hypertyrosyl phosphorylation trigger pathophysiological signaling that promotes HCM and cardiac fibrosis.
- Published
- 2020
15. Patient with confirmed LEOPARD syndrome developing multiple melanoma
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Isabelle Tromme, Deborah Franck, Gert Matthijs, Caroline Colmant, Liliane Marot, Sandrine Blomme, and Yves Sznajer
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medicine.medical_specialty ,Dermatology ,LEOPARD Syndrome ,Germline ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Genetics ,Medicine ,Sex organ ,Hypertelorism ,Molecular Biology ,LEOPARD syndrome ,business.industry ,Melanoma ,Articles ,medicine.disease ,PTPN11 ,Oncology ,RL1-803 ,030220 oncology & carcinogenesis ,medicine.symptom ,dermoscopy ,business ,Noonan Syndrome with Multiple Lentigines ,melanomas - Abstract
LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R), and sensorineural deafness (D). This condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in PTPN11 gene. Association of melanoma to NSML seems to be rare: to our knowledge, two patients so far were reported in the literature. We herein present a patient diagnosed with LEOPARD syndrome, in whom molecular investigation confirmed the presence of the c.1403C>T mutation in exon 12 of the PTPN11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. Three of the melanomas were achromic or hypochromic, three were in situ, and one had a Breslow index under 0.5 mm. Dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis. ispartof: Dermatology practical & conceptual vol:8 issue:1 pages:59-62 ispartof: location:Austria status: published
- Published
- 2018
16. Microduplication of 3p25.2 encompassing RAF1 associated with congenital heart disease suggestive of Noonan syndrome.
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Luo, Cheng, Yang, Yi-Feng, Yin, Bang-Liang, Chen, Jin-Lan, Huang, Can, Zhang, Wei-Zhi, Wang, Jian, Zhang, Hong, Yang, Jin-Fu, and Tan, Zhi-Ping
- Abstract
Noonan syndrome (NS) is a clinically variable and genetically heterogeneous disorder with congenital heart defects (CHD), short stature, and craniofacial dysmorphisms. Gain-of-function mutations in RAF1 can cause NS and the highly related NS with multiple lentigines (previously known as LEOPARD syndrome). Here we report on a 15-year-old male with NS phenotype: short stature, heart defects, low posterior hairline, facial malformations, malformed left ear with sensorineural hearing loss, widely spaced nipples, and unilateral upper limb anomaly. Using high-resolution SNP array technology, we identified in this patient a 0.25 Mb microduplication at 3p25.2 in which RAF1 is located. Sequence analysis did not identify mutations in genes associated with Holt-Oram syndrome. These findings suggest that duplications of genomic regions encompassing RAF1 could cause NS and are consistent with the notion that rare copy number variations encompassing causative genes may underlie a small percentage of patients with syndromic CHD like NS. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2012
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17. Pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: the multifaceted consequences of PTPN11 mutations
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Giulio Calcagni, Marco Tartaglia, Maria Cristina Digilio, and Bruno Marino
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Heart Defects, Congenital ,Male ,0301 basic medicine ,Mutation, Missense ,lcsh:Medicine ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Disease ,030105 genetics & heredity ,RASopathy ,Bioinformatics ,LEOPARD Syndrome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Pharmacology (medical) ,Letter to the Editor ,Genetics (clinical) ,business.industry ,lcsh:R ,Noonan Syndrome ,Hypertrophic cardiomyopathy ,MAPK ,PI3K-AKT-mTOR ,General Medicine ,Cardiomyopathy, Hypertrophic ,medicine.disease ,PTPN11 ,Mutation ,Noonan syndrome ,Female ,Differential diagnosis ,business ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines ,Signal Transduction - Abstract
The concomitant occurrence of hypertrophic cardiomyopathy and congenital heart defect in patients with RASopathies has previously been reported as associated to a worse clinical outcome, particularly closed to cardiac surgery. Different mechanisms of disease have been demonstrated to be associated with the two classes of PTPN11 mutations underlying Noonan syndrome and Noonan syndrome with multiple lentigines (also known as LEOPARD syndrome). Although differential diagnosis between these two syndromes could be difficult, particularly in the first age of life, we underline the relevance in discriminating these two disorders in terms of affected signaling pathway to allow an effective targeted pharmacological treatment.
- Published
- 2019
18. Generation of an induced pluripotent stem cell line (TRNDi003-A) from a Noonan syndrome with multiple lentigines (NSML) patient carrying a p.Q510P mutation in the PTPN11 gene
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Elizabeth A. Ottinger, Yongshun Lin, Jeanette Beers, Amy E. Roberts, Wei Zheng, Chengyu Liu, Rong Li, Fabrice Jaffré, Jizhong Zou, Amanda Baskfield, and Maria I. Kontaridis
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0301 basic medicine ,Adolescent ,Induced Pluripotent Stem Cells ,Cell Culture Techniques ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Biology ,medicine.disease_cause ,Peripheral blood mononuclear cell ,LEOPARD Syndrome ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Missense mutation ,Humans ,Induced pluripotent stem cell ,lcsh:QH301-705.5 ,Mutation ,Base Sequence ,Cell Biology ,General Medicine ,medicine.disease ,PTPN11 ,030104 developmental biology ,lcsh:Biology (General) ,Cancer research ,Female ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines ,Developmental Biology - Abstract
Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD Syndrome, is a rare autosomal dominant disorder. Approximately 90% of NSML cases are caused by missense mutations in the PTPN11 gene which encodes the protein tyrosine phosphatase SHP2. A human induced pluripotent stem cell (iPSC) line was generated using peripheral blood mononuclear cells (PBMCs) from a patient with NSML that carries a gene mutation of p.Q510P on the PTPN11 gene using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and a cell-based model for drug development to treat NSML.
- Published
- 2018
19. Caracterización clínica y molecular de niños con síndrome de Noonan y otras RASopatías en Argentina
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Josefina Chinton, M. Gabriela Obregon, Victoria Huckstadt, L Pablo Gravina, and Angélica Moresco
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musculoskeletal diseases ,Heart Defects, Congenital ,Male ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Argentina ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,RASopathy ,Gene mutation ,PTPN11 ,Cardiofaciocutaneous syndrome ,Diagnosis, Differential ,Proto-Oncogene Proteins p21(ras) ,Young Adult ,Costello syndrome ,Ectodermal Dysplasia ,Síndrome de Noonan ,medicine ,Noonan syndrome ,Humans ,HRAS ,RAF1 ,skin and connective tissue diseases ,Child ,RASopathies ,business.industry ,Costello Syndrome ,Noonan Syndrome ,Infant, Newborn ,Facies ,Infant ,medicine.disease ,Dermatology ,Failure to Thrive ,Proto-Oncogene Proteins c-raf ,RASopatías ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,Female ,business ,SOS1 Protein ,Noonan Syndrome with Multiple Lentigines - Abstract
Introducción. Las RASopatías son un conjunto de síndromes fenotípicamente superpuestos causados por mutaciones en genes implicados en la vía RAS/MAPK. La herencia es autosómica dominante, presentan características clínicas comunes, como baja talla, dismorfias craneofaciales, cardiopatia congénita, manifestaciones ectodérmicas y mayor riesgo de cáncer. El diagnóstico molecular es clave. Objetivo. Identificar mutaciones en los genes PTPN11, SOS1,RAF1, BRAFy HRAS,y comparar las principales características clínicas en pacientes con confirmación molecular. Población y métodos. Se estudiaron niños con diagnóstico clínico de RASopatía evaluados entre agosto de 2013 y febrero de 2017. Resultados. Se identificaron mutaciones en el 71 % (87/122) de los pacientes. El estudio molecular confirmó el diagnóstico en el 73 % de los pacientes con síndrome de Noonan. La mutación más prevalente fue c.922A>G (p.Asn308Asp) en el gen PTPN11. Se detectó una variante no descrita en RAF1, c.1467G>C (p.Leu489Phe). Se confirmó el sindrome cardiofaciocutáneo en el 67 % de los casos con mutaciones en el gen BRAF. El síndrome de Costello y el síndrome de Noonan con múltiples lentigos se confirmaron en todos los casos. Conclusión. La confirmación del diagnóstico clínico permitió un diagnóstico diferencial más preciso. Se determinó la prevalencia de las mutaciones en PTPN11 (el 58 %), SOS1 (el 10 %) y RAF1 (el 5 %) en niños con síndrome de Noonan, en PTPN11 (el 100 %) en el sindrome de Noonan con múltiples lentigos, en BRAF (el 67 %) en el síndrome cardiofaciocutáneo y en HRAS (el 100 %) en el sindrome de Costello. Introduction. RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway. They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer. A molecular diagnosis is a key factor. Objective. To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation. Population and methods. Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017. Results. Mutations were identified in 71 % (87/122) of patients. The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome. The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene. A previously undescribed variant in RAF1 was detected: c.1467G>C (p.Leu489Phe). Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations. Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases. Conclusion. The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis. The prevalence of PTPN11 (58 %), SOS1 (10 % ), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.
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- 2018
20. Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner
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Ronald R. Waclaw, Hong Zheng, Benjamin G. Neel, Wen Mei Yu, Cheng-Kui Qu, and Maria I. Kontaridis
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musculoskeletal diseases ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Ependymal Cell ,Mutant ,Mice, Transgenic ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Biology ,medicine.disease_cause ,Biochemistry ,LEOPARD Syndrome ,Article ,03 medical and health sciences ,0302 clinical medicine ,Neural Stem Cells ,Ependyma ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,STAT3 ,Molecular Biology ,Mice, Knockout ,Mutation ,Noonan Syndrome ,Cell Biology ,medicine.disease ,Cell biology ,Mice, Inbred C57BL ,PTPN11 ,030104 developmental biology ,Gain of Function Mutation ,Biocatalysis ,biology.protein ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines ,Hydrocephalus - Abstract
Catalytically activating mutations in Ptpn11, which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan Syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan Syndrome with Multiple Lentigines (NSML, formerly called LEOPARD Syndrome). Both types of disease mutations are gain-of-function mutations because they induce SHP2 to constitutively adopt an open conformation, yet they have opposing effects on SHP2 catalytic activity. Here, we report that the catalytic activity of SHP2 is required for the pathogenic effects of Ptpn11 gain-of-function disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knock-in of the Ptpn11 activating mutation E76K resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were completely suppressed by the additional mutation C459S, which abolishes catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the Ptpn11 inactivating mutation Y279C were also unaffected. Mechanistically, the Ptpn11E76K mutation induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcriptional activator STAT3. Whereas STAT3 activity was reduced in Ptpn11E76K/+ cells, the activities of the kinases ERK and AKT were enhanced, and neural cell–specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic–dependent role of Ptpn11 gain-of-function disease mutations in the pathogenesis of hydrocephalus.
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- 2018
21. Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders
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Lili Wang, Yongguo Yu, Shanshan Xu, Yu Sun, Xuefan Gu, and Yanjie Fan
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Male ,0301 basic medicine ,Oncology ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,PTPN11 ,Gene mutation ,Cardiofaciocutaneous syndrome ,LEOPARD Syndrome ,0302 clinical medicine ,RAF1 ,Child ,Genetics (clinical) ,Exome sequencing ,Sanger sequencing ,Genetics ,Noonan Syndrome ,Child, Preschool ,symbols ,Female ,Noonan Syndrome with Multiple Lentigines ,Research Article ,Proto-Oncogene Proteins B-raf ,lcsh:Internal medicine ,China ,medicine.medical_specialty ,lcsh:QH426-470 ,Adolescent ,Mutation, Missense ,Biology ,Polymorphism, Single Nucleotide ,BRAF ,03 medical and health sciences ,symbols.namesake ,Internal medicine ,Exome Sequencing ,medicine ,Humans ,lcsh:RC31-1245 ,Retrospective Studies ,Whole exome sequencing ,Infant ,medicine.disease ,Proto-Oncogene Proteins c-raf ,lcsh:Genetics ,030104 developmental biology ,Noonan syndrome ,030217 neurology & neurosurgery - Abstract
Background Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are autosomal dominant developmental disorders. NS and NSML are caused by abnormalities in genes that encode proteins related to the RAS-MAPK pathway, including PTPN11, RAF1, BRAF, and MAP2K. In this study, we diagnosed ten NS or NSML patients via targeted sequencing or whole exome sequencing (TS/WES). Methods TS/WES was performed to identify mutations in ten Chinese patients who exhibited the following manifestations: potential facial dysmorphisms, short stature, congenital heart defects, and developmental delay. Sanger sequencing was used to confirm the suspected pathological variants in the patients and their family members. Results TS/WES revealed three mutations in the PTPN11 gene, three mutations in RAF1 gene, and four mutations in BRAF gene in the NS and NSML patients who were previously diagnosed based on the abovementioned clinical features. All the identified mutations were determined to be de novo mutations. However, two patients who carried the same mutation in the RAF1 gene presented different clinical features. One patient with multiple lentigines was diagnosed with NSML, while the other patient without lentigines was diagnosed with NS. In addition, a patient who carried a hotspot mutation in the BRAF gene was diagnosed with NS instead of cardiofaciocutaneous syndrome (CFCS). Conclusions TS/WES has emerged as a useful tool for definitive diagnosis and accurate genetic counseling of atypical cases. In this study, we analyzed ten Chinese patients diagnosed with NS and related disorders and identified their correspondingPTPN11, RAF1, and BRAF mutations. Among the target genes, BRAF showed the same degree of correlation with NS incidence as that of PTPN11 or RAF1.
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- 2017
22. Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy
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Blaine L. Hart, Karen S. SantaCruz, Carol L. Clericuzio, and Geoffrey D. McWilliams
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Adult ,Male ,Risk ,Oncology ,medicine.medical_specialty ,Adolescent ,Childhood leukemia ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,Humans ,Medicine ,Child ,Genetics (clinical) ,DNET ,Brain Neoplasms ,Human Growth Hormone ,business.industry ,Dysembryoplastic Neuroepithelial Tumor ,Noonan Syndrome ,Cancer ,medicine.disease ,Neoplasms, Neuroepithelial ,PTPN11 ,Developmental disorder ,Endocrinology ,030220 oncology & carcinogenesis ,Noonan syndrome ,Female ,business ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome (NS) is an autosomal dominant developmental disorder caused by mutations in the RAS-MAPK signaling pathway that is well known for its relationship with oncogenesis. An 8.1-fold increased risk of cancer in Noonan syndrome has been reported, including childhood leukemia and solid tumors. The same study found a patient with a dysembryoplastic neuroepithelial tumor (DNET) and suggested that DNET tumors are associated with NS. Herein we report an 8-year-old boy with genetically confirmed NS and a DNET. Literature review identified eight other reports, supporting the association between NS and DNETs. The review also ascertained 13 non-DNET brain tumors in individuals with NS, bringing to 22 the total number of NS patients with brain tumors. Tumor growth while receiving growth hormone (GH) occurred in our patient and one other patient. It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. This issue was addressed in a 2015 Pediatric Endocrine Society report noting there is not enough data available to assess the safety of GH therapy in children with neoplasia-predisposition syndromes. The authors recommend that GH use in children with such disorders, including NS, be undertaken with appropriate surveillance for malignancies. Our case report and literature review underscore the association of NS with CNS tumors, particularly DNET, and call attention to the recommendation that clinicians treating NS patients with GH do so with awareness of the possibility of increased neoplasia risk.
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- 2015
23. Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines
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Radhika Dhamija, Jing Xie, Dusica Babovic-Vuksanovic, Erin Conboy, P. James B. Dyck, Robert J. Spinner, Margaret Wang, Robert E. Watson, Amy C. Clayton, Alina G. Bridges, and Ludwine Messiaen
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Pathology ,Neurofibromatosis 1 ,Neuromuscular disease ,Adolescent ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,030105 genetics & heredity ,LEOPARD Syndrome ,03 medical and health sciences ,Internal medicine ,Genetics ,medicine ,Humans ,Neurofibroma ,Neurofibromatosis ,Hypertelorism ,SMARCB1 ,Genetics (clinical) ,Spinal Neoplasms ,business.industry ,Noonan Syndrome ,Hypertrophy ,Middle Aged ,medicine.disease ,PTPN11 ,Endocrinology ,Mutation ,Female ,Mitogen-Activated Protein Kinases ,medicine.symptom ,business ,Noonan Syndrome with Multiple Lentigines - Abstract
Background Noonan 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 results We 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. Conclusions Neurogenic 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.
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- 2015
24. A novel heterozygousMAP2K1mutation in a patient with Noonan syndrome with multiple lentigines
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Eriko Nishi, Yoshimitsu Fukushima, Seiji Mizuno, Yuka Nanjo, Tomoki Kosho, Tetsuya Niihori, Yoichi Matsubara, and Yoko Aoki
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Male ,Heterozygote ,medicine.medical_specialty ,Adolescent ,DNA Mutational Analysis ,MAP Kinase Kinase 2 ,Molecular Sequence Data ,MAP Kinase Kinase 1 ,LEOPARD Syndrome ,Internal medicine ,Genetics ,medicine ,Humans ,Missense mutation ,Precocious puberty ,Amino Acid Sequence ,Hypertelorism ,Genetics (clinical) ,business.industry ,Facies ,medicine.disease ,Dermatology ,Hypotonia ,PTPN11 ,Phenotype ,Endocrinology ,Amino Acid Substitution ,Mutation ,Sensorineural hearing loss ,medicine.symptom ,business ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome with multiple lentigines (NSML), formerly referred to as LEOPARD syndrome, is a rare autosomal-dominant condition, characterized by multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and sensorineural deafness. To date, PTPN11, RAF1, and BRAF have been reported to be causal for NSML. We report on a 13-year-old Japanese boy, who was diagnosed with NSML. He was found to have a novel heterozygous missense variant (c.305A > G; p.E102G) in MAP2K1, a gene mostly causal for cardio-facio-cutaneous syndrome (CFCS). He manifested fetal macrosomia, and showed hypotonia and poor sucking in the neonatal period. He had mild developmental delay, and multiple lentigines appearing at approximately age 3 years, as well as flexion deformity of knees bilaterally, subtle facial characteristics including ocular hypertelorism, sensorineural hearing loss, and precocious puberty. He lacked congenital heart defects or hypertrophic cardiomyopathy, frequently observed in patients with NSML, mostly caused by PTPN11 mutations. He also lacked congenital heart defects, characteristic facial features, or intellectual disability, frequently observed in those with CFCS caused by MAP2K1 or MAP2K2 mutations. This may be the first patient clinically diagnosed with NSML, caused by a mutation in MAP2K1. © 2014 Wiley Periodicals, Inc.
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- 2014
25. Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation.
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Zhu, Guangya, Xie, Jingjing, Kong, Wenna, Xie, Jingfei, Li, Yichen, Du, Lin, Zheng, Qiangang, Sun, Lin, Guan, Mingfeng, Li, Huan, Zhu, Tianxin, He, Hao, Liu, Zhenying, Xia, Xi, Kan, Chen, Tao, Youqi, Shen, Hong C., Li, Dan, Wang, Siying, and Yu, Yongguo
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- *
MITOGEN-activated protein kinases , *PROTEIN-tyrosine phosphatase , *PROTEIN kinases , *PHOSPHOPROTEIN phosphatases , *ELECTROSTATIC interaction , *PHASE separation - Abstract
The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11 , plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted. • Disease-associated mutations endow SHP2 liquid-liquid phase separation capability • SHP2 LLPS is driven by electrostatic interactions mediated by PTP domain • SHP2 allosteric inhibitors block SHP2 LLPS by locking SHP2 in closed conformation • Mutant SHP2 can recruit and activate WT SHP2 in LLPS to promote MAPK activation Disease-associated mutants of a critical phosphatase in the RAS-MAPK pathway undergo phase separation through a dominant gain-of-function mechanism, explaining how both enzymatically activating and inactivating mutations dysregulate the pathway and can be therapeutically targeted. [ABSTRACT FROM AUTHOR]
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- 2020
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26. Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11
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Ineke van der Burgt, Jos M. T. Draaisma, Dorothée C. van Trier, Henricus P. M. Kunst, Emmanuel A. M. Mylanus, Ad F. M. Snik, Ronald J.C. Admiraal, and Josephine W. I. van Nierop
- Subjects
0301 basic medicine ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18] ,03 medical and health sciences ,0302 clinical medicine ,Audiometry ,medicine ,LEOPARD Syndrome ,Humans ,In patient ,Cochlear implantation ,Child ,Hearing Loss ,Retrospective Studies ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,Noonan Syndrome ,Infant ,Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16] ,General Medicine ,Severe hearing loss ,medicine.disease ,Cochlear Implantation ,Surgery ,PTPN11 ,Profound hearing loss ,030104 developmental biology ,Otorhinolaryngology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,Noonan syndrome ,Female ,business ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Item does not contain fulltext Existing literature only reports a few patients with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) who underwent cochlear implantation (CI). The present study describes four NS patients and one NSML patient with a PTPN11 mutation. They all had severe to profound hearing loss, and they received a CI. The age at which the CI surgery occurred ranged from 1 to 13 years old, and the audiological results in all five patients improved after the CI. Otological and audiological examinations in NS and NSML are important, and for those with severe hearing loss, the CI surgery improved the audiological outcome regardless of age.
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- 2017
27. In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy
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Maria I. Kontaridis, Brian Schwartz, Yi Yu, Vasanth Chandrasekhar, Jianxun Wang, and Giovanni Abbadessa
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0301 basic medicine ,Male ,Pathology ,Physiology ,Cancer Treatment ,Aminopyridines ,lcsh:Medicine ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,030204 cardiovascular system & hematology ,Left ventricular hypertrophy ,Cardiovascular Physiology ,LEOPARD Syndrome ,Muscle hypertrophy ,Diagnostic Radiology ,Mice ,0302 clinical medicine ,Diastole ,Ultrasound Imaging ,Medicine and Health Sciences ,Myocytes, Cardiac ,lcsh:Science ,Multidisciplinary ,Pharmaceutics ,Radiology and Imaging ,TOR Serine-Threonine Kinases ,Imidazoles ,Heart ,Physiological Parameters ,Oncology ,Echocardiography ,Anatomy ,Noonan Syndrome with Multiple Lentigines ,Research Article ,Signal Transduction ,medicine.medical_specialty ,Cardiotonic Agents ,Imaging Techniques ,Cardiac Hypertrophy ,Cardiology ,Mice, Transgenic ,Research and Analysis Methods ,03 medical and health sciences ,Drug Therapy ,Protein Domains ,Diagnostic Medicine ,Internal medicine ,medicine ,Animals ,Humans ,Protein kinase B ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Alleles ,AKT Inhibitor ARQ 092 ,business.industry ,Body Weight ,lcsh:R ,Biology and Life Sciences ,Cardiomyopathy, Hypertrophic ,medicine.disease ,Phosphoproteins ,PTPN11 ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Mutation ,Cardiovascular Anatomy ,lcsh:Q ,business ,Proto-Oncogene Proteins c-akt - Abstract
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.
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- 2017
28. Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype
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Yoko Aoki, Nobuhiko Okamoto, Tetsuya Niihori, Kimiko Ueda, and Masako Yaoita
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musculoskeletal diseases ,0301 basic medicine ,Heart Defects, Congenital ,Male ,Proto-Oncogene Proteins B-raf ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pathology ,Adolescent ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,RASopathy ,Craniosynostosis ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Craniosynostoses ,Costello syndrome ,Ectodermal Dysplasia ,Internal medicine ,Genetics ,medicine ,Humans ,cardiovascular diseases ,Neurofibromatosis ,skin and connective tissue diseases ,Child ,Genetics (clinical) ,Legius syndrome ,Mitogen-Activated Protein Kinase Kinases ,business.industry ,Noonan Syndrome ,Intracellular Signaling Peptides and Proteins ,Facies ,medicine.disease ,Failure to Thrive ,PTPN11 ,030104 developmental biology ,Endocrinology ,Phenotype ,Child, Preschool ,Mutation ,ras Proteins ,Noonan syndrome ,Female ,business ,Noonan Syndrome with Multiple Lentigines ,Signal Transduction - Abstract
RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported. Here, we describe patients with craniosynostosis and Noonan syndrome due to de novo mutations in PTPN11 and patients with craniosynostosis and CFC syndrome due to de novo mutations in BRAF or KRAS. All of these patients had cranial deformities in addition to the typical phenotypes of CFC syndrome and Noonan syndrome. In RASopathy, patients with cranial deformities, further assessments may be necessary to look for craniosynostosis. Future studies should attempt to elucidate the pathogenic mechanism responsible for craniosynostosis mediated by the RAS/MAPK signaling pathway.
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- 2016
29. Role of PTPN11 (SHP2) in Cancer
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Gordon Chan and Benjamin G. Neel
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musculoskeletal diseases ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Cell signaling ,Juvenile myelomonocytic leukemia ,Biology ,medicine.disease ,LEOPARD Syndrome ,PTPN11 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Germline mutation ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Noonan syndrome ,Noonan Syndrome with Multiple Lentigines ,Metachondromatosis - Abstract
Src homology-2 domain-containing phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a highly conserved, non-transmembrane protein-tyrosine phosphatase (PTP), found in all metazoans. The molecular details of SHP2 regulation by phosphotyrosyl (pTyr) peptide ligand binding are well-understood, and knowledge of these details is critical to understanding SHP2 function in health and disease. Studies using mice with gain- or loss-of-function alleles of Ptpn11 have provided much detail about the physiological functions and signaling pathways regulated by SHP2 at the cellular and whole organism levels. Germline mutations in PTPN11 cause Noonan syndrome, Noonan syndrome with multiple lentigines (previously, LEOPARD syndrome), as well as the cartilage tumor syndrome, metachondromatosis. Somatic PTPN11 mutations occur in several types of hematologic malignancy, most notably juvenile myelomonocytic leukemia and, more rarely, in neuroblastoma and other solid tumors. PTPN11 is crucial for transformation initiated by mutant receptor-tyrosine kinases (RTKs) and is an important effector of H. pylori virulence. However, the direct target(s) of SHP2 responsible for its physiological and pathological effects remain controversial and their identification remains a major goal for the future research.
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- 2016
30. Hypertrophic neuropathy in Noonan syndrome with multiple lentigines
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Fanny Morice-Picard, Guilhem Solé, Claire Maridet, and Alain Taïeb
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musculoskeletal diseases ,0301 basic medicine ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Heterozygote ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,030105 genetics & heredity ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Humans ,Neurofibromatosis ,Codon ,Lentigo ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,Lumbar plexus ,business.industry ,Noonan Syndrome ,Facies ,Peripheral Nervous System Diseases ,medicine.disease ,Dermatology ,Magnetic Resonance Imaging ,PTPN11 ,Endocrinology ,Phenotype ,Amino Acid Substitution ,Neuropathic pain ,Mutation ,Noonan syndrome ,Female ,Differential diagnosis ,business ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines - Abstract
RASopathies comprise several genetic syndromes with mainly cardio-facial-cutaneous manifestations. We report a patient with Noonan syndrome with multiple lentigines (NSML) due to a PTPN11 (p.Thr468Met) mutation associated with hypertrophic neuropathy of lumbar plexus in an adult woman, initially referred for neuropathic pain. Differential diagnosis of neurofibromatosis type 1 (NF1) and other RASopathies is difficult without molecular testing. © 2016 Wiley Periodicals, Inc.
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- 2015
31. Copy number variants including RAS pathway genesHow much RASopathy is in the phenotype?
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Christina Lissewski, Ina Schanze, Martin Zenker, Zornitza Stark, and Sarina G. Kant
- Subjects
Adult ,Male ,Adolescent ,DNA Copy Number Variations ,Noonan syndrome with multiple lentigines ,Locus (genetics) ,RASopathy ,Biology ,cardio-facio-cutaneous syndrome ,Gene duplication ,Genetics ,medicine ,Humans ,Noonan syndrome ,Copy-number variation ,Genetics (clinical) ,Facies ,Middle Aged ,medicine.disease ,Phenotype ,PTPN11 ,Genes, ras ,copy number variations ,Child, Preschool ,ras Proteins ,Female ,Noonan Syndrome with Multiple Lentigines ,Signal Transduction - Abstract
The RASopathies comprise a group of clinically overlapping developmental syndromes the common pathogenetic basis of which is dysregulated signal flow through the RAS-MAPK pathway. Mutations in several components or modifiers of the pathway have been identified in Noonan syndrome and related disorders. Over the past years copy number variants (CNVs) encompassing RAS pathway genes (PTPN11, RAF1, MEK2, or SHOC2) have been reported in children with developmental syndromes. These observations raised speculations that the associated phenotypes represent RASopathies, implying that the increased or reduced expression of the respective RAS pathway component and a consecutive dysregulation of RAS pathway signalling is responsible for the clinical picture. Herein, we present two individuals and three of their relatives harboring duplications of either 3p25.2 including the RAF1 locus or 19p13.3 including the MEK2 locus. Duplication carriers exhibited variable clinical phenotypes including non-specific facial dysmorphism, short stature, and learning difficulties. A careful review of the literature supported the impression that phenotypes associated with CNVs including RAS pathway genes commonly share non-specific symptoms with RASopathies, while the characteristic "gestalt" is lacking. Considering the known molecular pathogenesis of RASopathies, it is questionable that a modest increase in the expression of a functionally normal signaling component can mimic the effects of a qualitatively abnormal (hyperactive) mutant protein. We thus argue that current empirical and biological evidence is still insufficient to allow the conclusion that an altered copy number of a RAS pathway component is indeed the mechanism that is critical for the phenotype associated with CNVs including RASopathy genes.
- Published
- 2015
32. Noonan syndrome with multiple lentigines with PTPN11 (T468M) gene mutation accompanied with solitary granular cell tumor
- Author
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Si Hyung Lee and Seh Hyun Park
- Subjects
0301 basic medicine ,Granular cell tumor ,business.industry ,Dermatology ,General Medicine ,Gene mutation ,medicine.disease ,LEOPARD Syndrome ,PTPN11 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,business ,Noonan Syndrome with Multiple Lentigines - Published
- 2017
33. Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines
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Jacqueline A. Noonan, Clifford M. Takemoto, Wanda Robinson, Judith Allanson, Alicia A Romano, Bruce D. Gelb, Jovanna Dahlgren, Mary Ella M Pierpont, Bryan D. Hall, and Amy E. Roberts
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Genetic heterogeneity ,Noonan Syndrome ,RASopathy ,Gene mutation ,medicine.disease ,Short stature ,PTPN11 ,Pediatrics, Perinatology and Child Health ,SOS1 ,medicine ,Cancer research ,Humans ,Noonan syndrome ,medicine.symptom ,business ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome (NS) is a common, clinically and genetically heterogeneous condition characterized by distinctive facial features, short stature, chest deformity, congenital heart disease, and other comorbidities. Gene mutations identified in individuals with the NS phenotype are involved in the Ras/MAPK (mitogen-activated protein kinase) signal transduction pathway and currently explain ∼61% of NS cases. Thus, NS frequently remains a clinical diagnosis. Because of the variability in presentation and the need for multidisciplinary care, it is essential that the condition be identified and managed comprehensively. The Noonan Syndrome Support Group (NSSG) is a nonprofit organization committed to providing support, current information, and understanding to those affected by NS. The NSSG convened a conference of health care providers, all involved in various aspects of NS, to develop these guidelines for use by pediatricians in the diagnosis and management of individuals with NS and to provide updated genetic findings.
- Published
- 2010
34. Germline BRAF Mutations in Noonan, LEOPARD, and Cardiofaciocutaneous Syndromes: Molecular Diversity and Associated Phenotypic Spectrum
- Author
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Efisio Puxeddu, Giorgia Esposito, Angelo Selicorni, Cesare Rossi, Anna Sarkozy, Sonia Moretti, Maria Lisa Dentici, Marco Tartaglia, Grazia M.S. Mancini, Bruno Dallapiccola, Francesca Pantaleoni, Margherita Silengo, Viviana Cordeddu, Maria Cristina Digilio, Laura Mazzanti, Anna Paola Scioletti, Franco Stanzial, Luigi Memo, Bruno Marino, Giovanni Battista Ferrero, Francesca Faravelli, Claudio Carta, Giuseppe Zampino, Francesca Romana Lepri, Bruce D. Gelb, Valentina Petrangeli, Liborio Stuppia, Clinical Genetics, A. Sarkozy, C. Carta, S. Moretti, G. Zampino, M.C. Digilio, F. Pantaleoni, A.P. Scioletti, G. Esposito, V. Cordeddu, F. Lepri, V. Petrangeli, M.L. Dentici, G.M. Mancini, A. Selicorni, C. Rossi, L. Mazzanti, B. Marino, G:B. Ferrero, M.C. Silengo, L. Memo, F. Stanzial, F. Faravelli, L. Stuppia, E. Puxeddu, B.D. Gelb, B. Dallapiccola, and M. Tartaglia.
- Subjects
Heart Defects, Congenital ,Male ,Proto-Oncogene Proteins B-raf ,Genotype ,NOONAN, LEOPARD AND CARDIOFACIOCUTANEOUS SYNDROMES ,Mutation, Missense ,Biology ,RASopathy ,genotype-phenotype correlation ,Cardiofaciocutaneous syndrome ,LEOPARD Syndrome ,Article ,Germline ,Noonan syndrome ,Leopard syndrome ,BRAF ,Mutation ,Cohort Studies ,Germline mutation ,Gene Frequency ,SDG 3 - Good Health and Well-being ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Germ-Line Mutation ,Genetics (clinical) ,mutation analysis ,braf ,cardiofaciocutaneous syndrome ,cfcs ,functional studies ,leopard syndrome ,noonan syndrome ,LEOPARD syndrome ,CFCS ,Genetic Variation ,medicine.disease ,PTPN11 ,Phenotype ,BRAF MUTATIONS ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,LEOPARD AND CARDIOFACIOCUTANEOUS SYNDROMES ,Face ,Skin Abnormalities ,NOONAN ,Female ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan, LEOPARD, and cardiofaciocutaneous Syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS-mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N = 270), LS (N = 6), and CFCS (N = 33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (5296), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions. Hum Mutat 30, 695-702, 2009. (C) 2009 Wiley-Liss, Inc.
- Published
- 2009
35. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype phenotype relationships and overlap with Costello syndrome
- Author
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Béatrice Parfait, Annick Toutain, Alain Verloes, Clarisse Baumann, Benoit Arveiler, Eric Pasmant, Delphine Héron, Yoko Aoki, Caroline Michot, Sabine Sigaudy, Hélène Cavé, Caroline Nava, Nathalie Pouvreau, Tetsuya Niihori, Bruno Leheup, Didier Lacombe, Yoichi Matsubara, Marlène Rio, Nadine Hanna, Alice Goldenberg, and Sabrina Pereira
- Subjects
Heart Defects, Congenital ,Male ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,Adolescent ,Genotype ,MAP Kinase Signaling System ,DNA Mutational Analysis ,MAP Kinase Kinase 2 ,MAP Kinase Kinase 1 ,Mutation, Missense ,RASopathy ,Biology ,Cardiofaciocutaneous syndrome ,medicine.disease_cause ,Cohort Studies ,Diagnosis, Differential ,Costello syndrome ,Intellectual Disability ,Internal medicine ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,HRAS ,Child ,Genetics (clinical) ,Noonan Syndrome ,Infant ,Syndrome ,medicine.disease ,PTPN11 ,Genes, ras ,Phenotype ,Endocrinology ,Child, Preschool ,Face ,Skin Abnormalities ,Cancer research ,Noonan syndrome ,Female ,Original Article ,KRAS ,Noonan Syndrome with Multiple Lentigines ,Signal Transduction - Abstract
Cardio‐facio‐cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS‐negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS‐negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS‐negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term “Costello syndrome” should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily.
- Published
- 2007
36. SHP2 sails from physiology to pathology
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Audrey de Rocca Serra, Mylène Tajan, Philippe Valet, Thomas Edouard, and Armelle Yart
- Subjects
MAPK/ERK pathway ,Genetics ,Molecular Sequence Data ,Noonan Syndrome ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,General Medicine ,Protein tyrosine phosphatase ,Biology ,medicine.disease ,PTPN11 ,Mutation ,medicine ,Noonan syndrome ,Animals ,Humans ,Amino Acid Sequence ,Signal transduction ,Protein kinase B ,Genetics (clinical) ,Noonan Syndrome with Multiple Lentigines ,PI3K/AKT/mTOR pathway ,Signal Transduction - Abstract
Over the two past decades, mutations of the PTPN11 gene, encoding the ubiquitous protein tyrosine phosphatase SHP2 (SH2 domain-containing tyrosine phosphatase 2), have been identified as the causal factor of several developmental diseases (Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), and metachondromatosis), and malignancies (juvenile myelomonocytic leukemia). SHP2 plays essential physiological functions in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a wide range of growth factors and hormones, notably the pleiotropic Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide-3 Kinase (PI3K)/AKT cascades. Analysis of the biochemical impacts of PTPN11 mutations first identified both loss-of-function and gain-of-function mutations, as well as more subtle defects, highlighting the major pathophysiological consequences of SHP2 dysregulation. Then, functional genetic studies provided insights into the molecular dysregulations that link SHP2 mutants to the development of specific traits of the diseases, paving the way for the design of specific therapies for affected patients. In this review, we first provide an overview of SHP2's structure and regulation, then describe its molecular roles, notably its functions in modulating the Ras/MAPK and PI3K/AKT signaling pathways, and its physiological roles in organism development and homeostasis. In the second part, we describe the different PTPN11 mutation-associated pathologies and their clinical manifestations, with particular focus on the biochemical and signaling outcomes of NS and NS-ML-associated mutations, and on the recent advances regarding the pathophysiology of these diseases.
- Published
- 2015
37. Germline gain-of-function mutations in SOS1 cause Noonan syndrome
- Author
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Yosuf Yassin, Toshiyuki Araki, Benjamin G. Neel, Alex M. Tamburino, Kenneth D. Swanson, Amy E. Roberts, Kate Montgomery, Li Li, Taryn A. Schiripo, Raju Kucherlapati, and Victoria A. Joshi
- Subjects
musculoskeletal diseases ,Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,animal structures ,biology ,Son of Sevenless ,medicine.disease ,Cardiofaciocutaneous syndrome ,LEOPARD Syndrome ,PTPN11 ,Costello syndrome ,SOS1 ,medicine ,biology.protein ,Noonan syndrome ,skin and connective tissue diseases ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for
- Published
- 2006
38. PTPN11 (Shp2) Mutations in LEOPARD Syndrome Have Dominant Negative, Not Activating, Effects
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Benjamin G. Neel, Maria I. Kontaridis, David Barford, Kenneth D. Swanson, and Frank S. David
- Subjects
Mutation, Missense ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,medicine.disease_cause ,Biochemistry ,LEOPARD Syndrome ,Cell Line ,Catalytic Domain ,medicine ,Humans ,Missense mutation ,Gene Silencing ,Allele ,Hypertelorism ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Genetics ,Mutation ,Noonan Syndrome ,Intracellular Signaling Peptides and Proteins ,Cell Biology ,Phosphoproteins ,medicine.disease ,Protein Structure, Tertiary ,PTPN11 ,Noonan syndrome ,Protein Tyrosine Phosphatases ,medicine.symptom ,Noonan Syndrome with Multiple Lentigines - Abstract
Multiple lentigines/LEOPARD syndrome (LS) is a rare, autosomal dominant disorder characterized by Lentigines, Electrocardiogram abnormalities, Ocular hypertelorism, Pulmonic valvular stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. Like the more common Noonan syndrome (NS), LS is caused by germ line missense mutations in PTPN11, encoding the protein-tyrosine phosphatase Shp2. Enzymologic, structural, cell biological, and mouse genetic studies indicate that NS is caused by gain-of-function PTPN11 mutations. Because NS and LS share several features, LS has been viewed as an NS variant. We examined a panel of LS mutants, including the two most common alleles. Surprisingly, we found that in marked contrast to NS, LS mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-mitogen-activated protein kinase-mediated signaling. Molecular modeling and biochemical studies suggest that LS mutations contort the Shp2 catalytic domain and result in open, inactive forms of Shp2. Our results establish that the pathogenesis of LS and NS is distinct and suggest that these disorders should be distinguished by mutational analysis rather than clinical presentation.
- Published
- 2006
39. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines
- Author
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Sara M. Hough, Federico Damilano, Meaghan E. Flessa, Gabriel C. Segarra, Saumya Das, Ashbeel Roy, Lauren E. Miller, Janel Rodriguez Cabrera, Bonnie Wang, Maria I. Kontaridis, Jessica Lauriol, Roderick T. Bronson, Kyu-Ho Lee, and Kimberly Keith
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Heterozygote ,Heart disease ,Apoptosis ,Cardiomegaly ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,Muscle hypertrophy ,03 medical and health sciences ,Mice ,Internal medicine ,medicine ,Animals ,Cell Lineage ,Myocytes, Cardiac ,cardiovascular diseases ,Endocardium ,Lentigo ,Myocardium ,Homozygote ,Noonan Syndrome ,Hypertrophic cardiomyopathy ,General Medicine ,FOXP1 ,medicine.disease ,PTPN11 ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Mutation ,cardiovascular system ,Noonan syndrome ,Female ,Noonan Syndrome with Multiple Lentigines ,Signal Transduction ,Research Article - Abstract
Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium. Trabeculation and valvular hyperplasia were diminished in hearts of embryonic mice expressing a human NSML-associated variant of SHP2, and these defects were recapitulated in mice expressing NSML-associated SHP2 specifically in endothelial, but not myocardial or neural crest, cells. In contrast, mice with myocardial- but not endothelial-specific NSML SHP2 expression developed ventricular septal defects, suggesting that NSML-associated mutations have both cell-autonomous and nonautonomous functions in cardiac development. However, only endothelial-specific expression of NSML-associated SHP2 induced adult-onset cardiac hypertrophy. Further, embryos expressing the NSML-associated SHP2 mutation exhibited aberrant AKT activity and decreased downstream forkhead box P1 (FOXP1)/FGF and NOTCH1/EPHB2 signaling, indicating that SHP2 is required for regulating reciprocal crosstalk between developing endocardium and myocardium. Together, our data provide functional and disease-based evidence that aberrant SHP2 signaling during cardiac development leads to CHD and adult-onset heart hypertrophy.
- Published
- 2014
40. LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity
- Author
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Patrick Raynal, Karine Tréguer, Maithé Tauber, Mylène Tajan, Philippe Valet, Aurélie Batut, Sophie Le Gonidec, Marie-Adeline Marques, Armelle Yart, Thomas Edouard, Céline Saint Laurent, Claire Vinel, Jean-Pierre Salles, Oksana Kunduzova, Thomas Cadoudal, Hélène Cavé, Joffrey Pozzo, Estelle Wanecq, Simon Deleruyelle, Maëlle Vomscheid, Audrey De Rocca Serra-Nédélec, Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), and Université Toulouse - Jean Jaurès (UT2J)
- Subjects
Male ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Lipolysis ,MAP Kinase Kinase Kinase 1 ,Mice, Transgenic ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,medicine.disease_cause ,LEOPARD Syndrome ,Short stature ,Mice ,Thinness ,Internal medicine ,medicine ,Adipocytes ,Animals ,Insulin ,Obesity ,Hypertelorism ,ComputingMilieux_MISCELLANEOUS ,Adiposity ,2. Zero hunger ,Recombination, Genetic ,Mutation ,Multidisciplinary ,Lentivirus ,Cell Differentiation ,medicine.disease ,Phenotype ,3. Good health ,Diet ,PTPN11 ,Insulin receptor ,Disease Models, Animal ,Endocrinology ,PNAS Plus ,Adipose Tissue ,biology.protein ,Body Composition ,medicine.symptom ,Energy Metabolism ,Noonan Syndrome with Multiple Lentigines - Abstract
LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.
- Published
- 2014
41. Diverse Biochemical Properties of Shp2 Mutants
- Author
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Malcolm McGregor, Frank S. David, Heike Keilhack, Benjamin G. Neel, and Lewis C. Cantley
- Subjects
Genetics ,Mutant ,Genetic disorder ,Cell Biology ,Protein tyrosine phosphatase ,Biology ,medicine.disease ,Biochemistry ,LEOPARD Syndrome ,Phenotype ,PTPN11 ,medicine ,Noonan syndrome ,Molecular Biology ,Noonan Syndrome with Multiple Lentigines - Abstract
Mutations in the Src homology 2 (SH2)-containing protein-tyrosine phosphatase Shp2 (PTPN11) underlie half of the cases of the autosomal dominant genetic disorder Noonan syndrome, and somatic Shp2 mutations are found in several hematologic and solid malignancies. Earlier studies of small numbers of mutants suggested that disease-associated mutations cause constitutive (SH2 binding-independent) activation and that cancer-associated mutants are more active than those associated with Noonan syndrome. We have characterized a larger panel of Shp2 mutants and find that this "activity-centric" model cannot explain the behaviors of all pathogenic Shp2 mutations. Instead, enzymatic, structural, and mathematical modeling analyses show that these mutants can affect basal activation, SH2 domain-phosphopeptide affinity, and/or substrate specificity to varying degrees. Furthermore, there is no absolute correlation between the mutants' extents of basal activation and the diseases they induce. We propose that activated mutants of Shp2 modulate signaling from specific stimuli to a subset of effectors and provide a theoretical framework for understanding the complex relationship between Shp2 activation, intracellular signaling, and pathology.
- Published
- 2005
42. NOONAN SYNDROME AND RELATED DISORDERS: Genetics and Pathogenesis
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Bruce D. Gelb and Marco Tartaglia
- Subjects
Male ,Models, Molecular ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Genotype ,Positional cloning ,Genetic Linkage ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,Short stature ,LEOPARD Syndrome ,Paternal Age ,Mice ,Genetics ,medicine ,Animals ,Humans ,skin and connective tissue diseases ,Molecular Biology ,Genetics (clinical) ,Leukemia ,Genetic heterogeneity ,Noonan Syndrome ,Intracellular Signaling Peptides and Proteins ,History, 19th Century ,History, 20th Century ,medicine.disease ,PTPN11 ,Phenotype ,Mutation ,Webbed neck ,Noonan syndrome ,Female ,Protein Tyrosine Phosphatases ,medicine.symptom ,Noonan Syndrome with Multiple Lentigines - Abstract
▪ Abstract Noonan syndrome is a pleiomorphic autosomal dominant disorder with short stature, facial dysmorphia, webbed neck, and heart defects. In the past decade, progress has been made in elucidating the pathogenesis of this disorder using a positional cloning approach. Noonan syndrome is now known to be a genetically heterogeneous disorder with nearly one half of cases caused by gain-of-function mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2. Similar germ line mutations cause two related genetic disorders, Noonan-like disorder with multiple giant cell lesion syndrome and LEOPARD syndrome, and somatic PTPN11 mutations can underlie certain pediatric hematopoietic malignancies, including juvenile myelomonocytic, acute lymphoblastic, and acute myelogenous leukemias. A mouse model of PTPN11-related Noonan syndrome was recently generated, providing a reagent for studying disease pathogenesis in greater depth as well as experimenting with novel therapeutic strategies.
- Published
- 2005
43. PTPN11 Mutations in Noonan Syndrome: Molecular Spectrum, Genotype-Phenotype Correlation, and Phenotypic Heterogeneity
- Author
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Bruce D. Gelb, Han G. Brunner, Andra Ion, Ineke van der Burgt, Dan L. Musat, Michael A. Patton, Steve Jeffery, Marco Tartaglia, Andrew H. Crosby, Kamini Kalidas, Débora Romeo Bertola, Adam Shaw, Xiaoling Song, and Raju Kucherlapati
- Subjects
Male ,Models, Molecular ,medicine.medical_specialty ,Genotype ,Protein Conformation ,Heart malformation ,Elucidation of hereditary disorders and their molecular diagnosis ,DNA Mutational Analysis ,Buffers ,Biology ,Polymorphism, Single Nucleotide ,LEOPARD Syndrome ,Cohort Studies ,Genetic Heterogeneity ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Genetics ,Humans ,Missense mutation ,Genetics(clinical) ,Protein Phosphatase 2 ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Genetic heterogeneity ,Noonan Syndrome ,PTPN11 Gene Mutation ,Temperature ,Genetic Variation ,Exons ,Articles ,medicine.disease ,Introns ,Pedigree ,PTPN11 ,Phenotype ,Endocrinology ,Mutation ,Noonan syndrome ,Female ,Protein Tyrosine Phosphatases ,Opheldering van erfelijke ziekten en hun moleculaire diagnostiek ,030217 neurology & neurosurgery ,Noonan Syndrome with Multiple Lentigines - Abstract
Item does not contain fulltext 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
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- 2002
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44. A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype
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Lisa Edelmann, Ivan F M Lo, Bruce D. Gelb, Simone Martinelli, Jonathan J. Edwards, Lisong Shi, Luca Pannone, Marco Tartaglia, and Ho Ming Luk
- Subjects
Male ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,LEOPARD Syndrome ,Short stature ,Article ,Café au lait spot ,Genetics ,medicine ,Missense mutation ,Humans ,Global developmental delay ,Genetics (clinical) ,Alleles ,Noonan Syndrome ,Infant, Newborn ,Facies ,Infant ,medicine.disease ,PTPN11 ,Phenotype ,Child, Preschool ,Biocatalysis ,Noonan syndrome ,medicine.symptom ,Noonan Syndrome with Multiple Lentigines - Abstract
The RASopathies are a relatively common group of phenotypically similar and genetically related autosomal dominant genetic syndromes caused by missense mutations affecting genes participating in the RAS/mitogen-activated protein kinase (MAPK) pathway that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome). NS and NSML can be difficult to differentiate during infancy, but the presence of multiple lentigines, cafe au lait spots, and specific cardiac defects facilitate the diagnosis. Furthermore, individual PTPN11 missense mutations are highly specific to each syndrome and engender opposite biochemical alterations on the function of SHP-2, the protein product of that gene. Here, we report on a 5-year-old male with two de novo PTPN11 mutations in cis, c.1471C>T (p.Pro491Ser), and c.1492C>T (p.Arg498Trp), which are associated with NS and NSML, respectively. This boy's phenotype is intermediate between NS and NSML with facial dysmorphism, short stature, mild global developmental delay, pulmonic stenosis, and deafness but absence of cafe au lait spots or lentigines. The double-mutant SHP-2 was found to be catalytically impaired. This raises the question of whether clinical differences between NS and NSML can be ascribed solely to the relative SHP-2 catalytic activity.
- Published
- 2014
45. LEOPARD Syndrome: Clinical Features and Gene Mutations
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E. Martínez-Quintana and F. Rodríguez-González
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Genetics ,Mutation ,Pathology ,medicine.medical_specialty ,business.industry ,Review Article ,Gene mutation ,medicine.disease_cause ,medicine.disease ,LEOPARD Syndrome ,PTPN11 ,Germline mutation ,medicine ,Hypertelorism ,medicine.symptom ,Neurofibromatosis ,business ,Genetics (clinical) ,Noonan Syndrome with Multiple Lentigines - Abstract
The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations.
- Published
- 2012
46. Microduplication of 3p25.2 encompassing RAF1 associated with congenital heart disease suggestive of Noonan syndrome
- Author
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Jin-Lan Chen, Bangliang Yin, Can Huang, Zhi-Ping Tan, Hong Zhang, Cheng Luo, Yifeng Yang, Jinfu Yang, Weizhi Zhang, and Jian Wang
- Subjects
Genetics ,Heart Defects, Congenital ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Genetic heterogeneity ,Noonan Syndrome ,Biology ,medicine.disease ,Short stature ,LEOPARD Syndrome ,Polymorphism, Single Nucleotide ,PTPN11 ,Chromosome Duplication ,medicine ,Noonan syndrome ,Humans ,Sensorineural hearing loss ,Chromosomes, Human, Pair 3 ,medicine.symptom ,Genetics (clinical) ,Noonan Syndrome with Multiple Lentigines ,SNP array - Abstract
Noonan syndrome (NS) is a clinically variable and genetically heterogeneous disorder with congenital heart defects (CHD), short stature, and craniofacial dysmorphisms. Gain-of-function mutations in RAF1 can cause NS and the highly related NS with multiple lentigines (previously known as LEOPARD syndrome). Here we report on a 15-year-old male with NS phenotype: short stature, heart defects, low posterior hairline, facial malformations, malformed left ear with sensorineural hearing loss, widely spaced nipples, and unilateral upper limb anomaly. Using high-resolution SNP array technology, we identified in this patient a 0.25 Mb microduplication at 3p25.2 in which RAF1 is located. Sequence analysis did not identify mutations in genes associated with Holt-Oram syndrome. These findings suggest that duplications of genomic regions encompassing RAF1 could cause NS and are consistent with the notion that rare copy number variations encompassing causative genes may underlie a small percentage of patients with syndromic CHD like NS. © 2012 Wiley Periodicals, Inc.
- Published
- 2012
47. Noonan syndrome and clinically related disorders
- Author
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Marco Tartaglia, Martin Zenker, and Bruce D. Gelb
- Subjects
Heart Defects, Congenital ,Proto-Oncogene Proteins B-raf ,Neurofibromatosis 1 ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,RASopathy ,LEOPARD Syndrome ,Article ,Endocrinology ,Costello syndrome ,Ectodermal Dysplasia ,medicine ,Loose Anagen Hair Syndrome ,Humans ,Proto-Oncogene Proteins c-cbl ,Child ,Genetics ,Costello Syndrome ,Noonan Syndrome ,Intracellular Signaling Peptides and Proteins ,Autosomal dominant trait ,Facies ,Infant ,medicine.disease ,Failure to Thrive ,PTPN11 ,Proto-Oncogene Proteins c-raf ,SOS1 ,Noonan syndrome ,Mitogen-Activated Protein Kinases ,SOS1 Protein ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations.
- Published
- 2011
48. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders
- Author
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Yoko Narumi, Shigeo Kure, Tetsuya Niihori, Yoichi Matsubara, and Yoko Aoki
- Subjects
MAPK/ERK pathway ,Genetics ,MAP Kinase Signaling System ,Genetic Diseases, Inborn ,MAP2K2 ,Syndrome ,Biology ,medicine.disease ,Cardiofaciocutaneous syndrome ,PTPN11 ,Costello syndrome ,medicine ,Cancer research ,ras Proteins ,Noonan syndrome ,Animals ,Humans ,HRAS ,Genetics (clinical) ,Noonan Syndrome with Multiple Lentigines - Abstract
The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html).
- Published
- 2008
49. Germline gain-of-function mutations in RAF1 cause Noonan syndrome
- Author
-
Michiko Furutani, Katsumi Mizuno, Masaki Matsushima, Mika Tokuyama, Tsutomu Nishizawa, Hisato Yagi, Ryunosuke Amo, Yuko Fujiwara, Kazuo Momma, Toru Higashinakagawa, Jun Muneuchi, Masao Nakagawa, Yuta Komoike, Hamao Hirota, Hiroshi Katayama, Rumiko Matsuoka, M. Abdur Razzaque, and Mitsuhiro Kamisago
- Subjects
musculoskeletal diseases ,animal structures ,Mutation, Missense ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,RASopathy ,Cardiofaciocutaneous syndrome ,medicine.disease_cause ,LEOPARD Syndrome ,Cell Line ,Genetics ,medicine ,Animals ,Humans ,skin and connective tissue diseases ,Zebrafish ,Cell Line, Transformed ,Mutation ,Myocardium ,Noonan Syndrome ,Intracellular Signaling Peptides and Proteins ,Heart ,Zebrafish Proteins ,medicine.disease ,Protein Structure, Tertiary ,PTPN11 ,Proto-Oncogene Proteins c-raf ,SOS1 ,Noonan syndrome ,Female ,Protein Tyrosine Phosphatases ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects1,2. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause ∼60% of cases of Noonan syndrome3,4,5,6,7,8,9. However, the gene(s) responsible for the remainder are unknown. We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome; those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas affected individuals with mutations leading to changes in the CR3 domain did not. Cells transfected with constructs containing Noonan syndrome–associated RAF1 mutations showed increased in vitro kinase and ERK activation, and zebrafish embryos with morpholino knockdown of raf1 demonstrated the need for raf1 for the development of normal myocardial structure and function. Thus, our findings implicate RAF1 gain-of-function mutations as a causative agent of a human developmental disorder, representing a new genetic mechanism for the activation of the MAPK pathway.
- Published
- 2007
50. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy
- Author
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Giorgia Esposito, Christian Faul, Michael J. Ackerman, Simone Martinelli, Isabella Torrente, Francesca Romana Lepri, Kimihiko Oishi, Wendy Schackwitz, Edgar A. Pogna, Bruno Dallapiccola, Bruce D. Gelb, Bruno Marino, Juan Pedro López Siguero, Andrew P. Landstrom, Marco Tartaglia, Romano Tenconi, J. Martijn Bos, Maria Cristina Digilio, Anna Ustaszewska, Laura Mazzanti, Bhaswati Pandit, Giuseppe Zampino, Steve R. Ommen, Claudio Carta, Peter Mundel, Anna Sarkozy, Len A. Pennacchio, Angelo Selicorni, Cesare Rossi, Pandit B., Sarkozy A., Pennacchio L.A., Carta C., Oishi K., Martinelli S., Pogna E.A., Schackwitz W, Ustaszewska A., Landstrom A., Bos J.M., Ommen S.R., Esposito G., Lepri F., Faul C., Mundel P., Lòpez Siguero J.P., Tenconi ., Selicorni A., Rossi C., Mazzanti L., Torrente I., Marino B., Digilio M.C., Zampino G., Ackerman M.J., Dallapiccola B., Tartaglia M., and Gelb B.D.
- Subjects
musculoskeletal diseases ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Mutation, Missense ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,Cardiofaciocutaneous syndrome ,Transfection ,CARDIAC-HYPERTROPHY, PHENOTYPE CORRELATION, GERMLINE MUTATIONS, SIGNALING PATHWAY, COSTELLO-SYNDROME, PTPN11 MUTATIONS, TRANSGENIC MICE, HUMAN CANCER, C-RAF, B-RAF ,LEOPARD Syndrome ,Costello syndrome ,Internal medicine ,Chlorocebus aethiops ,Genetics ,medicine ,Animals ,Humans ,cardiovascular diseases ,Kinase activity ,Noonan Syndrome ,Intracellular Signaling Peptides and Proteins ,Cardiomyopathy, Hypertrophic ,medicine.disease ,Protein Structure, Tertiary ,PTPN11 ,Proto-Oncogene Proteins c-raf ,Endocrinology ,COS Cells ,SOS1 ,ras Proteins ,Noonan syndrome ,Protein Tyrosine Phosphatases ,Noonan Syndrome with Multiple Lentigines ,Signal Transduction - Abstract
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 approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. 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.
- Published
- 2007
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