The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Marco Tartaglia - One of the best experts on this subject based on the ideXlab platform.
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Cardiomyopathies in Noonan Syndrome and the other RASopathies
Progress in pediatric cardiology, 2015Co-Authors: Bruce D. Gelb, Amy E. Roberts, Marco TartagliaAbstract:Noonan Syndrome and related disorders (Noonan Syndrome with multiple lentigines, Costello Syndrome, cardiofaciocutaneous Syndrome, Noonan Syndrome with loose anagen hair, and other related traits) are autosomal dominant traits. Mutations causing these disorders alter proteins relevant for signaling through RAS. Thus, these traits are now collectively called the RASopathies. While the RASopathies have pleiomorphic features, this review will focus on the hypertrophic cardiomyopathy observed in varying percentages of all of these traits. In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy. The pathogeneses for the RASopathy-associated cardiomyopathies are being elucidated, principally using animal models, leading to genotype-specific insights into how signal transduction is perturbed. Based on those findings, small molecule therapies seem possible for RASopathy-associated cardiomyopathies.
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Noonan Syndrome and clinically related disorders
Best Practice & Research Clinical Endocrinology & Metabolism, 2011Co-Authors: Marco Tartaglia, Bruce D. Gelb, Martin ZenkerAbstract: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.
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Noonan Syndrome and related disorders dysregulated ras mitogen activated protein kinase signal transduction
Human Molecular Genetics, 2006Co-Authors: Bruce D. Gelb, Marco TartagliaAbstract:Noonan Syndrome is a relatively common, genetically heterogeneous Mendelian trait with a pleiomorphic phenotype. Prior to the period covered in this review, missense mutations in PTPN11 had been found to account for nearly 50% of Noonan Syndrome cases. That gene encodes SHP-2, a protein tyrosine kinase that plays diverse roles in signal transduction including signaling via the RAS-mitogen activated protein kinase (MAPK) pathway. Noonan Syndrome-associated PTPN11 mutations are gain-of-function, with most disrupting SHP-2’s activation –i nactivation mechanism. Here, we review recent information that has elucidated further the types and effects of PTPN11 defects in Noonan Syndrome and compare them to the related, but specific, missense PTPN11 mutations causing other diseases including LEOPARD Syndrome and leukemias. These new data derive from biochemical and cell biological studies as well as animal modeling with fruit flies and chick embryos. The discovery of KRAS missense mutation as a minor cause of Noonan Syndrome and the pathogenetic mechanisms of those mutants is discussed. Finally, the elucidation of gene defects underlying two phenotypically related disorders, Costello and cardio-facio-cutaneous Syndromes is also reviewed. As these genes also encode proteins relevant for RAS-MAPK signal transduction, all of the Syndromes discussed in this article now can be understood to constitute a class of disorders caused by dysregulated RAS-MAPK signaling.
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Noonan Syndrome and related disorders genetics and pathogenesis
Annual Review of Genomics and Human Genetics, 2005Co-Authors: Marco Tartaglia, Bruce D. GelbAbstract:▪ 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.
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Noonan Syndrome associated shp2 ptpn11 mutants cause egf dependent prolonged gab1 binding and sustained erk2 mapk1 activation
Human Mutation, 2004Co-Authors: Alessandra Fragale, Marco Tartaglia, Bruce D. GelbAbstract:Noonan Syndrome is a developmental disorder with dysmorphic facies, short stature, cardiac defects, and skeletal anomalies, which can be caused by missense PTPN11 mutations. PTPN11 encodes Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2 or SHP-2), a protein tyrosine phosphatase that acts in signal transduction downstream to growth factor, hormone, and cytokine receptors. We compared the functional effects of three Noonan Syndrome-causative PTPN11 mutations on SHP2's phosphatase activity, interaction with a binding partner, and signal transduction. All SHP2 mutants had significantly increased basal phosphatase activity compared to wild type, but that activity varied significantly between mutants and was further increased after epidermal growth factor stimulation. Cells expressing SHP2 mutants had prolonged extracellular signal-regulated kinase 2 activation, which was ligand-dependent. Binding of SHP2 mutants to Grb2-associated binder-1 was increased and sustained, and tyrosine phosphorylation of both proteins was prolonged. Coexpression of Grb2-associated binder-1-FF, which lacks SHP2 binding motifs, blocked the epidermal growth factor-mediated increase in SHP2's phosphatase activity and resulted in a dramatic reduction of extracellular signal-regulated kinase 2 activation. Taken together, these results document that Noonan Syndrome-associated PTPN11 mutations increase SHP2's basal phosphatase activity, with greater activation when residues directly involved in binding at the interface between the N-terminal Src homology 2 and protein tyrosine phosphatase domains are altered. The SHP2 mutants prolonged signal flux through the RAS/mitogen-activated protein kinase (ERK2/MAPK1) pathway in a ligand-dependent manner that required docking through Grb2-associated binder-1 (GAB1), leading to increased cell proliferation.
Bruce D. Gelb - One of the best experts on this subject based on the ideXlab platform.
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Cardiomyopathies in Noonan Syndrome and the other RASopathies
Progress in pediatric cardiology, 2015Co-Authors: Bruce D. Gelb, Amy E. Roberts, Marco TartagliaAbstract:Noonan Syndrome and related disorders (Noonan Syndrome with multiple lentigines, Costello Syndrome, cardiofaciocutaneous Syndrome, Noonan Syndrome with loose anagen hair, and other related traits) are autosomal dominant traits. Mutations causing these disorders alter proteins relevant for signaling through RAS. Thus, these traits are now collectively called the RASopathies. While the RASopathies have pleiomorphic features, this review will focus on the hypertrophic cardiomyopathy observed in varying percentages of all of these traits. In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy. The pathogeneses for the RASopathy-associated cardiomyopathies are being elucidated, principally using animal models, leading to genotype-specific insights into how signal transduction is perturbed. Based on those findings, small molecule therapies seem possible for RASopathy-associated cardiomyopathies.
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Noonan Syndrome and clinically related disorders
Best Practice & Research Clinical Endocrinology & Metabolism, 2011Co-Authors: Marco Tartaglia, Bruce D. Gelb, Martin ZenkerAbstract: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.
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Noonan Syndrome clinical features diagnosis and management guidelines
Pediatrics, 2010Co-Authors: Alicia A Romano, Bruce D. Gelb, Amy E. Roberts, Mary Ella M Pierpont, Judith E Allanson, Jovanna Dahlgren, Bryan D Hall, Wanda Robinson, Clifford M Takemoto, Jacqueline A NoonanAbstract: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.
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Noonan Syndrome and related disorders dysregulated ras mitogen activated protein kinase signal transduction
Human Molecular Genetics, 2006Co-Authors: Bruce D. Gelb, Marco TartagliaAbstract:Noonan Syndrome is a relatively common, genetically heterogeneous Mendelian trait with a pleiomorphic phenotype. Prior to the period covered in this review, missense mutations in PTPN11 had been found to account for nearly 50% of Noonan Syndrome cases. That gene encodes SHP-2, a protein tyrosine kinase that plays diverse roles in signal transduction including signaling via the RAS-mitogen activated protein kinase (MAPK) pathway. Noonan Syndrome-associated PTPN11 mutations are gain-of-function, with most disrupting SHP-2’s activation –i nactivation mechanism. Here, we review recent information that has elucidated further the types and effects of PTPN11 defects in Noonan Syndrome and compare them to the related, but specific, missense PTPN11 mutations causing other diseases including LEOPARD Syndrome and leukemias. These new data derive from biochemical and cell biological studies as well as animal modeling with fruit flies and chick embryos. The discovery of KRAS missense mutation as a minor cause of Noonan Syndrome and the pathogenetic mechanisms of those mutants is discussed. Finally, the elucidation of gene defects underlying two phenotypically related disorders, Costello and cardio-facio-cutaneous Syndromes is also reviewed. As these genes also encode proteins relevant for RAS-MAPK signal transduction, all of the Syndromes discussed in this article now can be understood to constitute a class of disorders caused by dysregulated RAS-MAPK signaling.
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Noonan Syndrome and related disorders genetics and pathogenesis
Annual Review of Genomics and Human Genetics, 2005Co-Authors: Marco Tartaglia, Bruce D. GelbAbstract:▪ 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.
Amy E. Roberts - One of the best experts on this subject based on the ideXlab platform.
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Cardiomyopathies in Noonan Syndrome and the other RASopathies
Progress in pediatric cardiology, 2015Co-Authors: Bruce D. Gelb, Amy E. Roberts, Marco TartagliaAbstract:Noonan Syndrome and related disorders (Noonan Syndrome with multiple lentigines, Costello Syndrome, cardiofaciocutaneous Syndrome, Noonan Syndrome with loose anagen hair, and other related traits) are autosomal dominant traits. Mutations causing these disorders alter proteins relevant for signaling through RAS. Thus, these traits are now collectively called the RASopathies. While the RASopathies have pleiomorphic features, this review will focus on the hypertrophic cardiomyopathy observed in varying percentages of all of these traits. In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy. The pathogeneses for the RASopathy-associated cardiomyopathies are being elucidated, principally using animal models, leading to genotype-specific insights into how signal transduction is perturbed. Based on those findings, small molecule therapies seem possible for RASopathy-associated cardiomyopathies.
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cardiovascular disease in Noonan Syndrome
Archives of Disease in Childhood, 2014Co-Authors: Terence Prendiville, Amy E. Roberts, Erica Tworogdube, Kimberlee Gauvreau, Lynne Patkin, Raju Kucherlapati, Ronald V LacroAbstract:Background Noonan Syndrome (NS), a relatively common autosomal dominant disorder with an incidence of 1 in 1000 to 2500 live births, is the most common syndromic cause of congenital heart disease after Trisomy 21. Objective To comprehensively define the spectrum of cardiac morphology and specific clinical course of a large cohort of NS patients. Design Retrospective, descriptive case series study. Patients An international Harvard-based NS registry was combined with clinical data from NS patients followed at Boston Children’s Hospital, Massachusetts, USA. Results We identified 293 patients with NS. Cardiovascular disease was seen in 81% (n=237) including pulmonary stenosis in 57%, secundum atrial septal defects in 32% and hypertrophic cardiomyopathy in 16%. A genetic mutation of the RAS-MAPK signalling pathway was identified in 62% (n=136). Genotype-phenotype associations were noted between PTPN11 mutations and atrial septal defects (p=0.001), and pulmonary stenosis (p RAF1 mutations were associated with hypertrophic cardiomyopathy (p Conclusions Patients with NS have a distinct spectrum of cardiac phenotypes that may have a natural history and response to therapy atypical to that normally seen in non-syndromic heart disease. A diagnosis of NS in a patient with pulmonary stenosis or infant-onset hypertrophic cardiomyopathy would facilitate condition-specific counselling on outcome and prognosis.
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Noonan Syndrome clinical features diagnosis and management guidelines
Pediatrics, 2010Co-Authors: Alicia A Romano, Bruce D. Gelb, Amy E. Roberts, Mary Ella M Pierpont, Judith E Allanson, Jovanna Dahlgren, Bryan D Hall, Wanda Robinson, Clifford M Takemoto, Jacqueline A NoonanAbstract: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.
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a restricted spectrum of nras mutations causes Noonan Syndrome
Nature Genetics, 2010Co-Authors: Ion C Cirstea, Amy E. Roberts, Denise Horn, Kerstin Kutsche, Radovan Dvorsky, Lothar Gremer, Claudio Carta, Francesca Romana Lepri, Torsten MerbitzzahradnikAbstract:Noonan Syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway. Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder. These findings provide evidence for an obligate dependency on proper NRAS function in human development and growth.
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genotype differences in cognitive functioning in Noonan Syndrome
Genes Brain and Behavior, 2009Co-Authors: Elizabeth I Pierpont, Amy E. Roberts, Mary Ella M Pierpont, Nancy J Mendelsohn, Erica Tworogdube, Mark S SeidenbergAbstract:Noonan Syndrome (NS) is an autosomal dominant genetic disorder associated with highly variable features, including heart disease, short stature, minor facial anomalies and learning disabilities. Recent gene discoveries have laid the groundwork for exploring whether variability in the NS phenotype is related to differences at the genetic level. Here we examine the influence of both genotype and non-genotypic factors on cognitive functioning. Data are presented from 65 individuals with Noonan Syndrome (ages 4 to 18) who were evaluated using standardized measures of intellectual functioning. The cohort included 33 individuals with PTPN11 mutations, 6 individuals with SOS1 mutations, 1 individual with a BRAF mutation, and 25 participants with negative, incomplete or no genetic testing. Results indicate that genotype differences may account for some of the variation in cognitive ability in NS. Whereas cognitive impairments were common among individuals with PTPN11 mutations and those with unknown mutations, all of the individuals with SOS1 mutations exhibited verbal and nonverbal cognitive skills in the average range or higher. Participants with N308D and N308S mutations in PTPN11 also demonstrated no (or mild) cognitive delays. Additional influences such as hearing loss, motor dexterity and parental education levels accounted for significant variability in cognitive outcomes. Severity of cardiac disease was not related to cognitive functioning. Our results suggest that some NS-causing mutations have a more marked impact on cognitive skills than others.
Alain Verloes - One of the best experts on this subject based on the ideXlab platform.
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oligo astrocytoma in lztr1 related Noonan Syndrome
European Journal of Medical Genetics, 2020Co-Authors: Adeline Jacquinet, Hélène Cavé, Adeline Bonnard, Yline Capri, Didier Martin, Bernard Sadzot, Elettra Bianchi, Laurent Servais, Jeanpaul Sacre, Alain VerloesAbstract:Abstract Mutations in LZTR1, already known to be causal in familial schwannomatosis type 2, have been recently involved in a small proportion of patients with autosomal dominant and autosomal recessive Noonan Syndrome. LZTR1 is also a driver gene in non syndromal glioblastoma. We report a 26-year-old patient with typical Noonan Syndrome, and the dominantly transmitted c.850C > T (p.(Arg284Cys)) variant in LZTR1. An oligoastrocytoma was diagnosed in the patient at the age of 22 years; recurrence of the tumor occurred at age 26, as a ganglioblastoma. The patient had been transiently treated with growth hormone between ages 15 and 17. Considering the implication of LZTR1 in sporadic tumors of the nervous system, we hypothesize that gliomas are a possible complication of LZTR1-related Noonan Syndrome. This report also supports a possible link between occurrence of a cerebral tumor in Noonan Syndrome and a previous treatment with growth hormone.
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extensive abdominal lipomatosis in a patient with Noonan leopard Syndrome Noonan Syndrome multiple lentigines
American Journal of Medical Genetics Part A, 2012Co-Authors: Juliette Piard, Hélène Cavé, Alain Verloes, Michel Peuchmaur, Selim Bennaceur, Bruno LeheupAbstract:Noonan Syndrome (NS) is a tumor predisposing disorder. Leukemia is observed in 1–3% of patients with NS, with rare occurrences of solid tumors. It also appears to predispose to non-malignant tumors. We report on a 26-year-old female with features of Noonan Syndrome–Multiple Lentigines and a heterozygous mutation: c.1517A > C–p.Gln506Pro in the PTPN11 gene. The patient developed an unusual extensive lipomatosis and we discuss possible relationship between her lipomatosis and NS. © 2012 Wiley Periodicals, Inc.
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SOS1 and PTPN11 mutations in five cases of Noonan Syndrome with multiple giant cell lesions
European Journal of Human Genetics, 2009Co-Authors: Claire Beneteau, Hélène Cavé, Anne Moncla, Nathalie Dorison, Arnold Munnich, Alain Verloes, Bruno LeheupAbstract:We report five cases of multiple giant cell lesions in patients with typical Noonan Syndrome. Such association has frequently been referred to as Noonan-like/multiple giant cell (NL/MGCL) Syndrome before the molecular definition of Noonan Syndrome. Two patients show mutations in PTPN11 (p.Tyr62Asp and p.Asn308Asp) and three in SOS1 (p.Arg552Ser and p.Arg552Thr). The latter are the first SOS1 mutations reported outside PTPN11 in NL/MGCL Syndrome. MGCL lesions were observed in jaws (‘cherubism’) and joints (‘pigmented villonodular synovitis’). We show through those patients that both types of MGCL are not PTPN11 -specific, but rather represent a low penetrant (or perhaps overlooked) complication of the dysregulated RAS/MAPK signaling pathway. We recommend discarding NL/MGCL Syndrome from the nosology, as this presentation is neither gene-nor allele-specific of Noonan Syndrome; these patients should be described as Noonan Syndrome with MGCL (of the mandible, the long bone…). The term cherubism should be used only when multiple giant cell lesions occur without any other clinical and molecular evidence of Noonan Syndrome, with or without mutations of the SH3BP2 gene.
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The spectrum of cardiac anomalies in Noonan Syndrome as a result of mutations in the PTPN11 gene.
Pediatrics, 2007Co-Authors: Yves Sznajer, Hélène Cavé, Boris Keren, Clarisse Baumann, Sabrina Pereira, Corinne Alberti, Jacques Elion, Alain VerloesAbstract:OBJECTIVE. Noonan Syndrome is a clinically homogeneous but genetically heterogeneous condition. Type 1 Noonan Syndrome is defined by the presence of a mutation in the PTPN11 gene, which is found in ∼40% of the cases. Phenotype descriptions and cardiac defects from cohorts with Noonan Syndrome were delineated in the “pregenomic era.” We report the heart defects and links to gene dysfunction in cardiac development in a large cohort of patients with type 1 Noonan Syndrome. METHODS. This was a retrospective, multicenter study based on clinical history, pictures, and medical and cardiologic workup over time. Data were collected by referral geneticists. Mutation screening was performed by direct sequencing of exons 2, 3, 4, 7, 8, 12, and 13 and their intron-exon boundaries, which harbor 98% of identified mutations the PTPN11 gene. RESULTS. A PTPN11 gene mutation was identified in 104 (38.25%) of 274 patients with Noonan Syndrome. Heart defect was present in 85%. The most prevalent congenital heart defects were pulmonary valve stenosis (60%), atrial septal defect, ostium secundum type (25%), and stenosis of the peripheral pulmonary arteries (in at least 15%). Pulmonary valve stenosis and atrial septal defect, ostium secundum type, were significantly associated with the identification of a mutation in the PTPN11 gene. Ventricular septal defect and most left-sided heart defects showed a trend toward overrepresentation in the group without a mutation. CONCLUSION. We compared our data with previous series and integrated the comprehension of molecular PTPN11 gene dysfunction in heart development.
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Iris coloboma, ptosis, hypertelorism, and mental retardation: Baraitser-Winter Syndrome or Noonan Syndrome?
Journal of medical genetics, 1993Co-Authors: Alain VerloesAbstract:Three children have been reported with a combination of iris coloboma, ptosis, hypertelorism, and growth and mental retardation with possible autosomal recessive inheritance. We report a single case whose clinical features encompass this Syndrome and Noonan Syndrome, and discuss the possible interpretations of this complex phenotype.
Tsutomu Ogata - One of the best experts on this subject based on the ideXlab platform.
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gain of function mutations in rit1 cause Noonan Syndrome a ras mapk pathway Syndrome
American Journal of Human Genetics, 2013Co-Authors: Yoko Aoki, Tsutomu Ogata, Tetsuya Niihori, Toshihiro Banjo, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Fumio Takada, Michihiro Yano, Toru AndoAbstract:RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan Syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway Syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning Syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan Syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan Syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan Syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan Syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan Syndrome and show a similar biological effect to mutations in other RASopathy-related genes.
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a 3 bp deletion mutation of ptpn11 in an infant with severe Noonan Syndrome including hydrops fetalis and juvenile myelomonocytic leukemia
American Journal of Medical Genetics Part A, 2004Co-Authors: Rie Yoshida, Masafumi Miyata, Toshiro Nagai, Toshio Yamazaki, Tsutomu OgataAbstract:A de novo 3-bp deletion (179–181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan Syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan Syndrome. © 2004 Wiley-Liss, Inc.
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ptpn11 protein tyrosine phosphatase nonreceptor type 11 mutations in seven japanese patients with Noonan Syndrome
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Kenjiro Kosaki, Toshiro Nagai, T Suzuki, Koji Muroya, Tomonobu Hasegawa, Seiji Sato, Nobutake Matsuo, Rika Kosaki, Yukihiro Hasegawa, Tsutomu OgataAbstract:Noonan Syndrome is an autosomal dominant disorder defined by short stature, delayed puberty, and characteristic dysmorphic features. Tartaglia et al. (Nature Genetics, 29:465-468) have recently shown that gain-of-function mutations in the gene PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) cause Noonan Syndrome in roughly half of patients that they examined. To further explore the relevance of PTPN11 mutations to the pathogenesis of Noonan Syndrome, we analyzed the PTPN11 gene in 21 Japanese patients. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed six different heterozygous missense mutations (Asp61Gly, Tyr63Cys, Ala72Ser, Thr73Ile, Phe285Ser, and Asn308Asp) in seven cases (six sporadic and one familial). The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. The results provide further support to the notion that PTPN11 mutations are responsible for the development of Noonan Syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan Syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11.
