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Bruno Dallapiccola - One of the best experts on this subject based on the ideXlab platform.
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ptpn11 gene mutations linking the gln510glu mutation to the LEOPARD Syndrome phenotype
European Journal of Pediatrics, 2006Co-Authors: Cristina M Digilio, Giuseppe Limongelli, Giuseppe Pacileo, Anna Sarkozy, Bruno Marino, Bruno DallapiccolaAbstract:We describe the “LEOPARD Syndrome (LS) phenotype” associated with the Gln510Glu mutation of the PTPN11 gene in two patients presenting with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy and structural abnormalities of the mitral valve, facial anomalies, cafe-au-lait spots and multiple lentigines.
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clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD Syndrome
Journal of Medical Genetics, 2004Co-Authors: Anna Sarkozy, R Calabro, Emanuela Conti, Cristina M Digilio, B Marino, Elisabetta Morini, G Pacileo, Meredith Wilson, Antonio Pizzuti, Bruno DallapiccolaAbstract:Multiple lentigines LEOPARD Syndrome (MIM 151100) is an autosomal dominant multiple congenital anomaly Syndrome, with high penetrance and markedly variable expression.1 The acronym LEOPARD was coined by Gorlin et al. in 1971 as a mnemonic of the major features of this disorder: multiple l entigines, E CG conduction abnormalities, o cular hypertelorism, p ulmonic stenosis, a bnormal genitalia, r etardation of growth, and sensorineural d eafness.2 It is also known as cardiocutaneous Syndrome, Moynahan Syndrome, lentiginosis profuse, and progressive cardiomyopathic lentiginosis.3,4 Voron et al. proposed some diagnostic criteria for multiple lentigines LEOPARD Syndrome.5 More than 100 cases have been described, and one review has been published.5,6 Multiple lentigines LEOPARD Syndrome shares many features with Noonan Syndrome (MIM 163950),7–9 in which lentigines and deafness usually are not present. About 40% of patients with Noonan Syndrome have missense mutations in the PTPN11 gene, which encodes for the protein tyrosine phosphatase SHP2.10–14 Multiple lentigines LEOPARD Syndrome has proved to be allelic to Noonan Syndrome,15,16 with two recurrent PTPN11 mutations in exons 7 (Tyr279Cys) and 12 (Thr468Met). Recently, we reported a novel PTPN11 mutation (Gln506Pro) in a unique patient with multiple lentigines LEOPARD Syndrome, which suggests that mutations other than Tyr279Cys and Thr468Met could be found in these patients.17 As PTPN11 mutations in multiple lentigines LEOPARD Syndrome and Noonan Syndrome are exclusive to these conditions, the distinctive manifestations of these disorders likely result from different molecular mechanisms. For instance, as commented in a recent report, the cardiac phenotypes in patients with Noonan Syndrome and those with multiple lentigines LEOPARD Syndrome with PTPN11 mutations are rather dissimilar, with pulmonary valve stenosis prevailing in the former and hypertrophic cardiomyopathy in the latter.18 We examined the PTPN11 gene in a consecutive series …
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familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy a boy with LEOPARD Syndrome due to ptpn11 mutation and his nonsyndromic father lacking ptpn11 mutations
Birth Defects Research Part A-clinical and Molecular Teratology, 2004Co-Authors: Cristina M Digilio, Giuseppe Limongelli, Giuseppe Pacileo, Anna Sarkozy, Bruno Marino, Emanuela Conti, Antonio Pizzuti, Raffaele Calabro, Fabiana Cerrato, Bruno DallapiccolaAbstract:BACKGROUND Nonsyndromic hypertrophic cardiomyopathy (HCM) is a primary cardiac disease transmitted as an autosomal dominant trait. Multiple chromosomal loci have been found to be involved in the etiology of this defect. LEOPARD Syndrome is a genetic condition characteristically associated with HCM. Additional features of the Syndrome include multiple lentigines, facial anomalies, sensorineural deafness, and growth retardation. Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q24, have been identified in patients with LEOPARD Syndrome. CASES We report here on a patient with HCM presenting with classic clinical features of LEOPARD Syndrome, whose father also has HCM, but lacks phenotypic anomalies of the Syndrome. Molecular analysis searching for PTPN11 mutations was performed in this family. A missense mutation (836AG; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD Syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members. CONCLUSIONS Aggregation of syndromic and nonsyndromic HCM in the same family is an unusual pattern of recurrence. Although genetic heterogeneity of LEOPARD and nonsyndromic HCM is not disputed, the existence of peculiar interactions linking genes causing nonsyndromic HCM and HCM in LEOPARD Syndrome can be hypothesized. Different genes can work together, and a more severe cardiac phenotype can be due to additive effects. The involvement of familial susceptibility to specific cardiac malformations based on the presence of common predisposing factors can also be considered. Further molecular studies may shed light on these observations. Birth Defects Research (Part A), 2003. © 2004 Wiley-Liss, Inc.
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a novel ptpn11 mutation in LEOPARD Syndrome
Human Mutation, 2003Co-Authors: Emanuela Conti, Anna Sarkozy, Antonio Pizzuti, Tania Dottorini, G E Tiller, Giorgia Esposito, Bruno DallapiccolaAbstract:PTPN11 gene mutations are common to both patients with Noonan (NS) and LEOPARD Syndrome (LS). So far only two recurrent mutations have been identified in LS patients by different research groups, i.e., Tyr279Cys and Thr468Met. In this work we describe the third PTPN11 mutation that has been found in a single LS patient. The mutation (c.1517A>C) substitutes a proline for a glutamine at amino acid 506 (Gln506Pro) in the phosphatase domain (PTP) of the PTPN11 peptide SHP2. This region is a mutation hotspot. Changes at amino acids 501 to 504 cause NS. Gln506Pro is predicted, by modeling analysis, to seriously disrupt the normal contacts between the regulating N-SH2 and the active PTP domains, leading to hyperactivity of the phosphatase. This report demonstrates that rarer mutations other than Tyr279Cys and Thr468Met can be found in LS patients and the need of screening the whole gene in those negative for the commonest mutations. © 2003 Wiley-Liss, Inc.
Anna Sarkozy - One of the best experts on this subject based on the ideXlab platform.
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severe early onset hypertrophic cardiomyopathy in a family with LEOPARD Syndrome
Journal of prenatal medicine, 2008Co-Authors: Giuseppe Limongelli, Giuseppe Pacileo, Maria Giovanna Russo, Anna Sarkozy, M Felicetti, Di Salvo G, Carmela Morelli, Paolo Calabro, Dario Paladini, Bruno MarinoAbstract:LEOPARD Syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness) is a rare inherited disease. Mutations in the PTPN11 and RAF-1 genes have been reported in patients with LEOPARD Syndrome. Although the clinical course is generally favourable, a number of sudden cardiac deaths have been reported in association with this Syndrome. Patients with hypertrophic cardiomyopathy (HCM) have potentially a higher risk of developing severe cardiac complications during follow-up. Here, we describe a family (mother and daughter) with clinical and molecular diagnosis of LEOPARD Syndrome 1 and HCM (mild, non obstructive HCM in the mother; severe, obstructive HCM in the daughter), and we report the prenatal diagnosis of a severe HCM in a fetus at risk for LEOPARD Syndrome.
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prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD Syndrome
American Journal of Cardiology, 2007Co-Authors: Giuseppe Limongelli, Giuseppe Pacileo, Anna Sarkozy, Paolo Calabro, Bruno Marino, Maria Cristina Digilio, Perry M Elliott, Paolo Versacci, Andrea De ZorziAbstract:The aim of this study was to characterize cardiovascular involvement in a large number of patients with LEOPARD Syndrome. Twenty-six patients (age range 0 to 63 years, median age at the time of the study evaluation 17 years) underwent clinical and genetic investigations. Familial disease was ascertained in 9 patients. Nineteen patients (73%) showed electrocardiographic abnormalities. Left ventricular (LV) hypertrophy was present in 19 patients (73%), including 9 with LV outflow tract obstructions; right ventricular hypertrophy was present in 8 patients (30%). Valve (57%) and coronary artery (15%) anomalies were also observed. Single patients showed LV apical aneurysm, LV noncompaction, isolated LV dilation, and atrioventricular canal defect. During follow-up (9.1 ± 4.5 years), 2 patients died suddenly, and 2 patients had cardiac arrest. These patients had LV hypertrophy. Despite the limited number of subjects studied, genotype-phenotype correlations were observed in familial cases. In conclusion, most patients with LEOPARD Syndrome showed LV hypertrophy, often in association with other valvular or congenital defects. A spectrum of underrecognized cardiac anomalies were also observed. Long-term prognosis was benign, but the occurrence of 4 fatal events in patients with LV hypertrophy indicates that such patients require careful risk assessment and, in some cases, consideration for prophylaxis against sudden death.
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ptpn11 gene mutations linking the gln510glu mutation to the LEOPARD Syndrome phenotype
European Journal of Pediatrics, 2006Co-Authors: Cristina M Digilio, Giuseppe Limongelli, Giuseppe Pacileo, Anna Sarkozy, Bruno Marino, Bruno DallapiccolaAbstract:We describe the “LEOPARD Syndrome (LS) phenotype” associated with the Gln510Glu mutation of the PTPN11 gene in two patients presenting with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy and structural abnormalities of the mitral valve, facial anomalies, cafe-au-lait spots and multiple lentigines.
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clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD Syndrome
Journal of Medical Genetics, 2004Co-Authors: Anna Sarkozy, R Calabro, Emanuela Conti, Cristina M Digilio, B Marino, Elisabetta Morini, G Pacileo, Meredith Wilson, Antonio Pizzuti, Bruno DallapiccolaAbstract:Multiple lentigines LEOPARD Syndrome (MIM 151100) is an autosomal dominant multiple congenital anomaly Syndrome, with high penetrance and markedly variable expression.1 The acronym LEOPARD was coined by Gorlin et al. in 1971 as a mnemonic of the major features of this disorder: multiple l entigines, E CG conduction abnormalities, o cular hypertelorism, p ulmonic stenosis, a bnormal genitalia, r etardation of growth, and sensorineural d eafness.2 It is also known as cardiocutaneous Syndrome, Moynahan Syndrome, lentiginosis profuse, and progressive cardiomyopathic lentiginosis.3,4 Voron et al. proposed some diagnostic criteria for multiple lentigines LEOPARD Syndrome.5 More than 100 cases have been described, and one review has been published.5,6 Multiple lentigines LEOPARD Syndrome shares many features with Noonan Syndrome (MIM 163950),7–9 in which lentigines and deafness usually are not present. About 40% of patients with Noonan Syndrome have missense mutations in the PTPN11 gene, which encodes for the protein tyrosine phosphatase SHP2.10–14 Multiple lentigines LEOPARD Syndrome has proved to be allelic to Noonan Syndrome,15,16 with two recurrent PTPN11 mutations in exons 7 (Tyr279Cys) and 12 (Thr468Met). Recently, we reported a novel PTPN11 mutation (Gln506Pro) in a unique patient with multiple lentigines LEOPARD Syndrome, which suggests that mutations other than Tyr279Cys and Thr468Met could be found in these patients.17 As PTPN11 mutations in multiple lentigines LEOPARD Syndrome and Noonan Syndrome are exclusive to these conditions, the distinctive manifestations of these disorders likely result from different molecular mechanisms. For instance, as commented in a recent report, the cardiac phenotypes in patients with Noonan Syndrome and those with multiple lentigines LEOPARD Syndrome with PTPN11 mutations are rather dissimilar, with pulmonary valve stenosis prevailing in the former and hypertrophic cardiomyopathy in the latter.18 We examined the PTPN11 gene in a consecutive series …
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LEOPARD Syndrome a new polyaneurysm association and an update on the molecular genetics of the disease
Journal of Vascular Surgery, 2004Co-Authors: Marineh Yagubyan, Anna Sarkozy, Emanuela Conti, Jean M Panneton, Noralane M Lindor, Antonio PizzutiAbstract:Abstract LEOPARD Syndrome, one of many cardiocutaneous Syndromes, is an acronym for some of the obvious manifestations of the disease, such as lentigines or ocular hypertelorism. The synonymous name progressive cardiomyopathic lentiginosis better indicates the morbid cardiac features that patients with the Syndrome have. A patient with LEOPARD Syndrome is presented. He had recurrent upper extremity aneurysms requiring multiple operations and finally PTFE reinforced venous grafts to prevent further aneurysmal degeneration. He has multiple other peripheral aneurysms, thus far asymptomatic. His diagnosis of LEOPARD Syndrome was confirmed on a genetic basis. Review of the literature reveals no previous preports of severe aneurysmal disease in these patients.
Benjamin G Neel - One of the best experts on this subject based on the ideXlab platform.
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structural insights into noonan LEOPARD Syndrome related mutants of protein tyrosine phosphatase shp2 ptpn11
BMC Structural Biology, 2014Co-Authors: Xiaonan Wang, V Romanov, Ashley Hutchinson, Maxim Ruzanov, K P Battaile, Benjamin G Neel, N Y ChirgadzeAbstract:Background The ubiquitous non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) plays a key role in RAS/ERK signaling downstream of most, if not all growth factors, cytokines and integrins, although its major substrates remain controversial. Mutations in PTPN11 lead to several distinct human diseases. Germ-line PTPN11 mutations cause about 50% of Noonan Syndrome (NS), which is among the most common autosomal dominant disorders. LEOPARD Syndrome (LS) is an acronym for its major syndromic manifestations: multiple Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. Frequently, LS patients have hypertrophic cardiomyopathy, and they might also have an increased risk of neuroblastoma (NS) and acute myeloid leukemia (AML). Consistent with the distinct pathogenesis of NS and LS, different types of PTPN11 mutations cause these disorders.
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Structural insights into Noonan/LEOPARD Syndrome-related mutants of protein-tyrosine phosphatase SHP2 ( PTPN11 )
BMC Structural Biology, 2014Co-Authors: Xiaonan Wang, V Romanov, Ashley Hutchinson, Maxim Ruzanov, K P Battaile, Benjamin G Neel, N Y ChirgadzeAbstract:Background The ubiquitous non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) plays a key role in RAS/ERK signaling downstream of most, if not all growth factors, cytokines and integrins, although its major substrates remain controversial. Mutations in PTPN11 lead to several distinct human diseases. Germ-line PTPN11 mutations cause about 50% of Noonan Syndrome (NS), which is among the most common autosomal dominant disorders. LEOPARD Syndrome (LS) is an acronym for its major syndromic manifestations: multiple Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. Frequently, LS patients have hypertrophic cardiomyopathy, and they might also have an increased risk of neuroblastoma (NS) and acute myeloid leukemia (AML). Consistent with the distinct pathogenesis of NS and LS, different types of PTPN11 mutations cause these disorders.
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ptpn11 shp2 mutations in LEOPARD Syndrome have dominant negative not activating effects
Journal of Biological Chemistry, 2006Co-Authors: Maria I Kontaridis, Kenneth D Swanson, Frank S David, David Barford, Benjamin G NeelAbstract: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 kinasemediated 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.
Giuseppe Limongelli - One of the best experts on this subject based on the ideXlab platform.
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severe early onset hypertrophic cardiomyopathy in a family with LEOPARD Syndrome
Journal of prenatal medicine, 2008Co-Authors: Giuseppe Limongelli, Giuseppe Pacileo, Maria Giovanna Russo, Anna Sarkozy, M Felicetti, Di Salvo G, Carmela Morelli, Paolo Calabro, Dario Paladini, Bruno MarinoAbstract:LEOPARD Syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness) is a rare inherited disease. Mutations in the PTPN11 and RAF-1 genes have been reported in patients with LEOPARD Syndrome. Although the clinical course is generally favourable, a number of sudden cardiac deaths have been reported in association with this Syndrome. Patients with hypertrophic cardiomyopathy (HCM) have potentially a higher risk of developing severe cardiac complications during follow-up. Here, we describe a family (mother and daughter) with clinical and molecular diagnosis of LEOPARD Syndrome 1 and HCM (mild, non obstructive HCM in the mother; severe, obstructive HCM in the daughter), and we report the prenatal diagnosis of a severe HCM in a fetus at risk for LEOPARD Syndrome.
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prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD Syndrome
American Journal of Cardiology, 2007Co-Authors: Giuseppe Limongelli, Giuseppe Pacileo, Anna Sarkozy, Paolo Calabro, Bruno Marino, Maria Cristina Digilio, Perry M Elliott, Paolo Versacci, Andrea De ZorziAbstract:The aim of this study was to characterize cardiovascular involvement in a large number of patients with LEOPARD Syndrome. Twenty-six patients (age range 0 to 63 years, median age at the time of the study evaluation 17 years) underwent clinical and genetic investigations. Familial disease was ascertained in 9 patients. Nineteen patients (73%) showed electrocardiographic abnormalities. Left ventricular (LV) hypertrophy was present in 19 patients (73%), including 9 with LV outflow tract obstructions; right ventricular hypertrophy was present in 8 patients (30%). Valve (57%) and coronary artery (15%) anomalies were also observed. Single patients showed LV apical aneurysm, LV noncompaction, isolated LV dilation, and atrioventricular canal defect. During follow-up (9.1 ± 4.5 years), 2 patients died suddenly, and 2 patients had cardiac arrest. These patients had LV hypertrophy. Despite the limited number of subjects studied, genotype-phenotype correlations were observed in familial cases. In conclusion, most patients with LEOPARD Syndrome showed LV hypertrophy, often in association with other valvular or congenital defects. A spectrum of underrecognized cardiac anomalies were also observed. Long-term prognosis was benign, but the occurrence of 4 fatal events in patients with LV hypertrophy indicates that such patients require careful risk assessment and, in some cases, consideration for prophylaxis against sudden death.
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is sudden cardiac death predictable in LEOPARD Syndrome
Cardiology in The Young, 2006Co-Authors: Giuseppe Limongelli, Giuseppe Pacileo, Raffaele CalabroAbstract:: We report the sudden cardiac death of a young male presenting with classic clinical features of LEOPARD Syndrome, shown to be due to a mutation in the PTPN11 gene, and severe non obstructive hypertrophic cardiomyopathy. We also discuss briefly the usefulness of prophylactic risk stratification in patients with syndromic and non syndromic hypertrophic cardiomyopathy.
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ptpn11 gene mutations linking the gln510glu mutation to the LEOPARD Syndrome phenotype
European Journal of Pediatrics, 2006Co-Authors: Cristina M Digilio, Giuseppe Limongelli, Giuseppe Pacileo, Anna Sarkozy, Bruno Marino, Bruno DallapiccolaAbstract:We describe the “LEOPARD Syndrome (LS) phenotype” associated with the Gln510Glu mutation of the PTPN11 gene in two patients presenting with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy and structural abnormalities of the mitral valve, facial anomalies, cafe-au-lait spots and multiple lentigines.
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familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy a boy with LEOPARD Syndrome due to ptpn11 mutation and his nonsyndromic father lacking ptpn11 mutations
Birth Defects Research Part A-clinical and Molecular Teratology, 2004Co-Authors: Cristina M Digilio, Giuseppe Limongelli, Giuseppe Pacileo, Anna Sarkozy, Bruno Marino, Emanuela Conti, Antonio Pizzuti, Raffaele Calabro, Fabiana Cerrato, Bruno DallapiccolaAbstract:BACKGROUND Nonsyndromic hypertrophic cardiomyopathy (HCM) is a primary cardiac disease transmitted as an autosomal dominant trait. Multiple chromosomal loci have been found to be involved in the etiology of this defect. LEOPARD Syndrome is a genetic condition characteristically associated with HCM. Additional features of the Syndrome include multiple lentigines, facial anomalies, sensorineural deafness, and growth retardation. Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q24, have been identified in patients with LEOPARD Syndrome. CASES We report here on a patient with HCM presenting with classic clinical features of LEOPARD Syndrome, whose father also has HCM, but lacks phenotypic anomalies of the Syndrome. Molecular analysis searching for PTPN11 mutations was performed in this family. A missense mutation (836AG; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD Syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members. CONCLUSIONS Aggregation of syndromic and nonsyndromic HCM in the same family is an unusual pattern of recurrence. Although genetic heterogeneity of LEOPARD and nonsyndromic HCM is not disputed, the existence of peculiar interactions linking genes causing nonsyndromic HCM and HCM in LEOPARD Syndrome can be hypothesized. Different genes can work together, and a more severe cardiac phenotype can be due to additive effects. The involvement of familial susceptibility to specific cardiac malformations based on the presence of common predisposing factors can also be considered. Further molecular studies may shed light on these observations. Birth Defects Research (Part A), 2003. © 2004 Wiley-Liss, Inc.
Zhong Yin Zhang - One of the best experts on this subject based on the ideXlab platform.
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molecular basis of gain of function LEOPARD Syndrome associated shp2 mutations
Biochemistry, 2014Co-Authors: Zhi Hong Yu, Chad D Walls, Lan Chen, Sheng Zhang, Ruoyu Zhang, Li Wu, Zhong Yin ZhangAbstract:The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan Syndrome (NS) and LEOPARD Syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme’s catalytic functionality exists. ...
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structural and mechanistic insights into LEOPARD Syndrome associated shp2 mutations
Journal of Biological Chemistry, 2013Co-Authors: Zhi Hong Yu, Jie Xu, Chad D Walls, Lan Chen, Sheng Zhang, Ruoyu Zhang, Li Wu, Lina Wang, Zhong Yin ZhangAbstract:Abstract SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation. Germ-line mutations in SHP2 cause clinically similar LEOPARD and Noonan Syndromes, two of several autosomal-dominant conditions characterized by gain-of-function mutations in the Ras pathway. Interestingly, Noonan Syndrome SHP2 mutants are constitutively active, whereas LEOPARD Syndrome SHP2 mutants exhibit reduced phosphatase activity. How do catalytically impaired LEOPARD Syndrome mutants engender gain-of-function phenotypes? Our study reveals that LEOPARD Syndrome mutations weaken the intramolecular interaction between the N-SH2 and phosphatase domains, leading to a change in SHP2 molecular switching mechanism. Consequently, LEOPARD Syndrome SHP2 mutants bind upstream activators preferentially and are hypersensitive to growth factor stimulation. They also stay longer with scaffolding adapters, thus prolonging substrate turnover, which compensates for the reduced phosphatase activity. The study provides a solid framework for understanding how individual SHP2 mutations cause diseases.