RESUMEN
OBJECTIVE: To investigate the prevalence of Noonan spectrum disorders in a pediatric population with pulmonary valve stenosis (PVS) and explore other characteristics of Noonan spectrum disorders associated with PVS. STUDY DESIGN: A retrospective medical record review was completed for patients with a diagnosis of PVS seen at the Children's Hospital Colorado Cardiology clinic between 2009 and 2019. Syndromic diagnoses, genotypes, cardiac characteristics, and extracardiac characteristics associated with Noonan spectrum disorders were recorded; statistical analysis was conducted using R. RESULTS: Syndromic diagnoses were made in 16% of 686 pediatric patients with PVS, with Noonan spectrum disorders accounting for 9% of the total diagnoses. Individuals with Noonan spectrum disorders were significantly more likely to have an atrial septal defect and/or hypertrophic cardiomyopathy than the non-Noonan spectrum disorder individuals. Supravalvar pulmonary stenosis was also correlated significantly with Noonan spectrum disorders. Extracardiac clinical features presenting with PVS that were significantly associated with Noonan spectrum disorders included feeding issues, failure to thrive, developmental delay, short stature, and ocular findings. The strongest predictors of a Noonan spectrum disorder diagnosis were cryptorchidism (70%), pectus abnormalities (66%), and ocular findings (48%). The presence of a second characteristic further increased this likelihood, with the highest probability occurring with cryptorchidism combined with ocular findings (92%). CONCLUSIONS: The 9% prevalence of Noonan spectrum disorder in patients with PVS should alert clinicians to consider Noonan spectrum disorders when encountering a pediatric patient with PVS. The presence of PVS with 1 or more Noonan spectrum disorder-related features should prompt a genetic evaluation and genetic testing for RAS pathway defects. Noonan spectrum disorders should also be included in the differential when a patient presents with supravalvar pulmonary stenosis.
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Síndrome de Noonan/epidemiología , Estenosis de la Válvula Pulmonar/epidemiología , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación , Síndrome de Noonan/genética , Síndrome de Noonan/fisiopatología , Fenotipo , Prevalencia , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Estudios RetrospectivosRESUMEN
Noonan syndrome (NS) and NS related disorders (NRD) are frequent monogenic diseases. Pathogenic variants in PTPN11 are observed in approximately 50% of these NS patients. Several pleiotropic phenotypes have previously been described in this condition. This study aimed at characterizing glucose and lipid profiles in patients with NS/NRD. We assessed fasting blood glucose, insulin, cholesterol (total and fractions), and triglyceride (TG) levels in 112 prepubertal children and 73 adults. Additionally, an oral glucose tolerance test (OGTT) was performed in 40 children and 54 adults. Data were analyzed between age groups according to the presence (+) or absence (-) of PTPN11 mutation. Prepubertal patients with NS/NRD were also compared with a control group. Despite the lean phenotype of children with NS/NRD, they presented an increased frequency of low HDL-cholesterol (63% in PTPN11+, 59% in PTPN11- and 16% in control, p < .001) and high TG levels (29% in PTPN11+, 18% in PTPN11- and 2.3% in control). PTPN11+ patients had a higher median HOMA-IR (1.0, ranged from 0.3 to 3.2) in comparison with PTPN11- (0.6; 0.2 to 4.4) and controls (0.6; 0.4 to 1.4, p = .027). Impaired glucose tolerance was observed in 19% (10:54) of lean adults with NS/NRD assessed by OGTT. Moreover, women with PTPN11 mutations had lower HDL-cholesterol levels than those without. Our results suggest that children and young adult patients with NS/NRD have an unfavorable metabolic profile characterized by low HDL, a tendency of elevated TGs, and glucose metabolism impairment despite a lean phenotype.
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Metaboloma , Síndrome de Noonan/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Fenotipo , Pronóstico , Adulto JovenRESUMEN
Non-nutritive sweeteners (NNSs) are commonly used to prevent weight gain and development of metabolic diseases associated with consumption of high-energy diets. Recent studies have demonstrated that these compounds may have unwanted detrimental effects under specific circumstances in vivo. In particular, an association between NNS consumption and changes in signaling pathways involved in the hunger-satiety system in the brain has been reported. Nonetheless, the extent of alterations in brain signaling pathways associated with consumption of these compounds has not been determined. The objective of this study was to determine the effect of frequent consumption of NNSs on the expression of proteins involved in signaling pathways related to appetite control in the brain in vivo. Eight-week-old BALB/c mice were supplemented with sucrose, sucralose, or steviol glycosides in their daily drinking water for 6 weeks. Subsequently, total brain protein extracts were used to analyze the expression of total and phosphorylated JAK2, STAT5, ERK 1/2, JNK, as well as SHP-2 and POMC, by western blot. Serum concentrations of leptin and α-MSH were quantified by ELISA. Results show that consumption of NNSs promotes significant changes in these signaling pathways, reducing the expression of pSTAT5/STAT5, pERK 1/2, SHP-2, and pJNK/JNK in male mice supplemented with steviol glycosides. Furthermore, consumption of steviol glycosides induced a decrease of α-MSH in male mice. In contrast, steviol glycosides induced overexpression of pSTAT5, pERK, and SHP-2 in females. These data suggest that chronic consumption of NNSs promotes sex-specific changes in signaling pathways related to the central hunger-satiety system in vivo.
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Regulación del Apetito , Encéfalo/efectos de los fármacos , Edulcorantes no Nutritivos/farmacología , Transducción de Señal , Animales , Encéfalo/metabolismo , Encéfalo/fisiología , Femenino , Janus Quinasa 2/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proopiomelanocortina/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Factor de Transcripción STAT5/metabolismoRESUMEN
Our aim was to characterize the phenotype and genotype of individuals with Noonan syndrome in Colombia. There are published cohorts of Noonan individuals from several countries in Latin America including Brazil, Chile, and Argentina, but none from Colombia. We described 26 individuals with NS from a single large referral center in the South West of Colombia using an established database in the genetics department and hospital records search using ICD-10 codes. All patients included in this study were evaluated by a medical geneticist and have molecular confirmation of NS diagnosis. The median age at referral was 3.5 years (range, 0-39), and at molecular diagnosis was 5 years (range, 0-40). Patients mostly originated from the southwest region of Colombia (19/26, 73%). Pathogenic variants in PTPN11 are the most common cause of NS in Colombian individuals followed by SHOC2 and SOS1 variants. The prevalence of cardiomyopathy was low in this population compared to other populations. Further research is needed with a larger sample size and including different regions of Colombia to correlate our findings. This study provides new information about time to diagnosis of NS in Colombia, genotypes, and provides important information to help develop guidelines for diagnosis and management of this disease in the region.
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Síndrome de Noonan , Adolescente , Adulto , Niño , Preescolar , Colombia/epidemiología , Genotipo , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Síndrome de Noonan/epidemiología , Síndrome de Noonan/genética , Fenotipo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteína SOS1/genética , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic stem and progenitor cells, characterized by accumulation of immature blasts in the bone marrow and peripheral blood of affected patients. Standard induction therapy leads to complete remission in approximately 50% to 75% of patients. In spite of favorable primary response rates, only 20% to 30% of patients enjoy long-term disease free survival. Identifying proteins involved in prognosis is important for proposing biomarkers that can aid in the clinical management of the disease. The aim of this study was to construct a protein-protein interaction (PPI) network based on serum proteins associated with unfavorable prognosis of AML, and analyze the biological pathways underlying molecular complexes in the network. We identified 16 candidate serum proteins associated with unfavorable prognosis (in terms of poor response to treatment, poor overall survival, short complete remission, and relapse) in AML via a search in the literature: IL2RA, FTL, HSP90AA1, D2HGDH, PLAU, COL18A1, FGF19, SPP1, FGA, PF4, NME1, TNF, ANGPT2, B2M, CD274, LGALS3. The PPI network was constructed with Cytoscape using association networks from String and BioGRID, and Gene Ontology enrichment analysis using the ClueGo pluggin was performed. The central protein in the network was found to be PTPN11 which is involved in modulating the RAS-ERK, PI3K-AKT and JAK-STAT pathways, as well as in hematopoiesis, and in the regulation of apoptotic genes. Therefore, a dysregulation of this protein and/or of the proteins connected to it in the network leads to the defective activation of these signaling pathways and to a reduction in apoptosis. Together, this could cause an increase in the frequency of leukemic cells and a resistance to apoptosis in response to treatment.
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Biomarcadores de Tumor/genética , Proteínas Sanguíneas/genética , Regulación Leucémica de la Expresión Génica , Redes Reguladoras de Genes , Leucemia Mieloide Aguda/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Proteínas Sanguíneas/metabolismo , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Supervivencia sin Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/sangre , Quinasas MAP Reguladas por Señal Extracelular/genética , Ontología de Genes , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Quinasas Janus/sangre , Quinasas Janus/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Anotación de Secuencia Molecular , Fosfatidilinositol 3-Quinasas/sangre , Fosfatidilinositol 3-Quinasas/genética , Pronóstico , Mapeo de Interacción de Proteínas , Proteína Tirosina Fosfatasa no Receptora Tipo 11/sangre , Proteínas Proto-Oncogénicas c-akt/sangre , Proteínas Proto-Oncogénicas c-akt/genética , Inducción de Remisión , Factores de Transcripción STAT/sangre , Factores de Transcripción STAT/genética , Transducción de Señal , Proteínas ras/sangre , Proteínas ras/genéticaRESUMEN
RAS-pathway mutations are recurrent events in myeloid malignancies. However, there is limited data on the significance of RAS-pathway mutations in patients with myelofibrosis (MF). We analyzed next-generation sequencing data of 16 genes, including RAS-pathway genes, from 723 patients with primary and secondary MF across three international centers and evaluated their significance. N/KRAS variants were present in 6% of patients and were typically sub-clonal (median VAF = 20%) relative to other genes variants. RAS variants were associated with advanced MF features including leukocytosis (p = 0.02), high somatic mutation burden (p < 0.01) and the presence of established "molecular high-risk" (MHR) mutations. MF patients with N/KRAS mutations had shorter 3-year overall survival (OS) (34% vs 58%, p < 0.001) and higher incidence of acute myeloid leukemia at 3 years (18% vs 11%, p = 0.03). In a multivariate Cox model, RAS mutations were associated with decreased OS (HR 1.93, p < 0.001). We created a novel score to predict OS incorporating RAS mutations, and it predicted OS across training and validation cohorts. Patients with intermediate risk/high-risk DIPSS with RAS mutations who received ruxolitinib had a nonsignificant longer 2-year OS relative to those who did not receive ruxolitinib. These data demonstrate the importance of identifying RAS mutations in MF patients.
Asunto(s)
Genes ras , Mutación , Mielofibrosis Primaria/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Policitemia Vera/genética , Mielofibrosis Primaria/diagnóstico , Pronóstico , Modelos de Riesgos Proporcionales , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirazoles/farmacología , Pirimidinas , Estudios Retrospectivos , Riesgo , Trombocitemia Esencial/genética , Resultado del Tratamiento , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
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.
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, cardiopatía congénita, manifestaciones ectodérmicas y mayor riesgo de cáncer. El diagnóstico molecular es clave. Objetivo. Identificar mutaciones en los genes PTPN11, SOS1, RAF1, BRAF y 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 síndrome 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 síndrome de Noonan con múltiples lentigos, en BRAF (el 67 %) en el síndrome cardiofaciocutáneo y en HRAS (el 100 %) en el síndrome de Costello.
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Síndrome de Costello/diagnóstico , Displasia Ectodérmica/diagnóstico , Insuficiencia de Crecimiento/diagnóstico , Cardiopatías Congénitas/diagnóstico , Síndrome de Noonan/diagnóstico , Adolescente , Argentina , Niño , Preescolar , Síndrome de Costello/genética , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Facies , Insuficiencia de Crecimiento/genética , Femenino , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Síndrome de Noonan/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína SOS1/genética , Adulto JovenRESUMEN
Shp2 and Shp1 make up a small family of protein tyrosine phosphatases. Finding selective inhibitors for Shp2 is useful because although its inhibition is advantageous for the treatment of some types of cancer, inhibition of Shp1 may have the opposite effect, since it acts as a suppressor of tumors. We combined molecular docking and semiempirical molecular orbital-based calculations to produce data that were effective for the identification of selective inhibitors for Shp2. After definition of the interaction modes of the inhibitors with Shp2 and Shp1 by molecular docking, the resulting interaction enthalpy values were calculated following refinement of the enzyme/inhibitor complexes' geometries with the PM7 semiempirical molecular orbital method. Despite the complexity of the thermodynamics involved in the enzyme/inhibitor interaction, the selectivity for Shp2 of a series of 76 inhibitors, divided in two groups, could be effectively correlated with the difference in their interaction enthalpy values with both enzymes. For the first group, composed by 52 Shp2-selective indoline inhibitors for which only Shp2 inhibition activity data are available, we demonstrated that the interaction enthalpy can be used as a criterion for identification of selective Shp2 inhibitors, as it is significantly more favorable for Shp2 than Shp1 at a 99% confidence level. For the second group, composed by 24 oxindole derivatives with available Shp2 and Shp1 inhibition activity data, a satisfactory correlation (R = 0.70) could be obtained between the selectivity, based on the IC50 data, and the relative percentage difference of the calculated interaction enthalpies with the two enzymes.
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Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Oxindoles/química , Oxindoles/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/antagonistas & inhibidores , TermodinámicaRESUMEN
SUMMARY OBJECTIVE: This study was to assess the genetic association of copy number variations in two genes (PRKAB2 and PPM1K) located in two regions (tetralogy of Fallot and ventricular septal defect) in a Chinese Han population. METHODS: A total of 200 congenital heart disease patients (100 tetralogy of Fallot patients and 100 ventricular septal defect patients) and 100 congenital heart defect-free controls were recruited, and quantitative real-time PCR analysis was used to replicate the association of two copy number variations with congenital heart defects in a Chinese Han population. RESULTS: One deletion at PRKAB2 and one duplication at PPM1K were found in two of the tetralogy of Fallot patients, respectively; while all these regions were duplicated in both ventricular septal defect patients and in the 100 congenital heart defects-free controls. CONCLUSIONS: We replicated the copy number variations at the disease-candidate genes of PRKAB2 and PPM1K with tetralogy of Fallot in a Chinese Han population, and in patients with ventricular septal defect mutations in these two genes were not found. These results indicate the same molecular population genetics exist in these two genes with different ethnicity. This shows that these two genes are possibly specific pf tetralogy of Fallot candidates.
RESUMO OBJETIVO: Este estudo teve como objetivo avaliar a associação genética do número de cópias em dois genes (PRKAB2 e PPM1K) localizados em duas regiões (tetralogia de Fallot e comunicação interventricular) em uma população chinesa da etnia Han. METODOLOGIA: Um total de 200 pacientes com doença cardíaca congênita (100 pacientes com tetralogia de Fallot e 100 com comunicação interventricular) e 100 indivíduos livres de defeitos cardíacos congênitos foram recrutados, e uma análise quantitativa de PCR em tempo real foi utilizada para replicar a associação de duas variações de número de cópia de defeitos cardíacos congênitos, em uma população chinesa da etnia Han. RESULTADOS: Uma supressão em PRKAB2 e duplicação em PPM1K foram encontradas em dois pacientes com tetralogia de Fallot, respectivamente; todas essas regiões estavam duplicadas nos pacientes com comunicação interventricular e nos 100 indivíduos livres de defeitos cardíacos congênitos. CONCLUSÃO: Nós replicado a variações no número de cópias de genes candidatos de doença PRKAB2 e PPM1K com tetralogia de Fallot em uma população chinesa da etnia Han; em pacientes com comunicação interventricular, não foram encontradas mutações nesses dois genes. Estes resultados indicam que a mesma genética de população molecular existe nestes dois genes em diferentes etnias. Isso mostra que esses dois genes são possivelmente candidatos a genes específicos de tetralogia de Fallot.
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Humanos , Tetralogía de Fallot/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Quinasas Activadas por AMP/genética , Variaciones en el Número de Copia de ADN , Defectos del Tabique Interventricular/genética , Valores de Referencia , Estudios de Casos y Controles , Estudios de Asociación Genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The Helicobacter pylori cytotoxin-associated gene A (CagA) is known for causing gastroduodenal diseases, such as atrophic gastritis and peptic ulcerations. Furthermore Helicobacter pylori CagA positive strains has been reported as one of the main risk factors for gastric cancer (Parsonnet et al., 1997). Structural variations in the CagA structure can alter its affinity with the host proteins, inducing differences in the pathogenicity of H. pylori. CagA N-terminal region is characterized for be conserved among all H. pylori strains since the C-terminal region is characterized by an intrinsically disorder behavior. We generated complete structural models of CagA using different conformations of the C-terminal region for two H. pylori strains. These models contain the same EPIYA (ABC1C2) motifs but different level of pathogenicity: gastric cancer and duodenal ulcer. Using these structural models we evaluated the pathogenicity level of the H. pylori strain, based on the affinity of the interaction with SHP-2 and Grb2 receptors and on the number of interactions with the EPIYA motif. We found that the main differences in the interaction was due to the contributions of certain types of energies from each strain and not from the total energy of the molecule. Specifically, the electrostatic energy, helix dipole energy, Wander Waals clashes, torsional clash, backbone clash and cis bond energy allowed a separation between severe and mild pathology for the interaction of only CagA with SHP2.
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Antígenos Bacterianos/química , Proteínas Bacterianas/química , Proteína Adaptadora GRB2/química , Helicobacter pylori/patogenicidad , Proteína Tirosina Fosfatasa no Receptora Tipo 11/química , Termodinámica , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Sitios de Unión , Úlcera Duodenal/etiología , Proteína Adaptadora GRB2/metabolismo , Helicobacter pylori/química , Simulación del Acoplamiento Molecular , Análisis de Componente Principal , Unión Proteica , Conformación Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Neoplasias Gástricas/etiologíaAsunto(s)
Tumor de Células Granulares , Fosfohidrolasa PTEN , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Adolescente , Adulto , Femenino , Adulto Joven , Análisis Mutacional de ADN , Tumor de Células Granulares/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Fosfohidrolasa PTEN/genética , HumanosRESUMEN
The small heat shock protein αB-Crystallin (CryAB, HspB5) and SH2 domain-containing tyrosine phosphatase 2 (Shp2) are important molecules in heart response to pathophysiological stress. Here we show that CryAB interacts with and potentially regulates Shp2 catalytic activity in stretched cardiomyocytes. Such an interaction requires CryAB oligomer to attenuate Shp2 activation. Stretched cardiomyocytes show a robust CryAB/Shp2 association accompanied by a reduction in the Shp2 phosphatase activity. Accordingly, CryAB knock-down in cardiomyocytes enhances Shp2 activity induced by mechanical stress. These results revealed a new role for CryAB, as a modulator of Shp2 phosphatase activity during a functionally relevant stimulus in cardiomyocytes.
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Cristalinas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Miocitos Cardíacos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Estrés Fisiológico/fisiología , Animales , Células Cultivadas , Cristalinas/genética , Activación Enzimática/fisiología , Técnicas de Silenciamiento del Gen , Proteínas Asociadas a Microtúbulos/genética , Miocitos Cardíacos/citología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Ratas , Ratas Wistar , Estrés MecánicoRESUMEN
The clinical and molecular findings of 77 cases of neonatal leukemia (NL) and 380 of infant leukemia (IL) were selected to distinguish features between NL and IL. Somatic gene mutations associated with acute leukemia including FLT3, RAS and PTPN11 were revisited. There were 42 cases of congenital leukemia associated with Down syndrome (DS) and 39 of these cases presented features of acute myeloid leukemia (AML)-M7. Twenty-seven of the DS cases underwent spontaneous remission and were reclassified as a transient myeloproliferative disorder. GATA1 mutations were found in 70% of these cases. In non-DS, frequent abnormalities were MLL rearrangements, mainly MLL-AFF1 in acute lymphoblastic leukemia and MLL-MLLT3 in AML. The FLT3 mutation was not found, while RAS (n = 4) and PTPN11 (n = 2) mutations were identified and reported for the first time in NL. There was substantial evidence to support that somatic abnormalities occur in utero. Thus, congenital leukemia is a good model for understanding leukemogenesis.
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Leucemia/epidemiología , Leucemia/genética , Mutación , Brasil/epidemiología , Análisis Citogenético/métodos , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Factor de Transcripción GATA1/genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Leucemia/tratamiento farmacológico , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Leucemia Megacarioblástica Aguda/epidemiología , Leucemia Megacarioblástica Aguda/genética , Masculino , Epidemiología Molecular , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Tirosina Quinasa 3 Similar a fms/genética , Proteínas ras/genéticaRESUMEN
BACKGROUND: Noonan syndrome (NS) is an autosomal dominant syndrome characterized by typical dysmorphic features, cardiac anomalies as well as postnatal growth retardation, and is associated with Ras-MAPK pathway gene mutations. The purpose of this study was to improve the diagnosis of Chilean patients with suspected NS through molecular analysis. METHODS: We screened 18 Chilean patients with a clinical diagnosis of NS for mutations in PTPN11 by high resolution melting (HRM) and subsequent sequencing. RESULTS: Three PTPN11 missense mutations were detected in 22% of analyzed patients. Of these, two (c.181G>A and c.1510A>G) were previously reported and one was the novel substitution c.328G>A (p.E110K) affecting the linker stretch between the N-SH2 and C-SH2 domains of SHP-2 protein. CONCLUSION: Molecular studies confirmed the clinical diagnosis of NS in 4 of 18 patients, which provided support for therapeutic decisions and improved genetic counseling for their families.
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Síndrome de Noonan/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Niño , Chile , Exones , Humanos , Mutación MissenseRESUMEN
We analyzed mutations in four genes (FLT3, KRAS/NRAS and PTPN11) that might disrupt the RAS/mitogen activated protein kinase (MAPKinase) signaling pathway, to evaluate their prognostic value in children younger than 16 years old with B-cell precursor acute lymphoblastic leukemia (Bcp-ALL). The overall survival (OS) was determined with the Kaplan-Meier method. MAPKinase genes were mutated in 25.4% and 20.1% of childhood and infant Bcp-ALL, respectively. Children with hyperdiploidy were more prone to harboring a MAPKinase gene mutation (odds ratio [OR] 3.18; 95% confidence interval [CI] 1.07-9.49). The mean OS of all cases was 54.0 months. FLT3 and PTPN11 mutations had no impact on OS. K/NRAS mutations were strongly associated with MLL-AFF1 (OR 5.78; 95% CI 1.00-33.24), and conferred poorer OS (p = 0.034) in univariate analysis.
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Genes ras , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Tirosina Quinasa 3 Similar a fms/genética , Brasil , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Oportunidad Relativa , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , PronósticoRESUMEN
OBJECTIVE: The aim of this study was to evaluate the expression of protein tyrosine kinase 2 and protein tyrosine phosphatase non-receptor type 11, which respectively encode focal adhesion kinase protein and src homology 2 domain-containing protein-tyrosine phosphatase 2, in hematopoietic cells from patients with myelodysplastic syndromes. METHODS: Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions were analyzed by quantitative polymerase chain reaction in bone marrow cells from patients with myelodysplastic syndromes and healthy donors. RESULTS: Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions did not significantly differ between normal cells and myelodysplastic cells. CONCLUSIONS: Our data suggest that despite the relevance of focal adhesion kinase and src homology 2 domain-containing protein-tyrosine phosphatase 2 in hematopoietic disorders, their mRNA expression do not significantly differ between total bone marrow cells from patients with myelodysplastic syndromes and healthy donors.
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Células de la Médula Ósea/metabolismo , Quinasa 2 de Adhesión Focal/metabolismo , Síndromes Mielodisplásicos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/análisis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Quinasa 2 de Adhesión Focal/análisis , Proteína-Tirosina Quinasas de Adhesión Focal/análisis , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Reacción en Cadena de la Polimerasa , Pronóstico , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Factores de Riesgo , Estadísticas no Paramétricas , Adulto Joven , Dominios Homologos src/fisiologíaRESUMEN
We investigated the expression of Src homology 2 domain-containing phosphatase (SHP-2) in laryngeal carcinoma and its clinical significance. Expression of SHP-2 was detected by immunohistochemical staining in normal mucosal tissues and various grades of laryngeal carcinoma. We looked for possible correlations between expression of SHP-2 in laryngeal carcinoma and clinical staging and lymph node metastasis. Immunochemical staining results revealed that the SHP-2 expression was significantly higher (88.24%) in laryngeal carcinoma than in normal mucosal tissue (25%). Additionally, the expression of SHP-2 was significantly correlated with lymph node metastasis, but not with clinical stage and gender of patients with laryngeal carcinoma. Therefore, SHP-2 may be useful as a prognostic marker for laryngeal carcinoma and as a therapeutic target in laryngeal carcinoma treatment.
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Carcinoma/enzimología , Neoplasias Laríngeas/enzimología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Carcinoma/mortalidad , Carcinoma/secundario , Femenino , Humanos , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Laringe/enzimología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
OBJECTIVES: Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement. METHODS: A standard questionnaire was administered. A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations. The molecular analysis of this cohort included sequencing of the following genes in all patients: PTPN1, SOS1, RAF1, KRAS, SHOC2 and BRAF. RESULTS: The most frequent tegumentary alterations were xeroderma (46%), photosensitivity (29%), excessive hair loss (24%), recurrent oral ulcers (22%), curly hair (20%), nevi (17%), markedly increased palmar and plantar creases (12%), follicular hyperkeratosis (12%), palmoplantar hyperkeratosis (10%), café-au-lait spots (10%) and sparse eyebrows (7%). Patients with mutations in PTPN11 had lower frequencies of palmar and plantar creases and palmar/plantar hyperkeratosis compared with the other patients. CONCLUSIONS: We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades (SOS1, BRAF, KRAS and RAF1) had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades (PTPN11).