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2.
Am J Med Genet C Semin Med Genet ; 181(2): 208-217, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30896080

RESUMO

RASopathies are a group of genetic disorders due to dysregulation of the RAS-MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety-one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well-known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re-evaluation of the current tumor surveillance recommendation maybe warranted.


Assuntos
Mutação , Fenótipo , Proteínas ras/genética , Síndrome de Costello/genética , Síndrome de Costello/patologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Hong Kong , Humanos , Síndrome LEOPARD/genética , Síndrome LEOPARD/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Estudos Retrospectivos
3.
Sci Rep ; 8(1): 2421, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402968

RESUMO

RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation.


Assuntos
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas ras/genética , Adolescente , Animais , Bioensaio , Criança , Pré-Escolar , Biologia Computacional , Síndrome de Costello/patologia , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , MAP Quinase Quinase 1/genética , Masculino , Mutação de Sentido Incorreto , Neurofibromatose 1/patologia , Síndrome de Noonan/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/genética , Peixe-Zebra , alfa-Macroglobulinas/genética
4.
Clin Cancer Res ; 23(12): e83-e90, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28620009

RESUMO

In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83-e90. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Assuntos
Anormalidades Múltiplas/epidemiologia , Hipotireoidismo Congênito/epidemiologia , Anormalidades Craniofaciais/epidemiologia , Deformidades Congênitas da Mão/epidemiologia , Deficiência Intelectual/epidemiologia , Unhas Malformadas/epidemiologia , Síndrome de Rubinstein-Taybi/epidemiologia , Síndrome de Sotos/epidemiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/patologia , Síndrome de Costello/epidemiologia , Síndrome de Costello/genética , Síndrome de Costello/patologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação , Unhas Malformadas/genética , Unhas Malformadas/patologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Síndrome de Noonan/epidemiologia , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Fatores de Risco , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patologia , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Fator Nuclear 1 de Tireoide/genética
5.
Eur J Hum Genet ; 25(7): 823-831, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28594414

RESUMO

RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.


Assuntos
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , GTP Fosfo-Hidrolases/genética , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/genética , Proteínas de Membrana/genética , Síndrome de Noonan/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Costello/patologia , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Feminino , Genótipo , Cardiopatias Congênitas/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Síndrome de Noonan/patologia , Fenótipo
6.
Eur J Med Genet ; 60(7): 395-398, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28455154

RESUMO

Costello syndrome (CS) is a rare multiple congenital disorder caused by activating germline mutations in HRAS gene and is characterized by coarse facial features, severe feeding difficulties, failure to thrive, mild to severe intellectual disability, severe postnatal growth retardation, cardiac abnormalities or cancer predisposition. Phenotypic spectrum associated with HRAS mutations is broad, ranging from attenuated CS phenotype to neonatal and lethal forms with limited genotype-phenotype correlations. Congenital myopathy with neuromuscular spindle excess has been rarely described in the literature. We report a new severe fetal case of CS with distal arthrogryposis due to neuromuscular spindle excess, confirmed by the detection of the p.Gly12Val mutation in HRAS gene. This case emphasizes the fact that HRAS is the only gene responsible for neuromuscular spindle excess, underlines a correlation between p.Gly12Val mutation and severe CS phenotype and points out the importance of a muscle biopsy performed according to the suitable procedure in neuromuscular disorders for any fetal arthrogryposis.


Assuntos
Síndrome de Costello/genética , Doenças Fetais/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Síndrome de Costello/diagnóstico por imagem , Síndrome de Costello/patologia , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/patologia , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal
8.
Am J Med Genet A ; 173(4): 1109-1114, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28328122

RESUMO

De novo germline mutations in HRAS cause Costello syndrome, with >95% of the mutations causing Costello syndrome affecting amino acid position 12 (p.Gly12) or 13 (p.Gly13). We report on a patient with de novo missense mutation causing an amino acid change at codon 146 of HRAS, c.436G > C:p.Ala146Pro, who presented with subtle dysmorphic features, failure to thrive, global developmental delay, and hypertrophic obstructive cardiomyopathy. Mutations affecting codon 146 are observed in <1% of patients with Costello syndrome. From literature search, there were only two other patients reported with mutations involving the same location. We summarized and updated their findings, and discussed evidence to show that these patients with less obvious signs of Costello syndrome may not necessarily run a more benign clinical course.


Assuntos
Cardiomiopatia Hipertrófica/genética , Síndrome de Costello/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras)/genética , Substituição de Aminoácidos , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/patologia , Pré-Escolar , Síndrome de Costello/diagnóstico , Síndrome de Costello/patologia , Análise Mutacional de DNA , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Expressão Gênica , Humanos , Masculino
10.
Pediatr Dermatol ; 34(2): 160-162, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28008647

RESUMO

Costello syndrome (CS) is a multisystem congenital disorder characterized by coarse facial features, cardiac defects, intellectual disability, and predisposition to malignancies. Dermatologic findings can include cutaneous papillomas, skin redundancy, acanthosis nigricans, and keratosis pilaris. Palmoplantar keratoderma (PPK) is present in approximately 76% of patients with CS, with disabling functional consequences in severe cases. We report a case of CS with severe PPK that improved dramatically with systemic administration of acitretin 0.3 mg/kg/day.


Assuntos
Acitretina/uso terapêutico , Síndrome de Costello/complicações , Síndrome de Costello/patologia , Ceratodermia Palmar e Plantar/tratamento farmacológico , Ceratodermia Palmar e Plantar/etiologia , Ceratolíticos/uso terapêutico , Feminino , Humanos , Ceratodermia Palmar e Plantar/patologia , Adulto Jovem
11.
Am J Med Genet A ; 170(12): 3197-3206, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27589201

RESUMO

Costello syndrome (CS) arises from a typically paternally derived germline mutation in the proto-oncogene HRAS, and is considered a rasopathy. CS results in failure-to-thrive, intellectual disabilities, short stature, coarse facial features, skeletal abnormalities, congenital heart disease, and a predisposition for cancer, most commonly embryonal rhabdomyosarcoma (ERMS). The goal of this study was to characterize CS ERMS at the molecular level and to determine how divergent it is from sporadic ERMS. We characterized eleven ERMS tumors from eight unrelated CS patients, carrying paternally derived HRAS c.34G>A (p.Gly12Ser; 6) or c.35G>C (p.Gly12Ala; 2) mutations. Loss of heterozygosity (LOH) was evaluated in all CS ERMS by microarray and/or short tandem repeat (STR) markers spanning the entire chromosome 11. Eight CS ERMS tumors displayed complete paternal uniparental disomy of chromosome 11 (pUPD11), whereas two displayed UPD only at 11p and a second primary ERMS tumor showed UPD limited to 11p15.5, the classical hallmark for ERMS. Three sporadic ERMS cell lines (RD, Rh36, Rh18) and eight formalin fixed paraffin embedded (FFPE) ERMS tumors were also analyzed for RAS mutations and LOH status. We found a higher than anticipated frequency of RAS mutations (HRAS or NRAS; 50%) in sporadic ERMS cell lines/tumors. Unexpectedly, complete uniparental disomy (UPD11) was observed in five specimens, while the other six showed LOH extending across the p and q arms of chromosome 11. In this study, we are able to clearly demonstrate complete UPD11 in both syndromic and sporadic ERMS. © 2016 Wiley Periodicals, Inc.


Assuntos
Síndrome de Costello/genética , Perda de Heterozigosidade/genética , Rabdomiossarcoma Embrionário/genética , Dissomia Uniparental/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 11/genética , Síndrome de Costello/complicações , Síndrome de Costello/patologia , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Lactente , Proteínas Proto-Oncogênicas p21(ras)/genética , Rabdomiossarcoma Embrionário/etiologia , Rabdomiossarcoma Embrionário/patologia , Dissomia Uniparental/patologia
12.
PLoS Genet ; 12(5): e1006039, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27195699

RESUMO

Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping.


Assuntos
Síndrome de Costello/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Criança , Códon/genética , Síndrome de Costello/patologia , Éxons/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Neoplasias/patologia , Fenótipo , Sítios de Splice de RNA/genética , Processamento de RNA/genética
13.
J Neurosci ; 36(1): 142-52, 2016 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-26740656

RESUMO

UNLABELLED: Increasing evidence implicates abnormal Ras signaling as a major contributor in neurodevelopmental disorders, yet how such signaling causes cortical pathogenesis is unknown. We examined the consequences of aberrant Ras signaling in the developing mouse brain and uncovered several critical phenotypes, including increased production of cortical neurons and morphological deficits. To determine whether these phenotypes are recapitulated in humans, we generated induced pluripotent stem (iPS) cell lines from patients with Costello syndrome (CS), a developmental disorder caused by abnormal Ras signaling and characterized by neurodevelopmental abnormalities, such as cognitive impairment and autism. Directed differentiation toward a neuroectodermal fate revealed an extended progenitor phase and subsequent increased production of cortical neurons. Morphological analysis of mature neurons revealed significantly altered neurite length and soma size in CS patients. This study demonstrates the synergy between mouse and human models and validates the use of iPS cells as a platform to study the underlying cellular pathologies resulting from signaling deficits. SIGNIFICANCE STATEMENT: Increasing evidence implicates Ras signaling dysfunction as a major contributor in psychiatric and neurodevelopmental disorders, such as cognitive impairment and autism, but the underlying cortical cellular pathogenesis remains unclear. This study is the first to reveal human neuronal pathogenesis resulting from abnormal Ras signaling and provides insights into how these phenotypic abnormalities likely contribute to neurodevelopmental disorders. We also demonstrate the synergy between mouse and human models, thereby validating the use of iPS cells as a platform to study underlying cellular pathologies resulting from signaling deficits. Recapitulating human cellular pathologies in vitro facilitates the future high throughput screening of potential therapeutic agents that may reverse phenotypic and behavioral deficits.


Assuntos
Síndrome de Costello/metabolismo , Síndrome de Costello/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Proteínas ras/metabolismo , Adolescente , Adulto , Diferenciação Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Lactente , Masculino , Pessoa de Meia-Idade , Regulação para Cima
14.
Am J Med Genet A ; 170(3): 559-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26572961

RESUMO

Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57(Kip2) protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith-Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Hiperinsulinismo Congênito/genética , Síndrome de Costello/genética , Impressão Genômica , Hipoglicemia/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Dissomia Uniparental/genética , Substituição de Aminoácidos , Sequência de Bases , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/patologia , Cromossomos Humanos Par 11/química , Células Clonais , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/patologia , Síndrome de Costello/diagnóstico , Síndrome de Costello/patologia , Evolução Fatal , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/patologia , Lactente , Padrões de Herança , Fator de Crescimento Insulin-Like II/genética , Perda de Heterozigosidade , Masculino , Dados de Sequência Molecular , Pâncreas/metabolismo , Pâncreas/patologia , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/patologia
15.
BMC Med Genet ; 16: 46, 2015 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-26138095

RESUMO

BACKGROUND: P19 H-Ras, a second product derived from the H-Ras gene by alternative splicing, induces a G1/S phase delay, thereby maintaining cells in a reversible quiescence state. When P21 H-Ras is mutated in tumour cells, the alternative protein P19 H-Ras is also mutated. The H-Ras mutation Q61L is frequently detected in different tumours, which acts as constitutive activator of Ras functions and is considered to be a strong activating mutant. Additionally, a rare congenital disorder named Costello Syndrome, is described as a H-Ras disorder in children, mainly due to mutation G12S in p19 and p21 H-Ras proteins, which is present in 90 % of the Costello Syndrome patients. Our aim is to better understand the role of p19 and p21 H-Ras proteins in the cancer and Costello Syndrome development, concerning the miRNAs expression. METHODS: Total miRNAs expression regulated by H-Ras proteins were first analyzed in human miRNA microarrays assays. Previously selected miRNAs, were further analyzed in developed cell lines containing H-Ras protein mutants, that included the G12S Costello Syndrome mutant, with PCR Real-Time Taq Man miRNA Assays primers. RESULTS: This study describes how p19 affects the RNA world and shows that: i) miR-342, miR-206, miR-330, miR-138 and miR-99b are upregulated by p19 but not by p19W164A mutant; ii) anti-miR-206 can restore the G2 phase in the presence of p19; iii) p19 and p21Q61L regulate their own alternative splicing; iv) miR-206 and miR-138 are differentially regulated by p19 and p21 H-Ras and v) P19G12S Costello mutants show a clear upregulation of miR-374, miR-126, miR-342, miR-330, miR-335 and let-7. CONCLUSIONS: These results allow us to conclude that the H-Ras G12S mutation plays an important role in miRNA expression and open up a new line of study to understand the consequences of this mutation on Costello syndrome. Furthermore, they suggest that oncogenes may have a sufficiently important impact on miRNA expression to promote the development of numerous cancers.


Assuntos
Síndrome de Costello/genética , Síndrome de Costello/patologia , MicroRNAs/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Proteínas ras/fisiologia , Animais , Transformação Celular Neoplásica/genética , Células Cultivadas , Embrião de Mamíferos , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Camundongos , Modelos Biológicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Neoplasias/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas ras/genética
16.
Br J Cancer ; 112(8): 1392-7, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25742478

RESUMO

BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown. METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry. RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4. CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.


Assuntos
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Neoplasias/epidemiologia , Síndrome de Noonan/genética , Proteínas ras/genética , Adolescente , Criança , Pré-Escolar , Síndrome de Costello/patologia , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Feminino , Mutação em Linhagem Germinativa , Alemanha/epidemiologia , Cardiopatias Congênitas/patologia , Humanos , Lactente , Masculino , Neoplasias/etiologia , Neoplasias/patologia , Síndrome de Noonan/patologia , Sistema de Registros , Fatores de Risco , Transdução de Sinais
17.
Pediatr Dev Pathol ; 18(3): 237-44, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25668678

RESUMO

Costello syndrome is characterized by constitutional mutations in the proto-oncogene HRAS, causing dysmorphic features, multiple cardiac problems, intellectual disability, and an increased risk of neoplasia. We report a male infant with dysmorphic features, born prematurely at 32 weeks, who, during his 3-month life span, had an unusually severe and ultimately fatal manifestation of hypertrophic cardiomyopathy and hyperinsulinemic hypoglycemia. Molecular studies in this patient demonstrated the uncommon Q22K mutation in the HRAS gene, diagnostic of Costello syndrome. The major autopsy findings revealed hypertrophic cardiomyopathy, congenital myopathy, and a 1.4-cm pancreatic nodule that was positive for insulin expression and morphologically identical to a focal lesion of congenital hyperinsulinism. Sequencing of KCNJ11 and ABCC8, the 2 most commonly mutated genes in focal lesion of congenital hyperinsulinism, revealed no mutations. While hyperinsulinism is a recognized feature of RASopathies, a focal proliferation of endocrine cells similar to a focal lesion of hyperinsulinism is a novel pathologic finding in Costello syndrome.


Assuntos
Cardiomiopatia Hipertrófica/congênito , Hiperinsulinismo Congênito/etiologia , Síndrome de Costello/complicações , Cardiomiopatia Hipertrófica/patologia , Hiperinsulinismo Congênito/patologia , Síndrome de Costello/genética , Síndrome de Costello/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Pâncreas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
18.
An. bras. dermatol ; 89(6): 1005-1006, Nov-Dec/2014. graf
Artigo em Inglês | LILACS | ID: lil-727653

RESUMO

Costello syndrome (CS) is a rare genetic disorder, first described by Costello in 1971, caused by mutations in the HRAS proto-oncogene. Clinical findings include facial dysmorphism, skin disorders, cognitive impairment, cardiac and musculoskeletal defects. There is an increased risk of malignancies in these patients, due to the proto-oncogene mutation, and also sudden death secondary to heart disease. We report a case with characteristic phenotype, highlighting the peculiar skin changes.


Assuntos
Humanos , Feminino , Adulto Jovem , Anormalidades da Pele/patologia , Síndrome de Costello/patologia , Ceratodermia Palmar e Plantar/patologia , Facies , Síndrome de Costello/complicações , Síndrome de Costello/fisiopatologia
19.
An Bras Dermatol ; 89(6): 1005-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25387514

RESUMO

Costello syndrome (CS) is a rare genetic disorder, first described by Costello in 1971, caused by mutations in the HRAS proto-oncogene. Clinical findings include facial dysmorphism, skin disorders, cognitive impairment, cardiac and musculoskeletal defects. There is an increased risk of malignancies in these patients, due to the proto-oncogene mutation, and also sudden death secondary to heart disease. We report a case with characteristic phenotype, highlighting the peculiar skin changes.


Assuntos
Síndrome de Costello/patologia , Anormalidades da Pele/patologia , Síndrome de Costello/complicações , Síndrome de Costello/fisiopatologia , Facies , Feminino , Humanos , Ceratodermia Palmar e Plantar/patologia , Adulto Jovem
20.
Pediatr Dermatol ; 30(6): 665-73, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24283439

RESUMO

Costello syndrome (CS) and cardiofaciocutaneous syndrome (CFCS) are congenital disorders involving the Ras-MAPK pathway with phenotypic overlap. These two entities are thought to share common cutaneous findings, although so far they have been poorly studied. The objective of this prospective observational study was to describe the spectrum of skin findings in CS and CFCS and to highlight those specific to each of these two diseases. Patients with a confirmed diagnosis of CFCS or CS underwent a systematic skin examination during the annual workshop organized by the French CS association in 2007 and 2009 in Bordeaux, France. Eighteen patients were included in the study. Specific skin abnormalities, including cutis laxa, curly hair, pruritus, and hyperhidrosis, are shared by CFCS and CS, whereas others may help to differentiate between these two syndromes. Acanthosis nigricans, papillomas, and loose thick skin of the dorsum of the hands are characteristic of CS, whereas sparse eyebrows and dry hyperkeratotic skin are suggestive of CFCS. Our results highlight that a systematic cutaneous examination, in addition to dysmorphologic and noncutaneous anomalies, may be helpful in establishing the diagnosis of CFCS and CS. The physiopathologic link between constitutional Ras-MAPK pathway activation and the observed ectodermal findings remains to be investigated.


Assuntos
Síndrome de Costello/etiologia , Síndrome de Costello/patologia , Displasia Ectodérmica/etiologia , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/etiologia , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/patologia , Pele/patologia , Criança , Pré-Escolar , Síndrome de Costello/metabolismo , Diagnóstico Diferencial , Displasia Ectodérmica/metabolismo , Facies , Insuficiência de Crescimento/metabolismo , Feminino , Cardiopatias Congênitas/metabolismo , Humanos , Lactente , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Pele/metabolismo , Adulto Jovem
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