18 results on '"Costello Syndrome genetics"'
Search Results
2. Studying Metabolic Abnormalities in the Costello Syndrome HRAS G12V Mouse Model: Isolation of Mouse Embryonic Fibroblasts and Their In Vitro Adipocyte Differentiation.
- Author
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Fidan M, Chennappan S, and Cirstea IC
- Subjects
- Adipocytes metabolism, Adipogenesis, Animals, Costello Syndrome genetics, Costello Syndrome metabolism, Embryo, Mammalian metabolism, Embryo, Mammalian pathology, Female, Fibroblasts metabolism, Homeostasis, In Vitro Techniques, Male, Mice, Mice, Knockout, Adipocytes pathology, Cell Differentiation, Costello Syndrome pathology, Disease Models, Animal, Fibroblasts pathology, Mutation, Proto-Oncogene Proteins p21(ras) physiology
- Abstract
Costello syndrome (CS), characterized by a developmental delay and a failure to thrive, is also associated with an impaired lipid and energy metabolism. White adipose tissue is a central sensor of whole-body energy homeostasis, and HRAS hyperactivation may affect adipocyte differentiation and mature adipocyte homeostasis. An extremely useful tool for delineating in vitro intrinsic cellular signaling leading to metabolic alterations during adipogenesis is mouse embryonic fibroblasts, known to differentiate into adipocytes in response to adipogenesis-stimulating factors. Here, we describe in detail the isolation and maintenance of CS HRAS G12V mouse embryonic fibroblasts, their differentiation into adipocytes, and an assessment of adipocyte differentiation.
- Published
- 2021
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3. Costello syndrome model mice with a Hras G12S/+ mutation are susceptible to develop house dust mite-induced atopic dermatitis.
- Author
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Katata Y, Inoue SI, Asao A, Kobayashi S, Terui H, Inoue-Shibui A, Abe T, Niihori T, Aiba S, Ishii N, Kure S, and Aoki Y
- Subjects
- Animals, Benzamides pharmacology, Cell Proliferation drug effects, Costello Syndrome complications, Costello Syndrome pathology, Cytokines metabolism, Dermatitis, Atopic complications, Dermatitis, Atopic pathology, Diphenylamine analogs & derivatives, Diphenylamine pharmacology, Disease Models, Animal, Disease Susceptibility, Ear pathology, Epidermis drug effects, Epidermis parasitology, Epidermis pathology, Inflammation Mediators metabolism, Interleukin-33 metabolism, Male, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Models, Biological, Protein Kinase Inhibitors pharmacology, Pruritus complications, Pruritus pathology, Pyroglyphidae drug effects, Costello Syndrome genetics, Dermatitis, Atopic genetics, Dermatitis, Atopic parasitology, Mutation genetics, Proto-Oncogene Proteins p21(ras) genetics, Pyroglyphidae physiology
- Abstract
Costello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an Hras G12S mutation (Hras
G12S/+ mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (Dermatophagoides farinae, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of HrasG12S/+ mice compared with Hras+/+ mice. Cultured HrasG12S/+ keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in HrasG12S/+ mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of HrasG12S/+ mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of HrasG12S/+ mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.- Published
- 2020
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4. Advancing RAS/RASopathy therapies: An NCI-sponsored intramural and extramural collaboration for the study of RASopathies.
- Author
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Gross AM, Frone M, Gripp KW, Gelb BD, Schoyer L, Schill L, Stronach B, Biesecker LG, Esposito D, Hernandez ER, Legius E, Loh ML, Martin S, Morrison DK, Rauen KA, Wolters PL, Zand D, McCormick F, Savage SA, Stewart DR, Widemann BC, and Yohe ME
- Subjects
- Biomarkers, Tumor antagonists & inhibitors, Biomarkers, Tumor genetics, Costello Syndrome genetics, Costello Syndrome pathology, Ectodermal Dysplasia genetics, Ectodermal Dysplasia pathology, Facies, Failure to Thrive genetics, Failure to Thrive pathology, Heart Defects, Congenital genetics, Heart Defects, Congenital pathology, Humans, Intersectoral Collaboration, National Cancer Institute (U.S.), Neurofibromatosis 1 genetics, Neurofibromatosis 1 pathology, Noonan Syndrome genetics, Noonan Syndrome pathology, Research Report, Signal Transduction, United States, ras Proteins genetics, Costello Syndrome therapy, Ectodermal Dysplasia therapy, Failure to Thrive therapy, Heart Defects, Congenital therapy, Molecular Targeted Therapy, Mutation, Neurofibromatosis 1 therapy, Noonan Syndrome therapy, ras Proteins antagonists & inhibitors
- Abstract
RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)
- Published
- 2020
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5. Genetic landscape of RASopathies in Chinese: Three decades' experience in Hong Kong.
- Author
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Yu KPT, Luk HM, Leung GKC, Mak CCY, Cheng SSW, Hau EWL, Chan DKH, Lam STS, Tong TMF, Chung BHY, and Lo IFM
- Subjects
- Costello Syndrome genetics, Costello Syndrome pathology, Ectodermal Dysplasia genetics, Ectodermal Dysplasia pathology, Facies, Failure to Thrive genetics, Failure to Thrive pathology, Female, Heart Defects, Congenital genetics, Heart Defects, Congenital pathology, Hong Kong, Humans, LEOPARD Syndrome genetics, LEOPARD Syndrome pathology, MAP Kinase Signaling System genetics, Male, Noonan Syndrome genetics, Noonan Syndrome pathology, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, Retrospective Studies, Mutation, Phenotype, ras Proteins genetics
- Abstract
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., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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6. FOXI2: a possible gene contributing to ectodermal dysplasia.
- Author
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Kurban M, Zeineddine SB, Hamie L, Safi R, Abbas O, Kibbi AG, Bitar F, and Nemer G
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- Child, Costello Syndrome diagnosis, Costello Syndrome genetics, Ectodermal Dysplasia diagnosis, Ectodermal Dysplasia pathology, Facies, Failure to Thrive diagnosis, Failure to Thrive genetics, Female, Heart Defects, Congenital diagnosis, Heart Defects, Congenital genetics, Humans, Noonan Syndrome diagnosis, Noonan Syndrome genetics, SOS1 Protein, Transcription Factors genetics, Tumor Suppressor Proteins genetics, Ectodermal Dysplasia genetics, Mutation
- Abstract
Cardio-facio-cutaneous syndrome (CFC), Noonan syndrome (NS), and Costello syndrome are a group of diseases that belong to the RASopathies. The syndromes share clinical features making diagnosis a challenge. To investigate the phenotype and genotype of a 10-year-old Iraqi girl with overlapping features of CFC, NS, and Costello syndromes, with additional features of ectodermal dysplasia. DNA was examined by exome sequencing and protein expression by immunohistochemistry. Exome sequencing identified a mutation in the SOS1 gene and a de novo deletion in the FOXI2 gene which was neither present in the international databases, nor in 400 chromosomes from the same population. Based on immunohistochemical staining, FOXI2 was identified in the basal cell layer of the skin and overlapped with the expression of P63, a major player in ectodermal dysplasia. We therefore suggest screening for FOXI2 mutation in the setting of ectodermal features that are not associated with genes known to contribute to ectodermal dysplasia.
- Published
- 2017
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7. Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics.
- Author
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Gripp KW, Kolbe V, Brandenstein LI, and Rosenberger G
- Subjects
- Alleles, Amino Acid Substitution, Autopsy, Cell Line, Costello Syndrome metabolism, Fatal Outcome, Genetic Association Studies, Genotype, Humans, Infant, Male, Proto-Oncogene Proteins p21(ras) metabolism, Signal Transduction, Costello Syndrome diagnosis, Costello Syndrome genetics, Mutation, Phenotype, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Costello syndrome (CS) is caused by heterozygous germline HRAS mutations. Most patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype. Although many disease-associated HRAS alterations trigger constitutive activation of HRAS-dependent signalling pathways, additional pathological consequences exist. An infant with failure-to-thrive and hypertrophic cardiomyopathy had a novel de novo HRAS mutation (c.179G>T; p.Gly60Val). He showed subtle dysmorphic findings consistent with attenuated CS and died from presumed cardiac cause. Functional studies revealed that amino acid change p.Gly60Val impairs HRAS binding to effectors PIK3CA, phospholipase C1, and RAL guanine nucleotide dissociation stimulator. In contrast, interaction with effector rapidly accelerated fibrosarcoma (RAF) and regulator NF1 GTPase-activating protein was enhanced. Importantly, expression of HRAS p.Gly60Val in HEK293 cells reduced growth factor sensitivity leading to damped RAF-MAPK and phosphoinositide 3-kinases-AKT signalling response. Our data support the idea that a variable range of dysregulated HRAS-dependent signalling dynamics, rather than static activation of HRAS-dependent signal flow, may underlie the phenotypic variability in CS., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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8. The rare Costello variant HRAS c.173C>T (p.T58I) with severe neonatal hypertrophic cardiomyopathy.
- Author
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Hiippala A, Vasilescu C, Tallila J, Alastalo TP, Paetau A, Tyni T, Suomalainen A, Euro L, and Ojala T
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Alleles, Biomarkers, DNA Mutational Analysis, Echocardiography, Genetic Association Studies, Genetic Testing, Genotype, Humans, Infant, Newborn, Male, Radiography, Thoracic, Severity of Illness Index, Cardiomyopathy, Hypertrophic diagnosis, Cardiomyopathy, Hypertrophic genetics, Costello Syndrome diagnosis, Costello Syndrome genetics, Mutation, Phenotype, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
We report a 10-year-old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide-selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.5 (Dassault Systèmes Biovia, San Diego, CA). The patient with hypertrophic cardiomyopathy and normal cognitive development was diagnosed with an HRAS mutation c.173C>T (p.T58I), a milder variant of Costello syndrome affecting a highly conserved amino acid, threonine 58. Our analysis suggests that the p.G12 mutations slow GTP hydrolysis rendering HRAS unresponsive to GTPase activating proteins, and resulting in permanently active state. The p.T58I mutation likely affects binding of guanidine-nucleotide-exchange factors, thereby promoting the active state but also allowing for slow inactivation. Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome. We expand the clinical and molecular picture of the rare HRAS mutation by reporting the first case in Europe and the fourth case in the literature. Our protein structure analysis offers insights into the mechanism of the mildly activating p.T58I mutation. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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9. Uniparental Trisomy of a Mutated HRAS Proto-Oncogene in Embryonal Rhabdomyosarcoma of a Patient With Costello Syndrome.
- Author
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Menke J, Pauli S, Sigler M, Kühnle I, Shoukier M, Zoll B, Ganster C, Salinas-Riester G, and Schaefer IM
- Subjects
- Abdominal Neoplasms chemistry, Abdominal Neoplasms diagnosis, Abdominal Neoplasms pathology, Abdominal Neoplasms surgery, Chemotherapy, Adjuvant, Child, Preschool, Costello Syndrome diagnosis, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Genetic Testing methods, Heredity, Heterozygote, Humans, Immunohistochemistry, Magnetic Resonance Imaging, Neoplasm Grading, Pedigree, Phenotype, Predictive Value of Tests, Proto-Oncogene Mas, Rhabdomyosarcoma, Embryonal chemistry, Rhabdomyosarcoma, Embryonal diagnosis, Rhabdomyosarcoma, Embryonal pathology, Rhabdomyosarcoma, Embryonal surgery, Treatment Outcome, Abdominal Neoplasms genetics, Biomarkers, Tumor genetics, Chromosomes, Human, Pair 11, Costello Syndrome genetics, Mutation, Proto-Oncogene Proteins p21(ras) genetics, Rhabdomyosarcoma, Embryonal genetics, Trisomy
- Published
- 2015
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10. HRAS mutations in bladder cancer at an early age and the possible association with the Costello Syndrome.
- Author
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Beukers W, Hercegovac A, and Zwarthoff EC
- Subjects
- Adolescent, Adult, Age Factors, Child, Class I Phosphatidylinositol 3-Kinases, Humans, Middle Aged, Phosphatidylinositol 3-Kinases genetics, Receptor, Fibroblast Growth Factor, Type 3 genetics, Young Adult, Costello Syndrome genetics, Genetic Predisposition to Disease genetics, Mutation, Urinary Bladder Neoplasms genetics, ras Proteins genetics
- Abstract
Bladder tumours of patients <20 years have a low incidence of genetic aberrations typically found in tumours in older patients. In this study, we investigated oncogene mutations in patients with bladder cancer (BC) <20 years and compared them to older age groups. Interestingly, we observed a relatively high number of HRAS mutations in tumour from young patients. These mutations were also highly uncommon in BCs of older patients, ie, p.(Gly12Ser) and p.(Gly12Ala). Germline mutations in the HRAS gene, especially p.(Gly12Ser/Ala), cause Costello Syndrome (CS), a severe congenital disorder. Indeed, one of the patients had been diagnosed with CS. We hypothesized that some of the other patients might be mosaic for the HRAS mutation and therefore could express some of the clinical features of CS, like tumour predisposition. Hence, we isolated DNA from microdissected stroma and analysed it for HRAS mutations. In the CS patient and in patient X, the mutation was also highly expressed in normal stroma. We conclude that patient X is possibly mosaic for the HRAS mutation. These results suggest that mosaicism for oncogenic HRAS mutations may increase the risk for developing BC at a young age.
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- 2014
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11. Clinical and molecular analysis of RASopathies in a group of Turkish patients.
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Şimşek-Kiper PÖ, Alanay Y, Gülhan B, Lissewski C, Türkyilmaz D, Alehan D, Cetin M, Utine GE, Zenker M, and Boduroğlu K
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple pathology, Costello Syndrome diagnosis, Costello Syndrome genetics, Costello Syndrome pathology, DNA Mutational Analysis, Ectodermal Dysplasia diagnosis, Ectodermal Dysplasia genetics, Ectodermal Dysplasia pathology, Facies, Failure to Thrive diagnosis, Failure to Thrive genetics, Failure to Thrive pathology, Genetic Association Studies, Heart Defects, Congenital diagnosis, Heart Defects, Congenital genetics, Heart Defects, Congenital pathology, Humans, Intellectual Disability genetics, Intracellular Signaling Peptides and Proteins genetics, LEOPARD Syndrome diagnosis, LEOPARD Syndrome genetics, LEOPARD Syndrome pathology, MAP Kinase Kinase 1 genetics, Noonan Syndrome diagnosis, Noonan Syndrome genetics, Noonan Syndrome pathology, Phenotype, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) genetics, SOS1 Protein genetics, Turkey, Abnormalities, Multiple genetics, Mutation, ras Proteins genetics
- Abstract
The 'RASopathies' are a group of disorders sharing many clinical features and a common pathophysiology. In this study, we aimed to clinically evaluate a group of Turkish patients and elucidate the underlying genetic etiology. Thirty-one patients with a clinical diagnosis of one of the RASopathy syndromes were included in the study. Of these, 26 (83.8%) had a clinical diagnosis of Noonan syndrome, whereas 5 had a clinical diagnosis of either Costello, LEOPARD or cardio-facio-cutaneous syndromes. Twenty of 31 (64.5%) patients were found to be mutation positive. Mutations in PTPN11, SOS1 and SHOC2 genes were detected in patients with Noonan syndrome (57.6%). Mutations in MEK1, PTPN11, BRAF and HRAS genes were detected in the remaining. Pulmonary stenosis was the most common (61.5%) cardiac anomaly. Among Noonan syndrome patients with a confirmed mutation, mild intellectual disability tended to be more common in patients with PTPN11 mutation than in those with SOS1 mutation. Hematologic evaluation revealed coagulation defects in three Noonan syndrome patients with a mutation. This is currently the largest clinical and molecular study in Turkish RASopathy patients. Our findings indicate that molecular epidemiology and genotype-phenotype correlations in RASopathies are relatively independent from the ethnic population background., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)
- Published
- 2013
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12. Transmission of the rare HRAS mutation (c. 173C > T; p.T58I) further illustrates its attenuated phenotype.
- Author
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Gripp KW, Hopkins E, Serrano A, Leonard NJ, Stabley DL, and Sol-Church K
- Subjects
- Abnormalities, Multiple, DNA Mutational Analysis, Family, Humans, Megalencephaly, Mosaicism, Phenotype, Proto-Oncogene Mas, Costello Syndrome genetics, Genes, ras genetics, Mutation
- Abstract
Costello syndrome was delineated based on its distinctive phenotype including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. With exception of two instances of parental mosaicism, one presumed gonadal and the other proven somatic mosaicism for the p.G12S change, all published cases resulted from de novo mutations, typically arising in the paternal germline. More than 90% of these mutations affect the glycine residues in position 12 or 13, and result in a gain-of-function of the altered protein. A rare heterozygous HRAS alteration (c.173C > T; p.T58I) associated with an attenuated phenotype was previously reported in one patient. We identified two additional individuals with this mutation, father and son. Further studies supported origin of the alteration in the grand-paternal germline. Transmission of the mutation underscores its attenuated phenotype compatible with reproduction. We reviewed the phenotype in the newly identified individuals (Patient 1, 2) and include updated information on the first previously reported individual with HRAS p.T58I (Patient 3). Macrocephaly was present in all three. Cardiac findings included hypertrophic cardiomyopathy with double-chambered right ventricle; or mitral valve prolapse in one patient each. While subtle neurologic abnormalities or developmental delay were present in all, only one showed significant cognitive and functional impairment. None developed papillomata or a malignant tumor. Genetic counseling for Costello syndrome needs to take into consideration the particular HRAS mutation., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2012
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13. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome.
- Author
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Niihori T, Aoki Y, Okamoto N, Kurosawa K, Ohashi H, Mizuno S, Kawame H, Inazawa J, Ohura T, Arai H, Nabatame S, Kikuchi K, Kuroki Y, Miura M, Tanaka T, Ohtake A, Omori I, Ihara K, Mabe H, Watanabe K, Niijima S, Okano E, Numabe H, and Matsubara Y
- Subjects
- Adolescent, Adult, Animals, Cell Line, Child, Child, Preschool, Codon genetics, DNA Mutational Analysis, Female, Genotype, Humans, Infant, Male, Mice, NIH 3T3 Cells, Phenotype, Proto-Oncogene Proteins p21(ras) metabolism, Signal Transduction genetics, Up-Regulation, Cellular Senescence genetics, Costello Syndrome genetics, Costello Syndrome physiopathology, Fibroblasts metabolism, Mutation genetics, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.
- Published
- 2011
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14. Clinical manifestations of mutations in RAS and related intracellular signal transduction factors.
- Author
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Zenker M
- Subjects
- Costello Syndrome diagnosis, Granuloma, Giant Cell, Humans, MAP Kinase Signaling System genetics, Neurofibromatosis 1 diagnosis, Noonan Syndrome diagnosis, Phenotype, ras Proteins genetics, Costello Syndrome genetics, Genes, ras, Mitogen-Activated Protein Kinases genetics, Mutation, Neurofibromatosis 1 genetics, Noonan Syndrome genetics
- Abstract
Purpose of Review: Recent advances in molecular genetic research have led to the definition of the new group of genetic syndromes, the RAS-mitogen-activated protein kinase (MAPK) pathway disorders or 'RASopathies'. They comprise Noonan syndrome and related disorders (cardio-facio-cutaneous and Costello syndromes), as well as neurofibromatosis type 1. This review summarizes the recent literature with a special focus on genotype-phenotype correlations., Recent Findings: Although the picture is still incomplete, and additional genes are likely to exist, the underlying genetic alteration can now be found in a large majority of patients with a RASopathy phenotype. The most recently discovered novel genes for Noonan syndrome or Noonan syndrome-like disorders, NRAS, SHOC2, and CBL, account for small fractions of the patient population. The increasing knowledge about the spectrum of gene mutations and associated clinical manifestations has led to a refinement of genotype-phenotype correlations. Recent studies have added new insights into tumor predisposition and prenatal manifestations. Model systems are being developed to investigate innovative treatment approaches., Summary: Constitutional overactivation at various levels of the RAS-MAPK pathway causes overlapping syndromes, comprising characteristic facial features, cardiac defects, cutaneous abnormalities, growth deficit, neurocognitive delay, and predisposition to malignancies. Each syndrome also exhibits unique features that probably reflect genotype-related specific biological effects.
- Published
- 2011
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15. Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.
- Author
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Gripp KW, Hopkins E, Sol-Church K, Stabley DL, Axelrad ME, Doyle D, Dobyns WB, Hudson C, Johnson J, Tenconi R, Graham GE, Sousa AB, Heller R, Piccione M, Corsello G, Herman GE, Tartaglia M, and Lin AE
- Subjects
- Adolescent, Adult, Brain abnormalities, Child, Child, Preschool, Costello Syndrome complications, Costello Syndrome diagnosis, Face abnormalities, Female, Heart Defects, Congenital etiology, Humans, Infant, Magnetic Resonance Imaging, Male, Musculoskeletal Abnormalities etiology, Neoplasms etiology, Pregnancy, Proto-Oncogene Mas, Young Adult, Costello Syndrome genetics, Mutation genetics, Phenotype, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings., (Copyright © 2011 Wiley-Liss, Inc.)
- Published
- 2011
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16. Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation.
- Author
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Girisha KM, Lewis LE, Phadke SR, and Kutsche K
- Subjects
- Amino Acid Sequence, Base Sequence, Cutis Laxa genetics, DNA Mutational Analysis, Female, Humans, Infant, Infant, Newborn, Male, Molecular Sequence Data, Pregnancy, Proto-Oncogene Proteins p21(ras) chemistry, Amino Acid Substitution genetics, Costello Syndrome complications, Costello Syndrome genetics, Cutis Laxa complications, Mosaicism, Mutation genetics, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Costello syndrome is a rare developmental disorder characterized by coarse face, postnatal growth retardation, skin and musculoskeletal anomalies, cardiovascular abnormalities, mental retardation, and tumor predisposition. Dermatological manifestations usually include redundant, soft and thickened skin. Loose skin is especially present over the neck, hands, and feet. Heterozygous missense mutations in HRAS are causative for Costello syndrome, with the c.34G > A (p.G12S) mutation as the most commonly found alteration. In the majority of affected individuals pathogenic sequence changes appeared de novo, however, two individuals with somatic mosaicism for the HRAS mutation have been reported. Here, we describe a boy with somatic mosaicism for the c.34G > A mutation in HRAS. Allelic quantitation revealed the mutation in approximately 58% of his lymphocytes; however, in DNA derived from buccal cells we could not detect the sequence change. The patient presented with the typical clinical findings of Costello syndrome such as increased birth weight, severe failure to thrive, characteristic facial appearance, and skin abnormalities. The dermatological anomalies were remarkable as he showed severe skin laxity with wrinkling of skin on all parts of the body due to loss of subcutaneous fat that decreased significantly by age 13 months. This case further adds to the phenotypic variability seen in patients with somatic mosaicism for an HRAS mutation and highlights the awareness of mosaic mutations in Costello syndrome when molecular testing is performed., (© 2010 Wiley-Liss, Inc.)
- Published
- 2010
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17. Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway.
- Author
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Tumurkhuu M, Saitoh M, Sato A, Takahashi K, Mimaki M, Takita J, Takeshita K, Hama T, Oka A, and Mizuguchi M
- Subjects
- Abnormalities, Multiple genetics, Child, Female, Genes, ras genetics, Humans, Infant, Male, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins p21(ras) genetics, Syndrome, ras Proteins genetics, Costello Syndrome genetics, Face abnormalities, Heart Defects, Congenital genetics, MAP Kinase Signaling System genetics, Mutation, Noonan Syndrome genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 2 genetics, Skin Abnormalities genetics, Son of Sevenless Proteins genetics
- Abstract
Background: Germline mutations in several members of RAS/RAF/MEK/ERK pathway cause clinically similar genetic disorders, including Noonan syndrome (NS), Costello syndrome (CS) and cardio-facio-cutaneous syndrome (CFC). Each of these syndromes has a wide spectrum of molecular etiology. The aim of the present study was to conduct a comprehensive genetic analysis of RAS/RAF/MEK/ERK pathway in these syndromes., Methods: Three patients with NS and two patients with CS/CFC were examined. Peripheral blood samples were collected from all patients as well as from 100 healthy Japanese volunteers. The protein phosphatase, non-receptor type II (PTPN11), KRAS, HRAS, NRAS, BRAF, RAF1, Son of Sevenless (SOS1) and MEK1genes were analyzed., Results: In a patient with a severe Noonan phenotype, a rare PTPN11 mutation was detected: A to G transition at position 172, causing an N58D substitution within the N-SH2 domain. In a CS/CFC patient no HRAS mutations were found, but a novel SOS1 missense mutation was found: A to G transition at position 473, causing a T158A substitution within domain of histone-like fold (HF)., Conclusions: A case mimicking CS with SOS1 T158A substitution, which has not been reported previously in CS, revealed the complex relationship between the genotype and phenotype of overlapping syndromes of the RAS/RAF/MEK/ERK pathway., (© 2010 Japan Pediatric Society.)
- Published
- 2010
- Full Text
- View/download PDF
18. High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities.
- Author
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Gripp KW, Hopkins E, Doyle D, and Dobyns WB
- Subjects
- Costello Syndrome surgery, Humans, Incidence, Infant, Newborn, Proto-Oncogene Mas, Cerebellum abnormalities, Cerebellum growth & development, Costello Syndrome epidemiology, Costello Syndrome genetics, Mutation genetics, Proto-Oncogene Proteins p21(ras) genetics, Spinal Cord abnormalities
- Abstract
Costello syndrome is a rasopathy caused by germline mutations in the proto-oncogene HRAS. Its presentation includes failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. In a systematic review we found absolute or relative macrocephaly (100%), ventriculomegaly (50%), and other abnormalities on brain and spinal cord imaging studies in 27/28 individuals. Posterior fossa crowding with cerebellar tonsillar herniation (CBTH) was noted in 27/28 (96%), and in 10/17 (59%) with serial studies posterior fossa crowding progressed. Sequelae of posterior fossa crowding and CBTH included hydrocephalus requiring shunt or ventriculostomy (25%), Chiari 1 malformation (32%), and syrinx formation (25%). Our data reveal macrocephaly with progressive frontal bossing and CBTH, documenting an ongoing process rather than a static congenital anomaly. Comparison of images obtained in young infants to subsequent studies demonstrated postnatal development of posterior fossa crowding. This process of evolving megalencephaly and cerebellar enlargement is in keeping with mouse model data, delineating abnormal genesis of neurons and glia, resulting in an increased number of astrocytes and enlarged brain volume. In Costello syndrome and macrocephaly-capillary malformation syndrome disproportionate brain growth is the main factor resulting in postnatal CBTH and Chiari 1 malformation., (Copyright 2010 Wiley-Liss, Inc.)
- Published
- 2010
- Full Text
- View/download PDF
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