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Rasopathy

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https://www.readbyqxmd.com/read/28224614/neurobehavioural-vulnerability-and-autistic-traits-in-rasopathies
#1
Yves Sznajer
No abstract text is available yet for this article.
February 22, 2017: Developmental Medicine and Child Neurology
https://www.readbyqxmd.com/read/28211980/constitutional-bone-impairment-in-noonan-syndrome
#2
Giuseppina Baldassarre, Alessandro Mussa, Diana Carli, Cristina Molinatto, Giovanni Battista Ferrero
Noonan syndrome (NS) is an autosomal dominant trait characterized by genotypic and phenotypic variability. It belongs to the Ras/MAPK pathway disorders collectively named Rasopathies or neurocardiofaciocutaneous syndromes. Phenotype is characterized by short stature, congenital heart defects, facial dysmorphisms, skeletal and ectodermal anomalies, cryptorchidism, mild to moderate developmental delay/learning disability, and tumor predisposition. Short stature and skeletal dysmorphisms are almost constant and several studies hypothesized a role for the RAS pathway in regulating bone metabolism...
March 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28166211/divergent-effects-of-intrinsically-active-mek-variants-on-developmental-ras-signaling
#3
Yogesh Goyal, Granton A Jindal, José L Pelliccia, Kei Yamaya, Eyan Yeung, Alan S Futran, Rebecca D Burdine, Trudi Schüpbach, Stanislav Y Shvartsman
Germline mutations in Ras pathway components are associated with a large class of human developmental abnormalities, known as RASopathies, that are characterized by a range of structural and functional phenotypes, including cardiac defects and neurocognitive delays. Although it is generally believed that RASopathies are caused by altered levels of pathway activation, the signaling changes in developing tissues remain largely unknown. We used assays with spatiotemporal resolution in Drosophila melanogaster (fruit fly) and Danio rerio (zebrafish) to quantify signaling changes caused by mutations in MAP2K1 (encoding MEK), a core component of the Ras pathway that is mutated in both RASopathies and cancers in humans...
February 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28144274/noonan-syndrome-a-new-survey
#4
Alireza Tafazoli, Peyman Eshraghi, Zahra Kamel Koleti, Mohammadreza Abbaszadegan
Noonan syndrome (NS) is an autosomal dominant disorder with vast heterogeneity in clinical and genetic features. Various symptoms have been reported for this abnormality such as short stature, unusual facial characteristics, congenital heart abnormalities, developmental complications, and an elevated tumor incidence rate. Noonan syndrome shares clinical features with other rare conditions, including LEOPARD syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome...
February 1, 2017: Archives of Medical Science: AMS
https://www.readbyqxmd.com/read/28117393/quantification-of-spatiotemporal-patterns-of-ras-isoform-expression-during-development
#5
Anna U Newlaczyl, Judy M Coulson, Ian A Prior
Ras proteins are important signalling hubs frequently dysregulated in cancer and in a group of developmental disorders called Rasopathies. Three Ras genes encode four proteins that differentially contribute to these phenotypes. Using quantitative real-time PCR (qRT-PCR) we have measured the gene expression profiles of each of the Ras isoforms in a panel of mouse tissues derived from a full developmental time course spanning embryogenesis through to adulthood. In most tissues and developmental stages we observe a relative contribution of KRas4B > > NRas ≥ KRas4A > HRas to total Ras expression with KRas4B typically representing 60-99% of all Ras transcripts...
January 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28098151/juvenile-myelomonocytic-leukemia-associated-variants-are-associated-with-neo-natal-lethal-noonan-syndrome
#6
Heather Mason-Suares, Diana Toledo, Jean Gekas, Katherine A Lafferty, Naomi Meeks, M Cristina Pacheco, David Sharpe, Thomas E Mullen, Matthew S Lebo
Gain-of-function variants in some RAS-MAPK pathway genes, including PTPN11 and NRAS, are associated with RASopathies and/or acquired hematological malignancies, most notably juvenile myelomonocytic leukemia (JMML). With rare exceptions, the spectrum of germline variants causing RASopathies does not overlap with the somatic variants identified in isolated JMML. Studies comparing these variants suggest a stronger gain-of-function activity in the JMML variants. As JMML variants have not been identified as germline defects and have a greater impact on protein function, it has been speculated that they would be embryonic lethal...
January 18, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28076348/reverse-pathway-genetic-approach-identifies-epistasis-in-autism-spectrum-disorders
#7
Ileena Mitra, Alinoë Lavillaureix, Erika Yeh, Michela Traglia, Kathryn Tsang, Carrie E Bearden, Katherine A Rauen, Lauren A Weiss
Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28067895/the-nf1-gene-in-tumor-syndromes-and-melanoma
#8
Maija Kiuru, Klaus J Busam
Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS...
February 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28050463/cardiofaciocutaneous-syndrome-case-report-of-a-rare-disorder
#9
Soutrik Seth, Tanmoy Biswas, Biswajit Biswas, Atanu Roy, Asok Kumar Datta
Cardiofaciocutaneous syndrome or CFC syndrome is a rare genetic disorder first described in 1986. It is one of the RASopathies involving multiple organs particularly the heart, skin and face affecting males and females equally. The phenotypic features overlap with 2 other conditions, the Noonan and Costello syndrome. We report on a 22-month-old boy with CFC syndrome presenting with typical craniofacial appearance, heart defects, ectodermal abnormalities, growth failure and developmental delay. Estimated population of affected individuals worldwide is a few hundreds...
November 2016: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28049852/in-vivo-severity-ranking-of-ras-pathway-mutations-associated-with-developmental-disorders
#10
Granton A Jindal, Yogesh Goyal, Kei Yamaya, Alan S Futran, Iason Kountouridis, Courtney A Balgobin, Trudi Schüpbach, Rebecca D Burdine, Stanislav Y Shvartsman
Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28027064/novel-pathogenic-variant-in-the-hras-gene-with-lethal-outcome-and-a-broad-phenotypic-spectrum-among-polish-patients-with-costello-syndrome
#11
Magdalena Pelc, Elżbieta Ciara, Aleksandra Jezela-Stanek, Monika Kugaudo, Agata Cieślikowska, Dorota Jurkiewicz, Magdalena Janeczko, Krystyna Chrzanowska, Małgorzata Krajewska-Walasek, Agata Skórka
Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p...
December 23, 2016: Clinical Dysmorphology
https://www.readbyqxmd.com/read/28002430/a-novel-hras-mutation-independently-contributes-to-left-ventricular-hypertrophy-in-a-family-with-a-known-myh7-mutation
#12
Maria Elena Sana, Lawrence A Quilliam, Andrea Spitaleri, Laura Pezzoli, Daniela Marchetti, Chiara Lodrini, Elisabetta Candiago, Anna Rita Lincesso, Paolo Ferrazzi, Maria Iascone
Several genetic conditions can lead to left ventricular hypertrophy (LVH). Among them, hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomere genes, is the most common inherited cardiac disease. Instead, RASopathies, a rare class of disorders characterized by neuro-cardio-facial-cutaneous abnormalities and sometimes presenting with LVH, are caused by mutations in the RAS-MAPK pathway. We report on a 62-years-old male who presented isolated severe obstructive LVH but did not carry the sarcomere mutation previously identified in his affected relatives...
2016: PloS One
https://www.readbyqxmd.com/read/27942422/expansion-of-the-rasopathies
#13
William E Tidyman, Katherine A Rauen
The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of cell cycle, differentiation, growth, cell senescence and apoptosis, all of which are critical to normal development. A class of neurodevelopmental disorders, RASopathies, is caused by germline mutations in genes of the Ras/MAPK pathway. Through the use of whole exome sequencing and targeted sequencing of selected genes in cohorts of panel-negative RASopathy patients, several new genes have been identified. These include: RIT1, SOS2, RASA2, RRAS and SYNGAP1, that likely represent new, albeit rare, causative RASopathy genes...
September 2016: Current Genetic Medicine Reports
https://www.readbyqxmd.com/read/27940666/rasopathies-are-associated-with-delayed-puberty-are-they-associated-with-precocious-puberty-too
#14
Daniëlle C M van der Kaay, Bat-Sheva Levine, Daniel Doyle, Roberto Mendoza-Londono, Mark R Palmert
RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway...
December 2016: Pediatrics
https://www.readbyqxmd.com/read/27924582/modeling-rasopathies-with-genetically-modified-mouse-models
#15
Isabel Hernández-Porras, Carmen Guerra
The RAS/MAPK signaling pathway plays key roles in development, cell survival and proliferation, as well as in cancer pathogenesis. Molecular genetic studies have identified a group of developmental syndromes, the RASopathies, caused by germ line mutations in this pathway. The syndromes included within this classification are neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML, formerly known as LEOPARD syndrome), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS, NF1-like syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), and hereditary gingival fibromatosis (HGF) type 1...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27900779/mosaic-nras-q61r-mutation-in-a-child-with-giant-congenital-melanocytic-naevus-epidermal-naevus-syndrome-and-hypophosphataemic-rickets
#16
R Ramesh, N Shaw, E K Miles, B Richard, I Colmenero, C Moss
The association of hypophosphataemic rickets with verrucous epidermal naevus (EN) and elevated fibroblast growth factor 23 levels is known as cutaneous-skeletal hypophosphataemia syndrome (CSHS), and can be caused by somatic activating mutations in RAS genes. We report a unique patient with CSHS associated with giant congenital melanocytic naevus (CMN), neurocutaneous melanosis and EN syndrome, manifesting as facial linear sebaceous naevus, developmental delay and ocular dermoids. An activating mutation Q61R in the NRAS gene was found in affected skin and ocular tissue but not blood, implying that the disparate manifestations are due to a multilineage activating mutation (mosaic RASopathy)...
January 2017: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/27868344/further-evidence-that-variants-in-ppp1cb-cause-a-rasopathy-similar-to-noonan-syndrome-with-loose-anagen-hair
#17
LETTER
Regina M Zambrano, Michael Marble, Stuart A Chalew, Christian Lilje, Alfonso Vargas, Yves Lacassie
No abstract text is available yet for this article.
February 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27862862/variability-in-clinical-and-neuropsychological-features-of-individuals-with-map2k1-mutations
#18
Elizabeth I Pierpont, Margaret Semrud-Clikeman, Mary Ella Pierpont
Mutations in MAP2K1, a gene expressed within the RAS-mitogen activated protein kinase (RAS/MAPK) pathway, are generally associated with the clinical phenotype of cardiofaciocutaneous syndrome. Here we describe two male patients (ages 16 and 20 years) with mutations in MAP2K1 and heterogeneous clinical presentations. Both young men had short stature, some facial features suggesting a RASopathy and minimal cardiac involvement. Detailed medical and neuropsychological findings are presented alongside a comprehensive review of features of patients with MAP2K1 mutations reported in the literature...
February 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27826699/a-unique-case-of-multiple-non-ossifying-fibromas-with-polyostotic-monomelic-distribution-and-aggressive-clinical-course
#19
Alessandro Corsi, Cristina Remoli, Mara Riminucci, Ernesto Ippolito, John Dimitriou
Multiple non-ossifying fibromas (MNOFs) occur either isolated or in association with other anomalies, are usually localized in the long bones of the lower limbs, may be radiographically confused with other skeletal lesions, and tend to heal spontaneously with the completion of the skeletal growth. Segmental distribution, either monomelic or polymelic and ipsilateral, is rare and commonly observed in the context of developmental diseases known as "RASopathies", which are caused by mutations in genes that encode components or regulators within the Ras/mitogen-activated protein kinase signaling pathway...
February 2017: Skeletal Radiology
https://www.readbyqxmd.com/read/27763634/phenotypic-predictors-and-final-diagnoses-in-patients-referred-for-rasopathy-testing-by-targeted-next-generation-sequencing
#20
Elizabeth J Bhoj, Zhenming Yu, Qiaoning Guan, Rebecca Ahrens-Nicklas, Kajia Cao, Minjie Luo, Tanya Tischler, Matthew A Deardorff, Elaine Zackai, Avni B Santani
INTRODUCTION: RASopathies include disorders generally characterized by developmental delay, specific heart defects, short stature, cardiac hypertrophy, and facial dysmorphisms. Next-generation sequencing (NGS)-based panels have widespread acceptance as a diagnostic tool for RASopathies. MATERIALS AND METHODS: The first 126 patients evaluated by clinical examination and the NGS RASopathy panel at the Children's Hospital of Philadelphia were enrolled. We calculated diagnosis rate, correlated reported clinical findings with positive or negative test results, and identified final molecular diagnoses in 28/96 patients who tested negative for RASopathies...
October 20, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
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