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Rasopathies

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https://www.readbyqxmd.com/read/28622382/correction-aberrant-neuronal-activity-induced-signaling-and-gene-expression-in-a-mouse-model-of-rasopathy
#1
Franziska Altmüller, Santosh Pothula, Anil Annamneedi, Saeideh Nakhaei-Rad, Carolina Montenegro-Venegas, Eneko Pina-Fernández, Claudia Marini, Monica Santos, Denny Schanze, Dirk Montag, Mohammad R Ahmadian, Oliver Stork, Martin Zenker, Anna Fejtova
[This corrects the article DOI: 10.1371/journal.pgen.1006684.].
June 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28620009/recommendations-for-cancer-surveillance-in-individuals-with-rasopathies-and-other-rare-genetic-conditions-with-increased-cancer-risk
#2
REVIEW
Anita Villani, Mary-Louise C Greer, Jennifer M Kalish, Akira Nakagawara, Katherine L Nathanson, Kristian W Pajtler, Stefan M Pfister, Michael F Walsh, Jonathan D Wasserman, Kristin Zelley, Christian P Kratz
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...
June 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28594414/genotype-and-phenotype-spectrum-of-nras-germline-variants
#3
Franziska Altmüller, Christina Lissewski, Debora Bertola, Elisabetta Flex, Zornitza Stark, Stephanie Spranger, Gareth Baynam, Michelle Buscarilli, Sarah Dyack, Jane Gillis, Helger G Yntema, Francesca Pantaleoni, Rosa LE van Loon, Sara MacKay, Kym Mina, Ina Schanze, Tiong Yang Tan, Maie Walsh, Susan M White, Marena R Niewisch, Sixto García-Miñaúr, Diego Plaza, Mohammad Reza Ahmadian, Hélène Cavé, Marco Tartaglia, Martin Zenker
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)...
June 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28582432/in-vivo-efficacy-of-the-akt-inhibitor-arq-092-in-noonan-syndrome-with-multiple-lentigines-associated-hypertrophic-cardiomyopathy
#4
Jianxun Wang, Vasanth Chandrasekhar, Giovanni Abbadessa, Yi Yu, Brian Schwartz, Maria I Kontaridis
Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age...
2017: PloS One
https://www.readbyqxmd.com/read/28524213/-update-on-the-treatment-of-rasopathies
#5
A Duat-Rodriguez, A Hernandez-Martin
INTRODUCTION: The term 'RASopathies' covers a series of diseases that present mutations in the genes that code for the proteins of the RAS/MAPK pathway. These diseases include neurofibromatosis type 1, Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome. Involvement of the RAS/MAPK pathway not only increases predisposition to develop tumours, but also determines the presence of phenotypic anomalies and alterations in learning processes...
May 17, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28523882/phacomatosis-pigmentokeratotica-a-mosaic-rasopathy-with-malignant-potential
#6
Amit Om, Sara S Cathey, Robert M Gathings, Michelle Hudspeth, Jennifer A Lee, Sean Marzolf, Lara Wine Lee
Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a nevus sebaceous arranged along the lines of Blaschko with a speckled lentiginous nevus (SLN). We report a novel KRAS mutation in a patient with a large nevus sebaceous and an SLN who subsequently developed a vaginal botryoid rhabdomyosarcoma, an association not previously reported in the literature. This case expands our knowledge of the genetic basis for phacomatosis, in which mutations in HRAS have been previously described, although this report provides evidence that activating mutations in KRAS or HRAS may cause PPK...
May 2017: Pediatric Dermatology
https://www.readbyqxmd.com/read/28456002/multiple-spinal-nerve-enlargement-and-sos1-mutation-further-evidence-of-overlap-between-neurofibromatosis-type-1-and-noonan-phenotype
#7
Claudia Santoro, Teresa Giugliano, Mariarosa Anna Beatrice Melone, Mario Cirillo, Carla Schettino, Pia Bernardo, Giovanni Cirillo, Silverio Perrotta, Giulio Piluso
Neurofibromatosis type 1 (NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines or RASopathy phenotype. We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of Noonan syndrome...
April 29, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28455524/mechanisms-underlying-cognitive-deficits-in-a-mouse-model-for-costello-syndrome-are-distinct-from-other-rasopathy-mouse-models
#8
Jadwiga Schreiber, Laura-Anne Grimbergen, Iris Overwater, Thijs van der Vaart, Jeffrey Stedehouder, Alberto J Schuhmacher, Carmen Guerra, Steven A Kushner, Dick Jaarsma, Ype Elgersma
RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas (G12V/G12V) mice...
April 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28423318/oligodendrocyte-nf1-controls-aberrant-notch-activation-and-regulates-myelin-structure-and-behavior
#9
Alejandro López-Juárez, Haley E Titus, Sadiq H Silbak, Joshua W Pressler, Tilat A Rizvi, Madeleine Bogard, Michael R Bennett, Georgianne Ciraolo, Michael T Williams, Charles V Vorhees, Nancy Ratner
The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice...
April 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28414188/a-case-of-splenomegaly-in-cbl-syndrome
#10
Rachel R Coe, Margaret L McKinnon, Maja Tarailo-Graovac, Colin J Ross, Wyeth W Wasserman, Jan M Friedman, Paul C Rogers, Clara D M van Karnebeek
INTRODUCTION: We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome and to draw attention to the power and utility of next generation genomic sequencing for providing rapid diagnosis and critical information to guide care in the pediatric clinical setting. CLINICAL REPORT: A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features...
April 13, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28390077/aberrant-hras-transcript-processing-underlies-a-distinctive-phenotype-within-the-rasopathy-clinical-spectrum
#11
Francesca Pantaleoni, Dorit Lev, Ion C Cirstea, Marialetizia Motta, Francesca Romana Lepri, Lisabianca Bottero, Serena Cecchetti, Ilan Linger, Stefano Paolacci, Elisabetta Flex, Antonio Novelli, Alessandra Carè, Mohammad R Ahmadian, Emilia Stellacci, Marco Tartaglia
RASopathies are a group of rare, clinically related conditions affecting development and growth, and are caused by germline mutations in genes encoding signal transducers and modulators with a role in the RAS signaling network. These disorders share facial dysmorphia, short stature, variable cognitive deficits, skeletal and cardiac defects, and a variable predisposition to malignancies. Here, we report on a de novo 10-nucleotide-long deletion in HRAS (c.481_490delGGGACCCTCT, NM_176795.4; p.Leu163ProfsTer52, NP_789765...
July 2017: Human Mutation
https://www.readbyqxmd.com/read/28371260/phenotypic-spectrum-of-costello-syndrome-individuals-harboring-the-rare-hras-mutation-p-gly13asp
#12
Débora Bertola, Michelle Buscarilli, Deborah L Stabley, Laura Baker, Daniel Doyle, Dennis W Bartholomew, Katia Sol-Church, Karen W Gripp
Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases...
May 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28349408/cancer-of-the-peripheral-nerve-in-neurofibromatosis-type-1
#13
REVIEW
Verena Staedtke, Ren-Yuan Bai, Jaishri O'Neill Blakeley
The RASopathy neurofibromatosis 1 is an autosomal dominant hereditary cancer syndrome that represents a major risk for the development of malignancies, particularly malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are unique sarcomas that originate from the peripheral nerve and represent the only primary cancer of the peripheral nervous system. To date, surgery is the only treatment modality proven to have survival benefit for MPNSTs and even when maximal surgery is feasible, these tumors are rarely curable, despite the use of chemotherapy and radiation...
April 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/28346493/aberrant-neuronal-activity-induced-signaling-and-gene-expression-in-a-mouse-model-of-rasopathy
#14
Franziska Altmüller, Santosh Pothula, Anil Annamneedi, Saeideh Nakhaei-Rad, Carolina Montenegro-Venegas, Eneko Pina-Fernández, Claudia Marini, Monica Santos, Denny Schanze, Dirk Montag, Mohammad R Ahmadian, Oliver Stork, Martin Zenker, Anna Fejtova
Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28343148/de-novo-mutations-in-cbl-causing-early-onset-paediatric-moyamoya-angiopathy
#15
Stéphanie Guey, Lou Grangeon, Francis Brunelle, Françoise Bergametti, Jeanne Amiel, Stanislas Lyonnet, Audrey Delaforge, Minh Arnould, Béatrice Desnous, Céline Bellesme, Dominique Hervé, Jan C Schwitalla, Markus Kraemer, Elisabeth Tournier-Lasserve, Manoelle Kossorotoff
BACKGROUND: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome...
March 25, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28340684/do-the-side-effects-of-braf-inhibitors-mimic-rasopathies
#16
Alicia Sfecci, Alain Dupuy, Monica Dinulescu, Catherine Droitcourt, Henri Adamski, Smail Hadj-Rabia, Sylvie Odent, Marie-Dominique Galibert, Lise Boussemart
Recent advances in targeted anticancer therapies have substantially improved the prognosis of several cancers. Such targeted therapies are not, however, free of side effects, and these side effects are clearly distinct from those induced by classical cytotoxic chemotherapies. This is likely so because targeted therapies are designed to interfere with specific oncogenic signaling pathways rather than to inhibit cell proliferation in general. In fact, interference with specific signaling pathways may lead to effects that mimic those associated with genetic disorders due to alterations in the corresponding signaling pathways...
April 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28328117/noonan-syndrome-ptpn11-mutations-and-brain-tumors-a-clinical-report-and-review-of-the-literature
#17
Aurore Siegfried, Claude Cances, Marie Denuelle, Najat Loukh, Maïté Tauber, Hélène Cavé, Marie-Bernadette Delisle
Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus...
April 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28289718/elucidation-of-mras-mediated-noonan-syndrome-with-cardiac-hypertrophy
#18
Erin M Higgins, J Martijn Bos, Heather Mason-Suares, David J Tester, Jaeger P Ackerman, Calum A MacRae, Katia Sol-Church, Karen W Gripp, Raul Urrutia, Michael J Ackerman
Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed "RASopathies," which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS-encoded RAS-related protein 3 as the cause of her disease...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28267273/nf1-mutated-melanoma-tumors-harbor-distinct-clinical-and-biological-characteristics
#19
Helena Cirenajwis, Martin Lauss, Henrik Ekedahl, Therese Törngren, Anders Kvist, Lao H Saal, Håkan Olsson, Johan Staaf, Ana Carneiro, Christian Ingvar, Katja Harbst, Nicholas K Hayward, Göran Jönsson
In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies...
April 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28224614/neurobehavioural-vulnerability-and-autistic-traits-in-rasopathies
#20
Yves Sznajer
No abstract text is available yet for this article.
February 22, 2017: Developmental Medicine and Child Neurology
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