RAS signalling in energy metabolism and rare human diseases.
Abstract
The RAS pathway is a highly conserved cascade of protein-protein interactions and phosphorylation that is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Recent findings indicate that the RAS pathway plays a role in the regulation of energy metabolism via the control of mitochondrial form and function but little is known on the participation of this effect in RAS-related rare human genetic diseases. Germline mutations that hyperactivate the RAS pathway have been discovered and linked to human developmental disorders that are known as RASopathies. I...
Source: Biochimica et Biophysica Acta - May 8, 2018 Category: Biochemistry Authors: Dard L, Bellance N, Lacombe D, Rossignol R Tags: Biochim Biophys Acta Source Type: research
Age and ASD symptoms in Costello syndrome
American Journal of Medical Genetics Part A,Volume 176, Issue 4, Page 1027-1028, April 2018. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - March 25, 2018 Category: Genetics & Stem Cells Source Type: research
Oligodendrocyte RasG12V expressed in its endogenous locus disrupts myelin structure through increased MAPK, nitric oxide, and notch signaling
Abstract
Costello syndrome (CS) is a gain of function Rasopathy caused by heterozygous activating mutations in the HRAS gene. Patients show brain dysfunction that can include abnormal brain white matter. Transgenic activation of HRas in the entire mouse oligodendrocyte lineage resulted in myelin defects and behavioral abnormalities, suggesting roles for disrupted myelin in CS brain dysfunction. Here, we studied a mouse model in which the endogenous HRas gene is conditionally replaced by mutant HRasG12V in mature oligodendrocytes, to separate effects in mature myelinating cells from developmental events. Increased myelin th...
Source: Glia - August 30, 2017 Category: Neurology Authors: Haley E. Titus, Alejandro L ópez‐Juárez, Sadiq H. Silbak, Tilat A. Rizvi, Madeleine Bogard, Nancy Ratner Tags: RESEARCH ARTICLE Source Type: research
Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype
RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen‐activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio‐facio‐cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan‐like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan sy...
Source: American Journal of Medical Genetics Part A - June 26, 2017 Category: Genetics & Stem Cells Authors: Kimiko Ueda, Masako Yaoita, Tetsuya Niihori, Yoko Aoki, Nobuhiko Okamoto Tags: ORIGINAL ARTICLE Source Type: research
A review of craniofacial and dental findings of the RASopathies
ConclusionsCareful description of craniofacial and dental features of the RASopathies can provide information for dental clinicians treating these individuals and can also give insight into the role of Ras signalling in craniofacial development. (Source: Orthodontics and Craniofacial Research)
Source: Orthodontics and Craniofacial Research - June 23, 2017 Category: Dentistry Authors: H. Cao, N. Alrejaye, O. D. Klein, A. F. Goodwin, S. Oberoi Tags: REVIEW ARTICLE Source Type: research
Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk.
Abstract
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...
Source: Clinical Cancer Research - June 15, 2017 Category: Cancer & Oncology Authors: Villani A, Greer MC, Kalish JM, Nakagawara A, Nathanson KL, Pajtler KW, Pfister SM, Walsh MF, Wasserman JD, Zelley K, Kratz CP Tags: Clin Cancer Res Source Type: research
[Update on the treatment of RASopathies].
CONCLUSIONS: Today, thanks to the results from the first studies conducted with MEK inhibitor based mainly on animal models, a number of promising clinical trials are being carried out.
PMID: 28524213 [PubMed - in process] (Source: Revista de Neurologia)
Source: Revista de Neurologia - May 17, 2017 Category: Neurology Authors: Duat-Rodriguez A, Hernandez-Martin A Tags: Rev Neurol Source Type: research
Phacomatosis pigmentokeratotica and precocious puberty associated with HRAS mutation.
This article is protected by copyright. All rights reserved.
PMID: 28489335 [PubMed - as supplied by publisher] (Source: The British Journal of Dermatology)
Source: The British Journal of Dermatology - May 10, 2017 Category: Dermatology Authors: Martin RJ, Arefi M, Splitt M, Redford L, Moss C, Rajan N Tags: Br J Dermatol Source Type: research
A comparison of the functional health of children with Costello syndrome in 1999 and in 2015
Costello Syndrome is a rare congenital condition characterized by failure‐to‐thrive, cardiac abnormalities, distinctive facial features, predisposition to malignant tumors, and developmental delay. In 1999, we analyzed the functional health in a cohort of 18 patients. Since then, a mutation in the HRAS gene has been found to be causative, medical management has been refined, and the level of awareness has increased. The purpose of this study is to compare the functional health outcomes from the 1999 cohort with data prospectively collected from a comparable cohort in 2015. The Pediatric Outcome Data Collection Instrume...
Source: American Journal of Medical Genetics Part A - May 9, 2017 Category: Genetics & Stem Cells Authors: Viviana Bompadre, Tressa Mattioli ‐Lewis, Walid K. Yassir, Michael J. Goldberg Tags: ORIGINAL ARTICLE Source Type: research
Fetal costello syndrome with neuromuscular spindles excess and p.Gly12Val HRAS mutation.
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.
PMID: 28455154 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - April 25, 2017 Category: Genetics & Stem Cells Authors: Quélin C, Loget P, Rozel C, D'Hervé D, Fradin M, Demurger F, Odent S, Pasquier L, Cavé H, Marcorelles P Tags: Eur J Med Genet Source Type: research
A case of splenomegaly in CBL syndrome.
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. Extensive haematological testing including a bone marrow biopsy showed mild megaloblastoid e...
Source: European Journal of Medical Genetics - April 13, 2017 Category: Genetics & Stem Cells Authors: Coe RR, McKinnon ML, Tarailo-Graovac M, Ross CJ, Wasserman WW, Friedman JM, Rogers PC, van Karnebeek CDM Tags: Eur J Med Genet Source Type: research
Age ‐related differences in prevalence of autism spectrum disorder symptoms in children and adolescents with Costello syndrome
We examined prevalence of ASD symptoms in 14 individuals (six females) age 1–18 years with molecularly confirmed CS. Caregivers completed the Modified Checklist for Autism in Toddlers (M‐CHAT) for ages 0–4 years (n = 7), and the Social Communication Questionnaire (SCQ) for ages 4 and older (n = 7). Age was associated with meeting ASD criteria: 5/7 (71.4%) younger children met the ASD cut‐off on the MCHAT, compared to 0/7 older children on the SCQ. The following medical and developmental factors were strongly associated with ASD criteria on the M‐CHAT: having a gastrostomy tube at time of assessment, not e...
Source: American Journal of Medical Genetics Part A - April 4, 2017 Category: Genetics & Stem Cells Authors: David D. Schwartz, Jennifer M. Katzenstein, Eric J. Highley, Deborah L. Stabley, Katia Sol ‐Church, Karen W. Gripp, Marni E. Axelrad Tags: ORIGINAL ARTICLE Source Type: research
Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp
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. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13...
Source: American Journal of Medical Genetics Part A - April 3, 2017 Category: Genetics & Stem Cells Authors: D ébora Bertola, Michelle Buscarilli, Deborah L. Stabley, Laura Baker, Daniel Doyle, Dennis W. Bartholomew, Katia Sol‐Church, Karen W. Gripp Tags: ORIGINAL ARTICLE Source Type: research
Cytotoxicity of Zardaverine in Embryonal Rhabdomyosarcoma from a Costello Syndrome Patient
Donna M. Cartledge, Katherine M. Robbins, Katherine M. Drake, Rachel Sternberg, Deborah L. Stabley, Karen W. Gripp, E. Anders Kolb, Katia Sol-Church, Andrew D. Napper (Source: Frontiers in Oncology)
Source: Frontiers in Oncology - April 3, 2017 Category: Cancer & Oncology Source Type: research
Phacomatosis pigmentokeratotica and precocious puberty associated with HRAS mutation
This article is protected by copyright. All rights reserved. (Source: British Journal of Dermatology)
Source: British Journal of Dermatology - April 1, 2017 Category: Dermatology Authors: R.J. Martin, M. Arefi, M. Splitt, L. Redford, C. Moss, N. Rajan Tags: Research Letter Source Type: research
