RAS-MPAK Pathway Signaling in Health and Disease
The p21ras (Ras) family of signal switch molecules is an essential component of proliferative responses to many extracellular stimuli including most hematopoietic growth factors and cytokines. Phosphorylation of tyrosine residues on activated cytokine/growth factor receptors triggers multiple signaling pathways including JAK/STAT, Ras and PI3K. Activated Ras proteins further activate downstream effectors such as RAF/MEK/ERK, PI3K and RalGDS. Point mutations of Ras proteins are commonly found in human cancers and are estimated to occur in about 30% of cancer cases. These mutations lock Ras in the constitutively active confo...
Source: Blood - November 21, 2018 Category: Hematology Authors: Li, Q. Tags: A MAP(K) to Pediatric RASopathies Source Type: research

Inherited Disorders of the Ras-MAPK Pathway
RASopathies are a group of rare congenital diseases in which dysregulated signaling through the RAS-MAPK signaling cases is the critical pathogenetic mechanism. This definition excludes postnatally acquired conditions (e.g. RAS-MAPK driven neoplasms) and PIK3-AKT pathway related disorders as well as conditions with only ancillary RAS pathway involvement (e.g. KAT6B-, RAP1A/B-related disorders). The definition, however, includes the following categories: (1) Noonan syndrome and related disorders, specifically Noonan syndrome (NS), NS with multiple lentigines, NS-like disorder with loose anagen hair, CBL syndrome, cardiofaci...
Source: Blood - November 21, 2018 Category: Hematology Authors: Kratz, C. P., Zenker, M. Tags: A MAP(K) to Pediatric RASopathies Source Type: research

Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1 –PPP1CB complexes
AbstractRASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identifiedLZTR1, PPP1CB andMRAS as new causative genes in RASopathies. However, information on the phenotypes ofLZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants ofLZTR1, PPP1CB, andMRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 pat...
Source: Human Genetics - October 27, 2018 Category: Genetics & Stem Cells Source Type: research

Encephalocraniocutaneous Lipomatosis
A 5-year-old boy presented with worsening headaches for 3 months. On examination, he was found to have a hairless fatty tissue nevus of the scalp (nevus psiloliparus), subcutaneous soft tissue masses on the right side of his face, neck, mandible and right buttock and epibulbar dermoid of the right eye (choristoma) (Figs. 1A, B). Magnetic resonance imaging revealed a large suprasellar mass, which was debulked and found to be a pilocytic astrocytoma. Testing was not performed for the BRAF/KIAA1549 fusion or BRAFV600E mutation. Seven years later, he was started on adjuvant chemotherapy for gradual tumor progression. Over the ...
Source: Journal of Pediatric Hematology Oncology - September 22, 2018 Category: Hematology Tags: Morphology Corner Source Type: research

Dermatological manifestations in cardiofaciocutaneous syndrome: A prospective multicentric study of 45 mutation-positive patients.
CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS. This article is protected by copyright. All rights reserved. PMID: 30141192 [PubMed - as supplied by publisher] (Source: The British Journal of Dermatology)
Source: The British Journal of Dermatology - August 23, 2018 Category: Dermatology Authors: Bessis D, Morice-Picard F, Bourrat E, Abadie C, Aouinti S, Baumann C, Best M, Bursztejn AC, Capri Y, Chiaverini C, Coubes C, Giuliano F, Hadj-Rabia S, Jacquemont ML, Lacombe D, Lyonnet S, Mallet S, Mazereeuw-Hautier J, Miquel J, Molinari N, Parfait B, Per Tags: Br J Dermatol Source Type: research

RAS signalling in energy metabolism and rare human diseases
Publication date: Available online 8 May 2018Source: Biochimica et Biophysica Acta (BBA) - BioenergeticsAuthor(s): L. Dard, N. Bellance, D. Lacombe, R. RossignolAbstractThe 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...
Source: Biochimica et Biophysica Acta (BBA) Bioenergetics - July 11, 2018 Category: Biochemistry Source Type: research

Deep Palmar and Plantar Creases in Costello Syndrome
A male was born at 39 weeks of gestation, weighing 3670 g. Prenatal ultrasound scan showed severe polyhydramnios, requiring amniodrainage. A normal 46XY karyotype was obtained by amniocentesis. On examination, he had macrocephaly, with coarse facial features (broad anterior fontanelle, prominent forehead, bulbous nose, wide mouth), rhizomelic shortening of limbs, and ulnar deviation of the hands, with deep palmar and plantar creases (Figure, A and B). He developed respiratory distress syndrome, which required noninvasive mechanical ventilation. (Source: The Journal of Pediatrics)
Source: The Journal of Pediatrics - June 25, 2018 Category: Pediatrics Authors: Jose Mar ía Lloreda-Garcia, Jose Miguel Pina-Molina, Jose Ramón Fernández-Fructuoso Tags: Rediscovering the Physical Exam Source Type: research

The Rasopathy family: Consequences of germline activation of the RAS/MAPK pathway.
Abstract Noonan syndrome (NS; Mendelian Inheritance in Men (MIM) ♯163950) and related syndromes (Noonan syndrome with multiple lentigines (NS-ML, formerly called LEOPARD syndrome; MIM ♯151100), Noonan-like syndrome with loose anagen hair (NS-LAH; MIM ♯607721), Costello syndrome (CS; MIM ♯218040), Cardio-Facio-Cutaneous syndrome (CFCS; MIM ♯115150), type I Neurofibromatosis (NF1; MIM ♯162200), and Legius syndrome (LS; MIM ♯611431)) are a group of related genetic disorders, associating distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental reta...
Source: ENDOCR REV - June 18, 2018 Category: Endocrinology Authors: Tajan M, Paccoud R, Branka S, Edouard T, Yart A Tags: Endocr Rev Source Type: research

RAS signalling in energy metabolism and rare human diseases
Publication date: Available online 8 May 2018 Source:Biochimica et Biophysica Acta (BBA) - Bioenergetics Author(s): L. Dard, N. Bellance, D. Lacombe, R. Rossignol 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...
Source: Biochimica et Biophysica Acta (BBA) Bioenergetics - May 9, 2018 Category: Biochemistry Source Type: research

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