Increased osteoclastogenesis contributes to bone loss in the Costello syndrome < em > Hras G12V < /em > mouse model
Front Cell Dev Biol. 2022 Oct 18;10:1000575. doi: 10.3389/fcell.2022.1000575. eCollection 2022.ABSTRACTRAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in RAS genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells and developmental disorders when the germline is affected. These disorders are generally termed as RASopathies and among them Costello syndrome (CS) is a distinctive entity that is caused by specific HRAS germline mutations. Th...
Source: Cancer Control - November 4, 2022 Category: Cancer & Oncology Authors: Sayantan Nandi Saravanakkumar Chennappan Yannik Andrasch Miray Fidan Melanie Engler Mubashir Ahmad Jan P Tuckermann Martin Zenker Ion Cristian Cirstea Source Type: research

34625 Cutaneous manifestations of a rare RASopathy: Costello syndrome
Introduction: Costello syndrome (CS) is a rare genetic condition with only approximately 350 affected individuals reported worldwide. CS manifests phenotypically in various anatomic, physiologic, and cutaneous abnormalities, from non-specific findings, such as failure to thrive, to more distinct features, like coarse facial features and papillomata of the face. CS belongs to the group of RASopathies, which have overlapping features caused by gene mutations in the RAS pathway. Presented here is a case of a young woman with previously-diagnosed CS (heterozygous germline mutation in HRAS) with characteristic phenotypic abnorm...
Source: Journal of the American Academy of Dermatology - September 1, 2022 Category: Dermatology Authors: Lauren Prusinski Fernung, Morgan W. Thakore Source Type: research

Diverse Clinical Manifestations of Cardiofaciocutaneous Syndrome Type 3 in Two Patients from South East Asia
Conclusion: The genetic findings for the 2 patients affirm the use of identified gene mutations to confirm the clinical diagnosis of syndromic disorders and add to the phenotypic spectrum of CFCS.Mol Syndromol (Source: Molecular Syndromology)
Source: Molecular Syndromology - July 21, 2022 Category: Molecular Biology Source Type: research

452 Molecular and histopathologic profiling of melanocytic nevi in patients with RASopathies
Melanocytic nevi are among the most common benign human neoplasms and are mimics, risk factors, and potential precursors for melanoma. Many drivers of melanoma and tumor progression have been identified, such as somatic mutations in the RAS pathway genes. It is also known that germline genetic variants influence nevus count in RASopathy patients. However, why nevi develop and why certain nevi undergo melanomagenesis remains largely unknown. This project aims to evaluate the role of RAS pathway germline mutations in nevogenesis and melanomagenesis by studying individuals with RASopathies, specifically cardio-facio-cutaneous...
Source: Journal of Investigative Dermatology - July 20, 2022 Category: Dermatology Authors: E. Simmons, I. Rybak, J. Urban, J.D. McPherson, K.A. Rauen, M. Kiuru Source Type: research

A novel HRAS c.466C>T p.(Phe156Leu) variant in two patients with attenuated features of Costello syndrome
European Journal of Human Genetics, Published online: 29 June 2022; doi:10.1038/s41431-022-01139-1A novel HRAS c.466C>T p.(Phe156Leu) variant in two patients with attenuated features of Costello syndrome (Source: European Journal of Human Genetics)
Source: European Journal of Human Genetics - June 29, 2022 Category: Genetics & Stem Cells Authors: Suzanna Lindsey-Temple Matt Edwards Verena Rickassel Theresa Nauth Georg Rosenberger Source Type: research

Mitochondria and the future of RASopathies: the emergence of bioenergetics
RASopathies are a family of rare autosomal dominant disorders that affect the canonical Ras/MAPK signaling pathway and manifest as neurodevelopmental systemic syndromes, including Costello syndrome (CS). In this issue of the JCI, Dard et al. describe the molecular determinants of CS using a myriad of genetically modified models, including mice expressing HRAS p.G12S, patient-derived skin fibroblasts, hiPSC-derived human cardiomyocytes, an HRAS p.G12V zebrafish model, and human lentivirally induced fibroblasts overexpressing HRAS p.G12S or HRAS p.G12A. Mitochondrial proteostasis and oxidative phosphorylation were altered in...
Source: Journal of Clinical Investigation - April 15, 2022 Category: Biomedical Science Authors: Maria I. Kontaridis, Saravanakkumar Chennappan Source Type: research

HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models
Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were als...
Source: Journal of Clinical Investigation - April 15, 2022 Category: Biomedical Science Authors: Laetitia Dard, Christophe Hubert, Pauline Esteves, Wendy Blanchard, Ghina Bou About, Lyla Baldasseroni, Elodie Dumon, Chloe Angelini, Mégane Delourme, Véronique Guyonnet-Dupérat, Stéphane Claverol, Laura Fontenille, Karima Kissa, Pierre-Emmanuel Ségu Source Type: research

Clinical and molecular characterization of Costello syndrome in unrelated Mexican patients
This study intends to describe for the first time a cohort of Mexican patients with Costello syndrome. The five exons of the HRAS gene were amplified in DNA samples from 13 patients with a clinical suspicion of Costello syndrome. PCR products were sequenced using the Ready Reaction Big Dye Terminator v.3.0 Kit and an ABI PRISM 310 sequencer. Only five patients (38%) showed causal variant in codon 12 of the HRAS gene (four with the p.Gly12Ser and one with the p.Gly12Ala variant). Three patients showed silent polymorphic variants (p.His27His and p.Leu159Leu). Clinical features in patients carrying the causal variant were var...
Source: Clinical Dysmorphology - March 10, 2022 Category: Genetics & Stem Cells Tags: Original Articles Source Type: research

A case of Costello syndrome diagnosed by trio whole exome sequencing
J Obstet Gynaecol. 2022 Mar 7:1-4. doi: 10.1080/01443615.2022.2034764. Online ahead of print.NO ABSTRACTPMID:35254197 | DOI:10.1080/01443615.2022.2034764 (Source: Journal of Obstetrics and Gynaecology)
Source: Journal of Obstetrics and Gynaecology - March 7, 2022 Category: OBGYN Authors: Helen McDermott Pallavi Karkhanis Samantha Doyle Harsha Gowda Source Type: research

An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies
AbstractThe RAS/mitogen-activated protein kinase (MAPK) pathway controls a plethora of developmental and post-developmental processes. It is now clear that mutations in the RAS-MAPK pathway cause developmental diseases collectively referred to as the RASopathies. The RASopathies include Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Costello syndrome. RASopathy patients exhibit a wide spectrum of congenital heart defects (CHD), such as valvular abnormalities and hypertrophic cardiomyopathy (HCM). Since the cardiovascular defects are the most serious a...
Source: Cardiovascular Drugs and Therapy - February 14, 2022 Category: Cardiology Source Type: research

The RASopathies: Biology, genetics and therapeutic options
Adv Cancer Res. 2022;153:305-341. doi: 10.1016/bs.acr.2021.07.007. Epub 2021 Aug 7.ABSTRACTThe RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and...
Source: Advances in Cancer Research - February 1, 2022 Category: Cancer & Oncology Authors: Jody Fromm Longo Steven L Carroll Source Type: research

The RASopathies: Biology, genetics and therapeutic options
Adv Cancer Res. 2022;153:305-341. doi: 10.1016/bs.acr.2021.07.007. Epub 2021 Aug 7.ABSTRACTThe RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and...
Source: Advances in Cancer Research - February 1, 2022 Category: Cancer & Oncology Authors: Jody Fromm Longo Steven L Carroll Source Type: research

The RASopathies: Biology, genetics and therapeutic options
Adv Cancer Res. 2022;153:305-341. doi: 10.1016/bs.acr.2021.07.007. Epub 2021 Aug 7.ABSTRACTThe RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and...
Source: Advances in Cancer Research - February 1, 2022 Category: Cancer & Oncology Authors: Jody Fromm Longo Steven L Carroll Source Type: research

The RASopathies: Biology, genetics and therapeutic options
Adv Cancer Res. 2022;153:305-341. doi: 10.1016/bs.acr.2021.07.007. Epub 2021 Aug 7.ABSTRACTThe RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and...
Source: Advances in Cancer Research - February 1, 2022 Category: Cancer & Oncology Authors: Jody Fromm Longo Steven L Carroll Source Type: research