scholarly journals Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome

2015 ◽  
Vol 36 (11) ◽  
pp. 1080-1087 ◽  
Author(s):  
Viviana Cordeddu ◽  
Jiani C. Yin ◽  
Cecilia Gunnarsson ◽  
Carl Virtanen ◽  
Séverine Drunat ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Activating Mutations ◽  
Dbl Homology Domain

scholarly journals Activating Mutations of the Noonan Syndrome-Associated SHP2/PTPN11 Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia

2004 ◽  
Vol 64 (24) ◽  
pp. 8816-8820 ◽  
Author(s):  
Mohamed Bentires-Alj ◽  
J. Guillermo Paez ◽  
Frank S. David ◽  
Heike Keilhack ◽  
Balazs Halmos ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Acute Myelogenous Leukemia ◽  
Noonan Syndrome ◽  
Myelogenous Leukemia ◽  
Ptpn11 Gene ◽  
Activating Mutations ◽  
Human Solid Tumors ◽  
Acute Myelogenous

scholarly journals Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

2019 ◽  
Vol 104 (6) ◽  
pp. 1223-1232 ◽  
Author(s):  
Yline Capri ◽  
Elisabetta Flex ◽  
Oliver H.F. Krumbach ◽  
Giovanna Carpentieri ◽  
Serena Cecchetti ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Activating Mutations

scholarly journals Inflammation potentiates JMML-like blood defects in Shp2 mutant Noonan syndrome

2020 ◽  
Author(s):  
Maja Solman ◽  
Sasja Blokzijl-Franke ◽  
Chuan Yan ◽  
Qiqi Yang ◽  
Sarah M. Kamel ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Noonan Syndrome ◽  
Juvenile Myelomonocytic Leukemia ◽  
Developmentally Regulated ◽  
Hematopoietic Stem ◽  
Activating Mutations ◽  
Stem And Progenitor Cells ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Myelomonocytic Leukemia

SummaryThe RASopathy Noonan syndrome (NS) is a frequent developmental disorder predominantly caused by activating mutations in the phosphatase SHP2. Among other features, NS children are predisposed to develop juvenile myelomonocytic leukemia (JMML). We developed a zebrafish mutant line carrying the NS-patient associated mutation Shp2-D61G. Shp2D61G zebrafish recapitulate major NS traits, including a JMML-like phenotype originating from defective hematopoietic stem and progenitor cells (HSPCs). Single cell RNA sequencing of mutant HSPCs revealed expansion of monocyte/macrophage progenitor cells associated with developmentally regulated cytokine production and elevated inflammation. Importantly, an anti-inflammatory agent rescued the JMML-like phenotype. Our results reveal a role for developmentally-induced inflammation in genesis of NS/JMML blood phenotypes and suggest anti-inflammatory drugs as potential new therapies.

Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy

2019 ◽  
Vol 29 (11) ◽  
pp. 1772-1783 ◽  
Author(s):  
Marialetizia Motta ◽  
Lena Sagi-Dain ◽  
Oliver H F Krumbach ◽  
Andreas Hahn ◽  
Amir Peleg ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Noonan Syndrome ◽  
De Novo ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Genetic Syndromes ◽  
Activating Mutations ◽  
High Level ◽  
Functional Analyses

Abstract The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

Rare NRAS mutation causing Noonan syndrome type 6 in a Saudi patient: case report

2021 ◽  
pp. 413-415
Author(s):  
Sara Alomar ◽  
Anfal Alsultan ◽  
Halah AlMuhaidib ◽  
Sarah Aldhahri ◽  
Dalal Bubshait
Keyword(s):  
Case Report ◽  
Noonan Syndrome ◽  
Syndrome Type ◽  
Patient Case ◽  
Nras Mutation
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