ArticleAmerican journal of human genetics2019
Germline-Activating RRAS2 Mutations Cause Noonan Syndrome.
Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 60 citations in OpenAlex.
- Clinical consensus guidelines for the management of Noonan syndrome in Japan.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2026Article
- A Rras2-BMPR2 feedback loop sustains osteogenesis and represents a therapeutic target for osteoporosis.Nature communications · 2026Article
- De Novo RRAS2 Pathogenic Variant in a Fetus With Bilateral Radial Ray and Multisystem Anomalies.Prenatal diagnosis · 2026Article
- Using modified mRNA for cardiomyocyte proliferation and cardiac genetic disease modelling and treatment.Biochemical Society transactions · 2025Review
- Ras-related protein 2 limits vascular smooth muscle cell phenotypic switching and abdominal aortic aneurysm development.Nature communications · 2025Article
- Active R-RAS2/TC21 prevents cell cycle arrest and morphological alterations in mouse embryonic fibroblasts lacking RAS proteins.Oncogene · 2025Article
- Osteosarcoma Arising in Noonan Syndrome/RASopathy Complex: First Case Report.Head and neck pathology · 2025Article
- Missense and truncated variants in ERF in individuals with a Noonan-like phenotype without craniosynostosis.Scientific reports · 2025Article
- Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation.Nature communications · 2025Article
- Mechanisms of brain overgrowth in autism spectrum disorder with macrocephaly.Frontiers in neuroscience · 2025Review
- Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy.Nature genetics · 2024Article
- Functional and structural insights into RAS effector proteins.Molecular cell · 2024Review
- RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.Disease models & mechanisms · 2024Review
- Non-Mammalian Models for Understanding Neurological Defects in RASopathies.Biomedicines · 2024Review
- Identification of a novel frameshift variation in ANKRD11: a case report of KBG syndrome.Frontiers in genetics · 2024Article
- Functional analysis ofFrontiers in genetics · 2024Article
- Mice Overexpressing Wild-TypeCancers · 2023Article
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- The molecular genetics of RASopathies: An update on novel disease genes and new disorders.American journal of medical genetics. Part C, Seminars in medical genetics · 2022Review
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Authors and funding
19 authors at 8 institutions in 2 countries.
Funding
Abstract
Noonan syndrome (NS) is characterized by distinctive craniofacial appearance, short stature, and congenital heart disease. Approximately 80% of individuals with NS harbor mutations in genes whose products are involved in the RAS/mitogen-activating protein kinase (MAPK) pathway. However, the underlying genetic causes in nearly 20% of individuals with NS phenotype remain unexplained. Here, we report four de novo RRAS2 variants in three individuals with NS. RRAS2 is a member of the RAS subfamily and is ubiquitously expressed. Three variants, c.70_78dup (p.Gly24_Gly26dup), c.216A>T (p.Gln72His), and c.215A>T (p.Gln72Leu), have been found in cancers; our functional analyses showed that these three changes induced elevated association of RAF1 and that they activated ERK1/2 and ELK1. Notably, prominent activation of ERK1/2 and ELK1 by p.Gln72Leu associates with the severe phenotype of the individual harboring this change. To examine variant pathogenicity in vivo, we generated zebrafish models. Larvae overexpressing c.70_78dup (p.Gly24_Gly26dup) or c.216A>T (p.Gln72His) variants, but not wild-type RRAS2 RNAs, showed craniofacial defects and macrocephaly. The same dose injection of mRNA encoding c.215A>T (p.Gln72Leu) caused severe developmental impairments and low dose overexpression of this variant induced craniofacial defects. In contrast, the RRAS2 c.224T>G (p.Phe75Cys) change, located on the same allele with p.Gln72His in an individual with NS, resulted in no aberrant in vitro or in vivo phenotypes by itself. Together, our findings suggest that activating RRAS2 mutations can cause NS and expand the involvement of RRAS2 proto-oncogene to rare germline disorders.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.