ArticleAmerican journal of medical genetics. Part A2012
A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development.
Article in American journal of medical genetics. Part A, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
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- Discovery of common molecular signatures and drug repurposing for COVID-19/Asthma comorbidity: ACE2 and multi-partite networks.Cell cycle (Georgetown, Tex.) · 2024Article
- New cytotoxic dammarane type saponins from Ziziphus spina-christi.Scientific reports · 2023Article
- Multidisciplinary Management of Costello Syndrome: Current Perspectives.Journal of multidisciplinary healthcare · 2022Review
- The novel duplication HRAS c.186_206dup p.(Glu62_Arg68dup): clinical and functional aspects.European journal of human genetics : EJHG · 2020Article
- Redefining the Etiologic Landscape of Cerebellar Malformations.American journal of human genetics · 2019Article
- Costello syndrome: Clinical phenotype, genotype, and management guidelines.American journal of medical genetics. Part A · 2019Article
- Inverse Molecular Docking as a Novel Approach to Study Anticarcinogenic and Anti-Neuroinflammatory Effects of Curcumin.Molecules (Basel, Switzerland) · 2018Article
- A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.American journal of medical genetics. Part A · 2016Article
- Respiratory system involvement in Costello syndrome.American journal of medical genetics. Part A · 2016Article
- An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences.American journal of medical genetics. Part A · 2015Article
- PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma.BMC cancer · 2013Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
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Abstract
Costello syndrome is caused by HRAS germline mutations affecting Gly(12) or Gly(13) in >90% of cases and these are associated with a relatively homogeneous phenotype. Rarer mutations in other HRAS codons were reported in patients with an attenuated or mild phenotype. Disease-associated HRAS missense mutations result in constitutive HRAS activation and increased RAF-MEK-ERK and PI3K-AKT signal flow. Here we report on a novel heterozygous HRAS germline alteration, c.266C>G (p.S89C), in a girl presenting with severe fetal hydrops and pleural effusion, followed by a more benign postnatal course. A sibling with the same mutation and fetal polyhydramnios showed a Dandy-Walker malformation; his postnatal course was complicated by severe feeding difficulties. Their apparently asymptomatic father is heterozygous for the c.266C>G change. By functional analyses we identified reduced levels of active HRAS(S89C) and diminished MEK, ERK and AKT phosphorylation in cells overexpressing HRAS(S89C) , which represent novel consequences of disease-associated HRAS mutations. Given our patients' difficult neonatal course and presence of this change in their asymptomatic father, we hypothesize that its harmful consequences may be time limited, with the late fetal stage being most sensitive. Alternatively, the phenotype may develop only in the presence of an additional as-yet-unknown genetic modifier. While the pathogenicity of the HRAS c.266C>G change remains unproven, our data may illustrate wide functional and phenotypic variability of germline HRAS mutations.
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