{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:15:22Z","timestamp":1789611322023,"version":"build-2803163510"},"reference-count":76,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2012,7,20]],"date-time":"2012-07-20T00:00:00Z","timestamp":1342742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Costello syndrome is caused by <jats:italic>HRAS<\/jats:italic> germline mutations affecting Gly<jats:sup>12<\/jats:sup> or Gly<jats:sup>13<\/jats:sup> in &gt;90% of cases and these are associated with a relatively homogeneous phenotype. Rarer mutations in other <jats:italic>HRAS<\/jats:italic> codons were reported in patients with an attenuated or mild phenotype. Disease\u2010associated <jats:italic>HRAS<\/jats:italic> missense mutations result in constitutive HRAS activation and increased RAF\u2010MEK\u2010ERK and PI3K\u2010AKT signal flow. Here we report on a novel heterozygous <jats:italic>HRAS<\/jats:italic> germline alteration, c.266C&gt;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\u2013Walker malformation; his postnatal course was complicated by severe feeding difficulties. Their apparently asymptomatic father is heterozygous for the c.266C&gt;G change. By functional analyses we identified reduced levels of active HRAS<jats:sup>S89C<\/jats:sup> and diminished MEK, ERK and AKT phosphorylation in cells overexpressing HRAS<jats:sup>S89C<\/jats:sup>, which represent novel consequences of disease\u2010associated <jats:italic>HRAS<\/jats:italic> 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\u2010yet\u2010unknown genetic modifier. While the pathogenicity of the <jats:italic>HRAS<\/jats:italic> c.266C&gt;G change remains unproven, our data may illustrate wide functional and phenotypic variability of germline <jats:italic>HRAS<\/jats:italic> mutations. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.a.35449","type":"journal-article","created":{"date-parts":[[2012,7,21]],"date-time":"2012-07-21T08:37:06Z","timestamp":1342859826000},"page":"2106-2118","source":"Crossref","is-referenced-by-count":25,"title":["A novel <i>HRAS<\/i> substitution (c.266C&gt;G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development"],"prefix":"10.1002","volume":"158A","author":[{"given":"Karen W.","family":"Gripp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Bifeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah L.","family":"Stabley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Hopkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Meien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Vinette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Sol\u2010Church","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Rosenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,7,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1641"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20748"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bti770"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/348503a0"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30270"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/28548"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.3.1903"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.425"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2010.05879.x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201005"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20616"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.11.10.4822"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.81.13.4008"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1988.tb03210.x"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20005"},{"key":"e_1_2_8_17_1","unstructured":"FriedmanJM.2009.Neurofibromatosis 1. 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