{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:02:36Z","timestamp":1789642956055,"version":"4.0.0"},"reference-count":12,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,6,4]],"date-time":"2015-06-04T00:00:00Z","timestamp":1433376000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","award":["NMSS\u2010RG 4680A1\/1"],"award-info":[{"award-number":["NMSS\u2010RG 4680A1\/1"]}],"id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH\u2010NS045103"],"award-info":[{"award-number":["NIH\u2010NS045103"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH\u2010NIGMS\u2010P20GM103464"],"award-info":[{"award-number":["NIH\u2010NIGMS\u2010P20GM103464"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH\u2010P20GM103446"],"award-info":[{"award-number":["NIH\u2010P20GM103446"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2016,3]]},"abstract":"RASopathies<\/jats:styled-content> are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS\u2010mitogen activated protein kinase (RAS\u2010MAPK<\/jats:styled-content>) pathway. Recently, mutations in RIT1<\/jats:styled-content><\/jats:italic> were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1<\/jats:styled-content><\/jats:italic> mutations and expand the associated phenotypic spectrum. We identified two de novo<\/jats:italic> missense variants p.Met90Ile<\/jats:styled-content> and p.Ala57Gly<\/jats:styled-content>. Both variants resulted in increased MEK\u2010ERK<\/jats:styled-content> signaling compared to wild\u2010type, underscoring gain\u2010of\u2010function as the primary functional mechanism. Introduction of p.Met90Ile<\/jats:styled-content> and p.Ala57Gly<\/jats:styled-content> into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1<\/jats:styled-content><\/jats:italic> for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1<\/jats:styled-content><\/jats:italic>, increased RAS\u2010MAPK<\/jats:styled-content>\/MEK\u2010ERK<\/jats:styled-content> signaling and the clinical phenotype. The mutant RIT1<\/jats:styled-content> protein may possess reduced GTPase<\/jats:styled-content> activity or a diminished ability to interact with cellular GTPase<\/jats:styled-content> activating proteins; however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma.<\/jats:p>","DOI":"10.1111\/cge.12608","type":"journal-article","created":{"date-parts":[[2015,5,9]],"date-time":"2015-05-09T17:32:55Z","timestamp":1431192775000},"page":"359-366","source":"Crossref","is-referenced-by-count":38,"title":["Mutations in RIT1<\/scp><\/i> cause Noonan syndrome \u2013 additional functional evidence and expanding the clinical phenotype"],"prefix":"10.1111","volume":"89","author":[{"given":"M.","family":"Koenighofer","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology Medical University of Vienna Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Y.","family":"Hung","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital Boston MA USA"},{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics Miller School of Medicine, University of Miami Miami FL USA"},{"name":"Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. L.","family":"McCauley","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics Miller School of Medicine, University of Miami Miami FL USA"},{"name":"John P. Hussman Institute for Human Genomics, Miller School of Medicine University of Miami Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Dallman","sequence":"additional","affiliation":[{"name":"Department of Biology University of Miami Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. J.","family":"Back","sequence":"additional","affiliation":[{"name":"Department of Biology University of Miami Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Mihalek","sequence":"additional","affiliation":[{"name":"Bioinformatics Institute A*STAR Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. W.","family":"Gripp","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Alfred I. duPont Hospital for Children Wilmington DE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Sol\u2010Church","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Cardiology, Miller School of Medicine University of Miami Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Rusconi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Cardiology, Miller School of Medicine University of Miami Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, College of Medicine University of Kentucky Lexington KY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u2010X.","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, College of Medicine University of Kentucky Lexington KY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. A.","family":"Andres","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, College of Medicine University of Kentucky Lexington KY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O. A.","family":"Bodamer","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital Boston MA USA"},{"name":"Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,6,4]]},"reference":[{"key":"e_1_2_7_2_1","unstructured":"YamamotoGL AguenaM GosMet al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet2015. 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