title: Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.
abstract: RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 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, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase 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.
authors.affiliation: Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Koenighofer
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.|Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.|John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: McCauley
authors.affiliation: Department of Biology, University of Miami, Miami, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dallman
authors.affiliation: Department of Biology, University of Miami, Miami, FL, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Back
authors.affiliation: Bioinformatics Institute A*STAR Singapore, Singapore.
authors.forename: I
authors.initials: I
authors.lastname: Mihalek
authors.affiliation: Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Gripp
authors.affiliation: Department of Pediatrics, Division of Pediatric Cardiology, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Sol-Church
authors.affiliation: Department of Pediatrics, Division of Pediatric Cardiology, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Rusconi
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: G-X
authors.initials: GX
authors.lastname: Shi
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Andres
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Bodamer
mesh_terms: D000293:Adolescent; D000818:Animals; D030801:Animals, Genetically Modified; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005124:Eye Abnormalities / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D035002:Lower Extremity; D008209:Lymphedema / Q000235:genetics; D020935:MAP Kinase Signaling System; D008297:Male; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D015027:Zebrafish / Q000235:genetics; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C486776:RIT1 protein, human; D018631:ras Proteins
keywords: Costello syndrome; Noonan syndrome; RASopathy; RIT1