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|Title:||Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome|
|Citation:||American Journal of Human Genetics, 2013; 93(1):173-180|
|Publisher:||Univ Chicago Press|
|Yoko Aok ... Christopher Barnett ... et al.|
|Abstract:||RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.|
|Keywords:||Muscle Spindles; NIH 3T3 Cells; Embryo, Nonmammalian; Animals; Zebrafish; Humans; Mice; Noonan Syndrome; Cardiomyopathy, Hypertrophic; ras Proteins; RNA, Messenger; Incidence; MAP Kinase Signaling System; Germ-Line Mutation; Mutation, Missense; Child, Preschool; Infant; Female; Male; ets-Domain Protein Elk-1; Transcriptional Activation; Mutation Rate; Genetic Carrier Screening|
|Rights:||© 2013 by The American Society of Human Genetics. All rights reserved.|
|Appears in Collections:||Paediatrics publications|
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