NDLI: Spectrum of mutations and genotype–phenotype analysis in Noonan syndrome patients with RIT1 mutations

Content Provider	Springer Nature Link
Author	Yaoita, Masako Niihori, Tetsuya Mizu, Seiji Okamoto, buhiko Hayashi, Shion Watanabe, Atsushi Yokozawa, Masato Suzumura, Hiroshi Nakahara, Akihiko Naka, Yusuke Hokosaki, Tatsuri Ohmori, Ayumi Sawada, Hirofumi Migita, Ohsuke Mima, Aya Lapunzina, Pablo Santos Simarro, Fernando García Miñaúr, Sixto Ogata, Tsutomu Kawame, Hiroshi Kurosawa, Kenji Ohashi, Hirofumi Iue, Shin ichi Matsubara, Yoichi Kure, Shigeo Aoki, Yoko
Copyright Year	2015
Abstract	RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype–phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.
Starting Page	209
Ending Page	222
Page Count	14
File Format	PDF
ISSN	03406717
Journal	Human Genetics
Volume Number	135
Issue Number	2
e-ISSN	14321203
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2015-12-29
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Human Genetics Molecular Medicine Gene Function Metabolic Diseases
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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