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

Masako Yaoita, Tetsuya Niihori, Seiji Mizuno, Nobuhiko Okamoto, Shion Hayashi, Atsushi Watanabe, Masato Yokozawa, Hiroshi Suzumura, Akihiko Nakahara, Yusuke Nakano, Tatsunori Hokosaki, Ayumi Ohmori, Hirofumi Sawada, Ohsuke Migita, Aya Mima, Pablo Lapunzina, Fernando Santos-Simarro, Sixto García-Miñaúr, Tsutomu Ogata, Hiroshi KawameKenji Kurosawa, Hirofumi Ohashi, Shin ichi Inoue, Yoichi Matsubara, Shigeo Kure, Yoko Aoki

研究成果: Article査読

49 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)209-222
ページ数14
ジャーナルHuman Genetics
135
2
DOI
出版ステータスPublished - 2016 2 1

ASJC Scopus subject areas

  • 遺伝学
  • 遺伝学(臨床)

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