Gain-of-function mutations in RIT1 cause noonan syndrome, a RAS/MAPK pathway syndrome

Yoko Aoki, Tetsuya Niihori, Toshihiro Banjo, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Tsutomu Ogata, Fumio Takada, Michihiro Yano, Toru Ando, Tadataka Hoshika, Christopher Barnett, Hirofumi Ohashi, Hiroshi Kawame, Tomonobu Hasegawa, Takahiro Okutani, Tatsuo Nagashima, Satoshi Hasegawa, Ryo Funayama, Takeshi NagashimaKeiko Nakayama, Shin Ichi Inoue, Yusuke Watanabe, Toshihiko Ogura, Yoichi Matsubara

Research output: Contribution to journalArticle

152 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)173-180
Number of pages8
JournalAmerican Journal of Human Genetics
Volume93
Issue number1
DOIs
Publication statusPublished - 2013 Jul 11

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Noonan Syndrome
Mitogen-Activated Protein Kinases
Mutation
Embryonic Structures
Sebaceous of Jadassohn Nevus
Craniofacial Abnormalities
NIH 3T3 Cells
Yolk Sac
Inborn Genetic Diseases
Mosaicism
Congenital Heart Defects
Germ-Line Mutation
Nevus
GTP Phosphohydrolases
Hypertrophic Cardiomyopathy
Zebrafish
Missense Mutation
Luciferases
Transcriptional Activation
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Aoki, Y., Niihori, T., Banjo, T., Okamoto, N., Mizuno, S., Kurosawa, K., ... Matsubara, Y. (2013). Gain-of-function mutations in RIT1 cause noonan syndrome, a RAS/MAPK pathway syndrome. American Journal of Human Genetics, 93(1), 173-180. https://doi.org/10.1016/j.ajhg.2013.05.021

Gain-of-function mutations in RIT1 cause noonan syndrome, a RAS/MAPK pathway syndrome. / Aoki, Yoko; Niihori, Tetsuya; Banjo, Toshihiro; Okamoto, Nobuhiko; Mizuno, Seiji; Kurosawa, Kenji; Ogata, Tsutomu; Takada, Fumio; Yano, Michihiro; Ando, Toru; Hoshika, Tadataka; Barnett, Christopher; Ohashi, Hirofumi; Kawame, Hiroshi; Hasegawa, Tomonobu; Okutani, Takahiro; Nagashima, Tatsuo; Hasegawa, Satoshi; Funayama, Ryo; Nagashima, Takeshi; Nakayama, Keiko; Inoue, Shin Ichi; Watanabe, Yusuke; Ogura, Toshihiko; Matsubara, Yoichi.

In: American Journal of Human Genetics, Vol. 93, No. 1, 11.07.2013, p. 173-180.

Research output: Contribution to journalArticle

Aoki, Y, Niihori, T, Banjo, T, Okamoto, N, Mizuno, S, Kurosawa, K, Ogata, T, Takada, F, Yano, M, Ando, T, Hoshika, T, Barnett, C, Ohashi, H, Kawame, H, Hasegawa, T, Okutani, T, Nagashima, T, Hasegawa, S, Funayama, R, Nagashima, T, Nakayama, K, Inoue, SI, Watanabe, Y, Ogura, T & Matsubara, Y 2013, 'Gain-of-function mutations in RIT1 cause noonan syndrome, a RAS/MAPK pathway syndrome', American Journal of Human Genetics, vol. 93, no. 1, pp. 173-180. https://doi.org/10.1016/j.ajhg.2013.05.021
Aoki, Yoko ; Niihori, Tetsuya ; Banjo, Toshihiro ; Okamoto, Nobuhiko ; Mizuno, Seiji ; Kurosawa, Kenji ; Ogata, Tsutomu ; Takada, Fumio ; Yano, Michihiro ; Ando, Toru ; Hoshika, Tadataka ; Barnett, Christopher ; Ohashi, Hirofumi ; Kawame, Hiroshi ; Hasegawa, Tomonobu ; Okutani, Takahiro ; Nagashima, Tatsuo ; Hasegawa, Satoshi ; Funayama, Ryo ; Nagashima, Takeshi ; Nakayama, Keiko ; Inoue, Shin Ichi ; Watanabe, Yusuke ; Ogura, Toshihiko ; Matsubara, Yoichi. / Gain-of-function mutations in RIT1 cause noonan syndrome, a RAS/MAPK pathway syndrome. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 1. pp. 173-180.
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AU - Okamoto, Nobuhiko

AU - Mizuno, Seiji

AU - Kurosawa, Kenji

AU - Ogata, Tsutomu

AU - Takada, Fumio

AU - Yano, Michihiro

AU - Ando, Toru

AU - Hoshika, Tadataka

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