Germline-Activating RRAS2 Mutations Cause Noonan Syndrome

Am J Hum Genet. 2019 Jun 6;104(6):1233-1240. doi: 10.1016/j.ajhg.2019.04.014.

Tetsuya Niihori ¹, Koki Nagai ², Atsushi Fujita ³, Hirofumi Ohashi ⁴, Nobuhiko Okamoto ⁵, Satoshi Okada ⁶, Atsuko Harada ⁷, Hirotaka Kihara ⁸, Thomas Arbogast ⁹, Ryo Funayama ¹⁰, Matsuyuki Shirota ¹¹, Keiko Nakayama ¹⁰, Taiki Abe ², Shin-Ichi Inoue ², I-Chun Tsai ⁹, Naomichi Matsumoto ³, Erica E Davis ⁹, Nicholas Katsanis ¹², Yoko Aoki ²

Affiliations

1 Department of Medical Genetics, Tohoku University School of Medicine, Sendai 980-8574, Japan; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA. Electronic address: tniihori@med.tohoku.ac.jp.
2 Department of Medical Genetics, Tohoku University School of Medicine, Sendai 980-8574, Japan.
3 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
4 Division of Medical Genetics, Saitama Children's Medical Center, Saitama 330-8777, Japan.
5 Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka 594-1101, Japan.
6 Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima 734-8551, Japan.
7 Department of Pediatric Neurosurgery, Takatsuki General Hospital, Osaka 569-1192, Japan.
8 Department of Pediatrics, Onomichi General Hospital, Hiroshima 722-8508, Japan.
9 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
10 Department of Cell Proliferation, United Center for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
11 Division of Interdisciplinary Medical Sciences, United Center for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
12 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA. Electronic address: katsanis@cellbio.duke.edu.

PMID: 31130285 DOI: 10.1016/j.ajhg.2019.04.014

Abstract

Noonan syndrome (NS) is characterized by distinctive craniofacial appearance, short stature, and congenital heart disease. Approximately 80% of individuals with NS harbor mutations in genes whose products are involved in the Ras/mitogen-activating protein kinase (MAPK) pathway. However, the underlying genetic causes in nearly 20% of individuals with NS phenotype remain unexplained. Here, we report four de novo RRAS2 variants in three individuals with NS. RRAS2 is a member of the Ras subfamily and is ubiquitously expressed. Three variants, c.70_78dup (p.Gly24_Gly26dup), c.216A>T (p.Gln72His), and c.215A>T (p.Gln72Leu), have been found in cancers; our functional analyses showed that these three changes induced elevated association of RAF1 and that they activated ERK1/2 and ELK1. Notably, prominent activation of ERK1/2 and ELK1 by p.Gln72Leu associates with the severe phenotype of the individual harboring this change. To examine variant pathogenicity in vivo, we generated zebrafish models. Larvae overexpressing c.70_78dup (p.Gly24_Gly26dup) or c.216A>T (p.Gln72His) variants, but not wild-type RRAS2 RNAs, showed craniofacial defects and macrocephaly. The same dose injection of mRNA encoding c.215A>T (p.Gln72Leu) caused severe developmental impairments and low dose overexpression of this variant induced craniofacial defects. In contrast, the RRAS2 c.224T>G (p.Phe75Cys) change, located on the same allele with p.Gln72His in an individual with NS, resulted in no aberrant in vitro or in vivo phenotypes by itself. Together, our findings suggest that activating RRAS2 mutations can cause NS and expand the involvement of RRAS2 proto-oncogene to rare germline disorders.

Keywords

Noonan syndrome; RAS/MAPK; RASopathies; RRAS2; exome sequencing; functional profiling; macrocephaly; zebrafish.

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