ZFIN ID: ZDB-PUB-190528-21
Germline-Activating RRAS2 Mutations Cause Noonan Syndrome
Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., Shirota, M., Nakayama, K., Abe, T., Inoue, S.I., Tsai, I.C., Matsumoto, N., Davis, E.E., Katsanis, N., Aoki, Y.
Date: 2019
Source: American journal of human genetics   104(6): 1233-1240 (Other)
Registered Authors: Davis, Erica, Katsanis, Nicholas, Tsai, I-Chun
Keywords: Noonan syndrome, RAS/MAPK, RASopathies, RRAS2, exome sequencing, functional profiling, macrocephaly, zebrafish
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Child
  • Child, Preschool
  • Exome
  • Female
  • Gain of Function Mutation*
  • Germ-Line Mutation*
  • Humans
  • Male
  • Membrane Proteins/chemistry
  • Membrane Proteins/genetics*
  • Membrane Proteins/metabolism
  • Monomeric GTP-Binding Proteins/chemistry
  • Monomeric GTP-Binding Proteins/genetics*
  • Monomeric GTP-Binding Proteins/metabolism
  • Noonan Syndrome/etiology*
  • Noonan Syndrome/pathology
  • Phenotype
  • Protein Conformation
  • Sequence Homology
  • Zebrafish/genetics
  • Zebrafish/growth & development*
  • Zebrafish/metabolism
PubMed: 31130285 Full text @ Am. J. Hum. Genet.
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.
ADDITIONAL INFORMATION No data available