Germline-Activating RRAS2 Mutations Cause Noonan Syndrome

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Noonan syndrome (NS) is a genetic disorder characterized by distinctive facial features, short stature, and heart defects.
• Mutations in RAS/mitogen-activating protein kinase (MAPK) pathway genes explain ~80% of NS cases, leaving ~20% genetically unexplained.
• The RRAS2 gene, a RAS subfamily member, has not been previously linked to germline disorders like NS.

Purpose of the Study:

• To investigate the genetic basis of Noonan syndrome in individuals with unexplained cases.
• To identify and characterize novel genetic variants associated with Noonan syndrome.
• To determine the functional consequences of identified RRAS2 variants in vitro and in vivo.

Main Methods:

• Identified de novo RRAS2 variants in individuals with Noonan syndrome.
• Performed in vitro functional analyses to assess variant effects on RAF1 association and MAPK pathway activation (ERK1/2, ELK1).
• Generated zebrafish models to evaluate in vivo pathogenicity of RRAS2 variants, observing craniofacial and developmental phenotypes.

Main Results:

• Four de novo RRAS2 variants were identified in three individuals with Noonan syndrome.
• Three variants (p.Gly24_Gly26dup, p.Gln72His, p.Gln72Leu) demonstrated increased RAF1 association and activated ERK1/2 and ELK1 signaling.
• Zebrafish models overexpressing pathogenic RRAS2 variants exhibited craniofacial defects and macrocephaly, consistent with NS phenotypes.

Conclusions:

• Activating mutations in RRAS2 are a novel cause of Noonan syndrome.
• These findings expand the genotypic spectrum of NS and highlight RRAS2's role in rare germline disorders.
• The study establishes RRAS2 as a significant gene in the RAS/MAPK pathway's involvement in human developmental disorders.