RRAS – Noonan syndrome

RRAS has been implicated in Noonan syndrome through rare germline gain-of-function variants. Two unrelated individuals among 504 screened were identified with heterozygous RRAS variants, including c.163G>A (p.Val55Met), presenting with facial dysmorphism (HP:0000271), cardiac defects and growth delay overlapping the Noonan spectrum in the absence of familial segregation (PMID:24705357). These variants are absent from population databases and support a limited autosomal dominant genetic contribution.

Functional assays of c.163G>A (p.Val55Met) demonstrated enhanced RRAS GTPase activity and stimulus-dependent MAPK activation in patient cells, while expression of the corresponding mutant homolog in Caenorhabditis elegans recapitulated RASopathy-linked phenotypes (PMID:24705357). This concordant in vitro and in vivo data underpin a gain-of-function mechanism in Noonan syndrome. Key Take-home: Rare activating RRAS mutations underlie an autosomal dominant Noonan syndrome phenotype via enhanced MAPK signalling, with diagnostic and therapeutic implications.

References

• Human Molecular Genetics • 2014 • Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. PMID:24705357

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