Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

Abstract

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

SHP2 mutations induce precocious gliogenesis of Noonan syndrome-derived iPSCs during neural development in vitro

“…NS is caused by mutations of genes which encode a variety of signaling molecules related to the RAS-MAPK pathway, including PTPN11 [5], SOS1 [6,7], RAF1 [8,9], and RIT1 [10,11]. Recently, it has been rarely detected in mutations of KRAS [12,13], NRAS [14], LZTR1 [15], MRAS [16,17], and RRAS2 [18,19]. Among the various mutations, the PTPN11 mutations which encodes Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) are most frequently occurring in NS patients [5,20,21].…”

Germline-Activating RRAS2 Mutations Cause Noonan Syndrome

“…In summary, we identified four de novo RRAS2 variants in three individuals with NS, three of which are likely drivers of pathology through the hyperactivation of the RAS/ MAPK pathway. Together with an accompanying study showing RRAS2 mutations in individuals with NS or NS-like phenotype, 32 these findings broaden our understanding of roles of RRAS2 in human development, expanding the mutational landscape of NS and related disorders. Our work also highlights how, given the rarity of the remaining genes for this group of disorders, the combination of genetic, in vitro, and in vivo studies might be necessary to establish the identity of causal loci.…”

Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy

“…This mirrors work in a preclinical PTPN11 D61Y mouse model, which showed similar activation of pathways outside of RAS including PI3K/AKT/mTOR and JAK/STAT signaling ( Altmüller et al., 2017 ). More recently, work on a rare RASopathy variant in the RRAS2 gene reported dysregulation of the Hippo pathway ( Nussinov et al., 2018 ; Capri et al., 2019 ). Future studies can dissect whether other RASopathy variants can regulate other non-RAS/MAPK pathway networks.…”