Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy

RAS Proteins and Their Regulators in Human Disease

“…This model was based on biochemical analysis of MRAS in cell-based systems (Rodriguez-Viciana et al, 2006), but was confirmed by analysis of gain-of-function mutations in SHOC2 that cause Noonan syndrome (NS) (discussed below): these mutations create a myristoylation site at the amino terminus so that SHOC2 is localized in the plasma membrane constitutively, leading to hyperactivation of MAPK signaling (Cordeddu et al, 2009). More recently, PP1 mutations and MRAS mutations have been identified in NS, adding more weight to the model (Gripp et al, 2016; Higgins et al, 2017). SHOC2 was recently identified as one of five genes necessary for proliferation of RAS mutant AML relative to RAS-wild-type AML (the others were RCE1, ICMT, CRAF, and PREX1) (Wang et al, 2017), further underscoring the importance of MRAS/SHOC2/PP1c in RAS signaling.…”

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

“…The four major genes of this disorder are PTPN11 (Tartaglia et al, ), SOS1 (Roberts et al, ; Tartaglia et al, ), RAF1 (Pandit et al, ; Razzaque et al, ), and RIT1 (Aoki et al, ). Pathogenic mutations in KRAS (Schubbert et al, ), SHOC2 (Cordeddu et al, ), NRAS (Cirstea et al, ), CBL (Martinelli et al, ), RRAS (Flex et al, ), SOS2 and LZTR1 (Cordeddu et al, ; Yamamoto et al, ), PPP1CB (Gripp et al, ), and MRAS (Higgins et al, ) have rarely been reported in individuals with NS or a similar phenotype. Variants in the two genes RASA2 (MIM 601589) and A2ML1 (MIM 610627) have recently been described in few individuals with NS‐like phenotypes (Chen et al, ; Vissers et al, ), however, these findings are still awaiting confirmation.…”

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

“…4 While mutations in PTPN11 (MIM: 176876), SOS1 (MIM: 182530), RAF1 (MIM: 164760), and RIT1 (MIM: 609591) have been docu-mented to occur most frequently, [5][6][7][8][9][10][11] a smaller proportion of cases has been ascribed to mutations in other functionally related genes, including NRAS (MIM: 164790), KRAS (MIM: 190070), BRAF (MIM: 164757), MAP2K1 (MIM: 176872), SOS2 (MIM: 601247), LZTR1 (MIM: 600574), MRAS (MIM: 608435), and RASA2 (MIM: 601589). [12][13][14][15][16][17][18][19][20] Although the causal link between mutations in a subset of these genes and the disorder still remains to be confirmed, 4 the accumulated molecular evidence strongly supports the view that NS is caused by upregulated intracellular traffic through the RAS-mitogen-activated protein kinase (MAPK) signaling pathway. 21,22 Other disorders clinically related to NS (e.g., cardio-facio-cutaneous syndrome [MIM: PS151100]) are also caused by mutations in genes encoding key proteins of the RAS-MAPK signaling backbone or upstream regulators (i.e., CBL, HRAS, KRAS, NF1, SPRED1, SHOC2, BRAF, MAP2K1, and MAP2K2).…”

“…More recently, the use of wholeexome sequencing (WES) has allowed the discovery of RASopathy-associated genes encoding signal transducers or modulators that do not belong to the canonical RAS-MAPK pathway, but when functionally perturbed, are predicted to impact RAS signaling by still poorly characterized circuits. 20,[23][24][25][26][27][28][29] A remarkable finding of the molecular genetics of NS and other RASopathies is the occurrence of conserved themes in the mechanism of disease. This applies in particular to mutations affecting genes encoding the various members of the RAS superfamily of GTPases that have been implicated in these disorders, including KRAS, HRAS, NRAS, RRAS, MRAS, and CDC42.…”

“…This applies in particular to mutations affecting genes encoding the various members of the RAS superfamily of GTPases that have been implicated in these disorders, including KRAS, HRAS, NRAS, RRAS, MRAS, and CDC42. [11][12][13][14]20,[23][24][25][26]30 Missense mutations in these genes affect a small number of highly conserved amino acid residues that lead to overactivation of these proteins by decreasing/impairing their GTPase activity in response to GTPase-activating proteins (GAPs), increasing guanine nucleotide exchange factor (GEF)-independent GDP release, altering binding properties to effectors, or a combination of these mechanisms. 31 Notably, while these germline mutations may affect the same residues that are generally mutated in cancer, multiple lines of evidence indicate that RASopathy-causing changes are generally less activating than their respective cancer-associated somatic lesions.…”