Four RASopathies of the study population
| RASopathy | Estimated prevalence | Gene | Protein type | Protein function |
|---|---|---|---|---|
| Neurofibromatosis type 1 | 1/3000 | NF1 | GTPase-activating protein (GAP) | Inhibits Ras activity |
| Noonan syndrome | 1/2500 | PTPN11 | Protein tyrosine phosphatase | In its active form, increases downstream Ras activity |
| SOS1 | Guanine-nucleotide-exchange factor (GEF) | Modulates Ras activity by controlling the transition between GDP-bound (inactive) and GTP-bound (active) states of Ras proteins | ||
| KRAS NRAS* | GTPases | Activates Raf by recruiting to the cell membrane | ||
| RAF1/CRAF BRAF | Kinases | Activates MEK1 and/or MEK2 | ||
| MEK1† MEK2† | Kinases | Activates ERK1 and/or ERK2 | ||
| CBL* | E3 ubiquitin ligase | Inhibits Ras activity by targeting phosphorylated substrates for proteasome degradation | ||
| SHOC2* | Scaffolding protein | Promotes Ras-Raf association to positively enhance downstream activation | ||
| Costello syndrome | Unknown‡ | HRAS | GTPase | Activates Raf by recruiting to the cell membrane |
| Cardio-facio-cutaneous syndrome | Unknown‡ | KRAS | GTPase | Activates Raf by recruiting to the cell membrane |
| BRAF | Kinase | Activates MEK1 and/or MEK2 | ||
| MEK1 MEK2 | Kinases | Activates ERK1 and/or ERK2 |
For each of the four RASopathies included, the estimated prevalence and the names and functions of genes and proteins implicated in each syndrome.73 ,74
*Recently identified mutations.75–77
†Rarely associated with NS.78
‡Prevalence estimated to be hundreds worldwide.