Table 2.

Functional characterization of genes associated with RASopathies

Class	Gene	Protein name	Protein function	Pathogenetic mechanism
GTPase	HRAS	HRAS: Harvey rat sarcoma viral oncogene homologue	Hydrolyzes GTP) and activates Raf by recruiting to the cell membrane	Activating mutations
	KRAS	KRAS: the V-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog	Hydrolyzes GTP and activates Raf by recruiting to the cell membrane	Activating mutations
	NRAS	NRAS: neuroblastoma Ras viral (V-Ras) oncogene homolog	Hydrolyzes GTP and activates Raf by recruiting to the cell membrane	Activating mutations
	RRAS	RRAS: Related Ras viral R-Ras) oncogene homologue	Hydrolyzes GTP and activates Raf by recruiting to the cell membrane	Activating mutations
	RIT1	RIT1; Ras-like protein in tissue	Hydrolyzes GTP and participates in Ras/MAPK and p38 signaling	Activating mutations
RasGAP	NF1	Neurofibromin	Binds activated G-proteins and stimulate their GTPase activity switching the active GTP-bound Ras to the inactive GDP-bound form	Loss of function
	RASA1	RASA1: p120-RasGTPase-activating protein	Binds activated G proteins and stimulate their GTPase activity switching the active GTP-bound Ras to the inactive GDP-bound Ras	Loss of function
	RASA2	RASA2: Ras p21 protein activator 2	Binds activated G proteins and stimulates GTPase activity switching the active GTP-bound Ras to the inactive GDP-bound Ras	Loss of function
	SYNGAP1	SynGAP: Synaptic Ras GAP	Neuron-specific RasGAP that binds activated G proteins and stimulates GTPase activity switching the active GTP-bound Ras to the inactive GDP-bound Ras	Loss of function
RasGEF	SOS1	SOS1: Son of sevenless homologue 1	RasGEF that stimulates the conversion of Ras from the inactive GDP-bound form to the GTP-bound active form	Activating mutations
	SOS2	SOS2: Son of sevenless homologue 2	Ras-GEF that stimulates the conversion of Ras from the inactive GDP-bound form to the GTP-bound active form	Activating mutations
Scaffolding	SHOC2	SHOC2: Homologue of suppressor of clear (SOC-2) in Caenorhabditis elegans	Binds GTP-Ras and mediates protein phosphatase 1 translocation to the cell membrane.	Activating mutation
Ubiquitin Ligase	CBL	CBL: casitas B-lineage lymphoma	E3 ubiquitin ligase that inhibits Ras activity by targeting phosphorylated substrates for proteasome degradation	Loss of function
Phosphatase	PTPN11	SHP2: Tyrosine-protein phosphatase non-receptor type 11; Src Homology 2	Non-receptor protein tyrosine phosphatase that in its active form, increases downstream Ras activity	Activating mutations
Kinase	BRAF	BRAF: v-Raf murine sarcoma viral oncogene homolog B	Serine/threonine protein kinase that activates MEK1 and/or MEK2 by phosphorylation	Activating mutations
	RAF1	CRAF: v-Raf-1 murine leukemia viral oncogene homolog 1	Serine/threonine protein kinase that activates MEK1 and/or MEK2 by phosphorylation	Activating mutations
	MAP2K1	MEK1: Mitogen-activated protein kinase kinase 1	Threonine/tyrosine kinase that activates ERK1 and/or ERK2 by phosphorylation	Activating mutations
	MAP2K2	MEK2: Mitogen-activated protein kinase kinase 2	Threonine/tyrosine kinase that activates ERK1 and/or ERK2 by phosphorylation	Activating mutations
	MAP3K8	MAP3K8: Mitogen-activated protein kinase kinase kinase 8	Serine/threonine protein kinase which can activate both the Ras/MAPK and JNK pathways.	Activating mutation
SproutyRelatedprotein	SPRED1	SPRED1: Sprouty-related EVH1 domain containing 1	Negative regulator of Ras by inhibiting phosphorylation of Raf. Also, SPRED1 binds to the RasGAP, NF1, inducing the membrane localization of NF1 which in turn inhibits Ras	Loss of function
	SPRY1	SPRY1/Sprouty1	Negative regulator of Ras/MAPK pathway signaling	Loss of function
Acetyltransferase	MYST4	MYST4: Histone Acetyltransferase (Monocytic Leukemia-4)	Epigenetic modification of DNA by transferring an acetyl group from acetyl-CoA to histone proteins.	Loss of function
Adaptor protein	LZTR1	LZTR1: Leucine-zipper-like transcriptional regulator 1	Unknown	Unknown
Protease inhibitor	A2ML1	A2ML1: Alpha-2-macroglobulin-like 1	Protease inhibitor that binds lipoprotein receptor-related protein 1, which is an upstream activator of the Ras/MAPK pathway	Unknown