GNAQ (guanine nucleotide binding protein (G protein), q polypeptide)

	Diagram of GNAQ gene. The transcribed exons are represented in purple, the 5' and 3' untranslated region is represented in yellow. The exon numbers are indicated on the top and the number of base pairs per exon is indicated at the bottom. Introns are represented by black bars along with the number of base pairs. The arrows represent the start and stop codons.
Description	The GNAQ gene is composed of 7 exons spanning a region of 310993 nucleotides.
Transcription	Transcript length is 6539 bp. Length of ORF is 1080 bp.
Pseudogene	GNAQP in 2q14.3-q21.

	Schematic diagram of functional domains of GNAQ protein. The blue boxes represent the exons with exon numbers and the amino acid numbers on the top. The inner boxes represent the different domains: Helical domain (Green), Switch regions (Orange) (SR1: 182-192, SR2: 204-224, SR3: 236-247) are involved in conformational change based on the binding of GDP or GTP, GTPase domain (Pink) is essential for hydrolysis of GTP to GDP. N and C represent the amino and carboxy terminals of the protein respectively. The two arrows (R183, Q209) represent the hotspot mutations. Adapted from Mizuno and Itoh, 2009.
Description	Amino acid residues: 359. Molecular weight: 42141 daltons. GNAQ is a proto oncogene which encodes for alpha subunit of 'q' class of heterotrimeric GTP binding protein.
Expression	GNAQ is ubiquitously expressed in all tissues.
Localisation	Cytoplasm. Signaling occurs at the membrane.
Function	GNAQ mediates signal between the G protein coupled receptor (GPCR) and downstream effectors. Receptor activation by ligand binding causes the activation of GNAQ by catalyzing the release of GDP and binding of GTP. In its active form GTP-bound GNAQ causes the release of the beta and gamma subunits of the heterotrimeric G-protein. GTP-GNAQ and beta and gamma subunits transfer the receptor-mediated signal to downstream effectors through secondary messengers which participate in diverse signaling pathways to evoke different effectors. The known effectors for GNAQ include PLC beta, p63-RhoGEF, Trio, and Duet (Maize et al., 2005; Eom et al., 2009). GNAQ has been shown to activate the MAP kinase pathway, possibly via DAG-mediated activation of protein kinase C isoforms. GNAQ has an intrinsic GTPase domain at the C terminus which causes the hydrolysis of GTP to GDP and the G-alpha-GDP re-associates with G-beta and G-gamma subunits.
Homology	GNAQ is one of the four members belonging to the Gq-alpha family. Compared to GNAQ the other three members G11alpha, G14alpha, G16 alpha have 90%, 80%, and 57% amino acid sequence homology, respectively (Eom et al., 2009).

Note	Somatic mutations of GNAQ affect codons 183 and 209 resulting in R183Q, Q209L, Q209P, Q209R, and Q209Y.
	Schematic representation of GNAQ mutations in melanocytic neoplasms. The purple boxes represent the exons with the exon numbers indicated within the boxes, amino acid numbers indicated on top. The arrows represent the two hotspot mutations along with the amino acid change. N and C represent the amino and carboxy terminal of GNAQ protein.
Germinal	No germinal mutations have been described.
Somatic	Somatic mutations in GNAQ have been described in melanocytic neoplasia (Hubbard et al., 2006; Onken et al., 2008; Küsters-Vandevelde et al., 2009). In Uveal Melanoma, 97% of the hotspot mutations cause the amino acid substitution Q209L, the other 3% of mutations cause amino acid change to R183Q. The Glutamine 209 of GNAQ is similar to residue 61 of RAS protein. The Q209 and R183 mutations cause complete or partial loss of intrinsic GTPase activity respectively thereby locking the protein in a constitutively active form. Q209 and R183 mutations occur in a mutually exclusive pattern in human neoplasia. Mutations in GNAQ are also mutually exclusive from the hotspot mutations in GNA11, which belongs to the same family and shares 90% sequence homology. GNAQ mutations are not concomitant with other common oncogenic mutations in BRAF, NRAS or KIT found in melanocytic neoplasia. Categories Subtypes GNA11 Ex5 GNAQ Ex5 Neither Total     number of samples % number of samples % number of samples %   Blue nevi Amelanotic blue nevus 0 0.0% 7 70.0% 3 30.0% 10 Cellular blue nevus 3 8.3% 26 72.2% 7 19.4% 36 Common blue nevus 4 6.7% 39 65.0% 17 28.3% 60 Nevus of Ito 0 0.0% 0 0.0% 7 100.0% 7 Nevus of Ota 1 5.0% 2 10.0% 17 85.0% 20 Malignant blue nevus 1 16.7% 2 33.3% 3 50.0% 6 Total 9 6.5% 76 54.7% 54 38.8% 139 Ocular melanocytic tumors Conjunctival melanoma 0 0.0% 0 0.0% 9 100.0% 9 Uveal melanoma, primary 52 31.9% 73 44.8% 38 23.3% 163 Uveal melanoma, metastasis 13 56.5% 5 21.7% 5 21.7% 23 Uveal nevus 0 0.0% 1 100.0% 0 0.0% 1 Total 65 33.2% 79 40.3% 52 26.5% 196 Other nevi Common nevus 0 0.0% 0 0.0% 22 100.0% 22 Congenital nevus 0 0.0% 0 0.0% 17 100.0% 17 Deep penetrating nevus 0 0.0% 0 0.0% 27 100.0% 27 Spitz nevus 0 0.0% 0 0.0% 19 100.0% 19 Atypical Spitz tumor 0 0.0% 0 0.0% 20 100.0% 20 Total 0 0.0% 0 0.0% 105 100.0% 105 Extra-ocular melanomas Acral 0 0.0% 0 0.0% 47 100.0% 47 CSD 0 0.0% 1 1.4% 73 98.6% 74 Mucosal 0 0.0% 0 0.0% 62 100.0% 62 NonCSD 0 0.0% 0 0.0% 90 100.0% 90 Total 0 0.0% 1 0.4% 272 99.6% 273 Grand Total 713 Table representing the exon 5 mutation frequencies of GNAQ and GNA11 in melanocytic neoplams.

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