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| 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. |
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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. |
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| 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. |
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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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Entity | Blue nevi |
Note | The hotspot mutation of Q209 in Exon 5 is found in 55% of blue nevi. The R183 mutation in Exon 4 is less common and is found in 1% of blue nevi. The mutations of GNAQ or its paralog GNA11 are expected to be early events in oncogenesis. A mutation in either gene alone is often found in benign proliferations of dermal melanocytes such as blue nevi. |
Prognosis | Blue nevi are typically benign melanocytic nevi that rarely progress to melanoma (malignant blue nevus). |
Cytogenetics | Blue nevi typically lack the presence of chromosomal aberrations. 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 | Table representing the exon 5 mutation frequencies of GNAQ and GNA11 in blue nevi. |
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Entity | Uveal melanoma |
Note | The hotspot mutation of Q209 in Exon 5 is found in 45% of primary uveal melanoma and 22% of metastatic uveal melanomas. R183 mutation in Exon 4 is less common and is found in 3% of uveal melanoma. |
Prognosis | Uveal melanoma is the most common primary intraocular malignancy with a 10 year survival rate of approximately 50%. Uveal melanoma has a high propensity of metastasis to the liver. The prognosis of uveal melanoma is highly dependent on the presence of additional genetic alterations, primarily loss of chromosome 3 and trisomy 8q. |
Cytogenetics | Uveal melanoma has been shown to have frequent chromosomal aberrations like monosomy 3, trisomy 8q and recently 80% of uveal metastasis have been shown to have mutations in BAP1. Categories | Subtypes | GNA11 Ex5 | GNAQ Ex5 | Neither | Total | | | number of samples | % | number of samples | % | number of samples | % | | 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 | Table representing the exon 5 mutation frequencies of GNAQ and GNA11 in uveal melanoma. |
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Entity | Primary melanocytic neoplasms of the central nervous system |
Note | Recently GNAQ Q209 mutations have also been shown to be present in primary melanocytic neoplasms of the central nervous system, (in this study GNAQ exon 4 was not investigated). Primary melanocytic neoplasms of the central nervous system (CNS) are rather rare tumors, originating from melanocytes that are considered to be derived from the leptomeninges. The tumors represent a spectrum in terms of malignant potential. Some are classified as low-grade melanocytomas, others as intermediate malignancy and some as overtly malignant melanomas. |
Prognosis | Highly varied, depending on the grade of the tumor. |
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Entity | Other diseases |
Note | So far no activating mutations of GNAQ in other cancers have been reported. Collectively four studies to date have sequenced more than 1500 tumor samples of a collection of various major tumor types and failed to identify any mutations in other settings than the ones described above. There have been two reports indicating that promoter associated expression of GNAQ may be of importance. One of the reports indicates the presence of a dinucleotide SNP in the promoter region as a genetic risk factor for cardiac hypertrophy. The second report links promoter associated expression differences to polycystic ovary syndrome, raising the possibility that expression levels could be relevant in some settings. |
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Somatic mutation of GNAQ gene is rare in common solid cancers and leukemias. |
Eom HS, Kim MS, Hur SY, Yoo NJ, Lee SH. |
Acta Oncol. 2009;48(7):1082-4. |
PMID 19551532 |
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Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans. |
Frey UH, Lieb W, Erdmann J, Savidou D, Heusch G, Leineweber K, Jakob H, Hense HW, Lowel H, Brockmeyer NH, Schunkert H, Siffert W. |
Eur Heart J. 2008 Apr;29(7):888-97. Epub 2008 Mar 6. |
PMID 18326504 |
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Cytogenetic analysis of uveal melanoma. Consistent occurrence of monosomy 3 and trisomy 8q. |
Horsman DE, White VA. |
Cancer. 1993 Feb 1;71(3):811-9. |
PMID 8431862 |
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Cell signalling diversity of the Gqalpha family of heterotrimeric G proteins. |
Hubbard KB, Hepler JR. |
Cell Signal. 2006 Feb;18(2):135-50. Epub 2005 Sep 22. (REVIEW) |
PMID 16182515 |
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Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system. |
Kusters-Vandevelde HV, Klaasen A, Kusters B, Groenen PJ, van Engen-van Grunsven IA, van Dijk MR, Reifenberger G, Wesseling P, Blokx WA. |
Acta Neuropathol. 2009 Nov 22. [Epub ahead of print] |
PMID 19936769 |
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Mutational profile of GNAQQ209 in human tumors. |
Lamba S, Felicioni L, Buttitta F, Bleeker FE, Malatesta S, Corbo V, Scarpa A, Rodolfo M, Knowles M, Frattini M, Marchetti A, Bardelli A. |
PLoS One. 2009 Aug 31;4(8):e6833. |
PMID 19718445 |
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Genomic analysis of blue nevi and related dermal melanocytic proliferations. |
Maize JC Jr, McCalmont TH, Carlson JA, Busam KJ, Kutzner H, Bastian BC. |
Am J Surg Pathol. 2005 Sep;29(9):1214-20. |
PMID 16096412 |
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Oncogenic mutations in GNAQ occur early in uveal melanoma. |
Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, Harbour JW. |
Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5230-4. Epub 2008 Aug 21. |
PMID 18719078 |
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Prognostic implications of monosomy 3 in uveal melanoma. |
Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R. |
Lancet. 1996 May 4;347(9010):1222-5. |
PMID 8622452 |
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Uveal melanoma: epidemiologic aspects. |
Singh AD, Bergman L, Seregard S. |
Ophthalmol Clin North Am. 2005 Mar;18(1):75-84, viii. (REVIEW) |
PMID 15763193 |
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