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

Identity

Other namesG-ALPHA-q
GAQ
HGNC (Hugo) GNAQ
LocusID (NCBI) 2776
Location 9q21.2
Location_base_pair Starts at 80331190 and ends at 80646365 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Between GNA14, CEP78.

DNA/RNA

 
  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.

Protein

 
  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).

Mutations

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.

Implicated in

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.
  
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.
  
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.
  
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.
  

External links

Nomenclature
HGNC (Hugo)GNAQ   4390
Cards
AtlasGNAQID43280ch9q21
Entrez_Gene (NCBI)GNAQ  2776  guanine nucleotide binding protein (G protein), q polypeptide
GeneCards (Weizmann)GNAQ
Ensembl (Hinxton) [Gene_View]  chr9:80331190-80646365 [Contig_View]  GNAQ [Vega]
AceView (NCBI)GNAQ
Genatlas (Paris)GNAQ
WikiGenes2776
SOURCE (Princeton)NM_002072
Genomic and cartography
GoldenPath (UCSC)GNAQ  -  9q21.2   chr9:80331190-80646365 -  9q21   [Description]    (hg19-Feb_2009)
EnsemblGNAQ - 9q21 [CytoView]
Mapping of homologs : NCBIGNAQ [Mapview]
OMIM163000   185300   600998   
Gene and transcription
Genbank (Entrez)AB073896 AF011496 AF329284 AF493896 AJ420425
RefSeq transcript (Entrez)NM_002072
RefSeq genomic (Entrez)AC_000141 NC_000009 NC_018920 NG_027904 NT_008470 NW_001839221 NW_004929366
Consensus coding sequences : CCDS (NCBI)GNAQ
Cluster EST : UnigeneHs.594695 [ NCBI ]
CGAP (NCI)Hs.594695
Alternative Splicing : Fast-db (Paris)GSHG0030897
Gene ExpressionGNAQ [ NCBI-GEO ]     GNAQ [ SEEK ]   GNAQ [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP50148 (Uniprot)
NextProtP50148  [Medical]
With graphics : InterProP50148
Splice isoforms : SwissVarP50148 (Swissvar)
Domains : Interpro (EBI)Gprotein_alpha_Q    Gprotein_alpha_su    GproteinA_insert    P-loop_NTPase   
Related proteins : CluSTrP50148
Domain families : Pfam (Sanger)G-alpha (PF00503)   
Domain families : Pfam (NCBI)pfam00503   
Domain families : Smart (EMBL)G_alpha (SM00275)  
DMDM Disease mutations2776
Blocks (Seattle)P50148
Peptide AtlasP50148
HPRD02998
IPIIPI00288947   IPI01012971   IPI00514067   
Protein Interaction databases
DIP (DOE-UCLA)P50148
IntAct (EBI)P50148
BioGRIDGNAQ
IntegromeDBGNAQ
STRING (EMBL)GNAQ
Ontologies - Pathways
QuickGOP50148
Ontology : AmiGOskeletal system development  action potential  GTPase activity  signal transducer activity  GTPase activator activity  protein binding  GTP binding  cytoplasm  lysosomal membrane  heterotrimeric G-protein complex  plasma membrane  GTP catabolic process  negative regulation of protein kinase activity  adenylate cyclase-activating G-protein coupled receptor signaling pathway  activation of phospholipase C activity  glutamate receptor signaling pathway  heart development  blood coagulation  post-embryonic development  neuron remodeling  forebrain neuron development  platelet activation  G-protein beta/gamma-subunit complex binding  type 2A serotonin receptor binding  nuclear membrane  regulation of catenin import into nucleus  maternal behavior  embryonic digit morphogenesis  positive regulation of GTPase activity  regulation of melanocyte differentiation  metal ion binding  developmental pigmentation  protein stabilization  phospholipase C-activating dopamine receptor signaling pathway  extracellular vesicular exosome  
Ontology : EGO-EBIskeletal system development  action potential  GTPase activity  signal transducer activity  GTPase activator activity  protein binding  GTP binding  cytoplasm  lysosomal membrane  heterotrimeric G-protein complex  plasma membrane  GTP catabolic process  negative regulation of protein kinase activity  adenylate cyclase-activating G-protein coupled receptor signaling pathway  activation of phospholipase C activity  glutamate receptor signaling pathway  heart development  blood coagulation  post-embryonic development  neuron remodeling  forebrain neuron development  platelet activation  G-protein beta/gamma-subunit complex binding  type 2A serotonin receptor binding  nuclear membrane  regulation of catenin import into nucleus  maternal behavior  embryonic digit morphogenesis  positive regulation of GTPase activity  regulation of melanocyte differentiation  metal ion binding  developmental pigmentation  protein stabilization  phospholipase C-activating dopamine receptor signaling pathway  extracellular vesicular exosome  
Pathways : BIOCARTAAngiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling [Genes]    Effects of calcineurin in Keratinocyte Differentiation [Genes]    Pertussis toxin-insensitive CCR5 Signaling in Macrophage [Genes]    Thrombin signaling and protease-activated receptors [Genes]    PKC-catalyzed phosphorylation of inhibitory phosphoprotein of myosin phosphatase [Genes]    Links between Pyk2 and Map Kinases [Genes]    G-Protein Signaling Through Tubby Proteins [Genes]    Activation of PKC through G protein coupled receptor [Genes]    CCR3 signaling in Eosinophils [Genes]    CXCR4 Signaling Pathway [Genes]    Signaling Pathway from G-Protein Families [Genes]    Neuropeptides VIP and PACAP inhibit the apoptosis of activated T cells [Genes]   
Pathways : KEGGRap1 signaling pathway    Calcium signaling pathway    Adrenergic signaling in cardiomyocytes    Vascular smooth muscle contraction    Gap junction    Circadian entrainment    Long-term potentiation    Retrograde endocannabinoid signaling    Glutamatergic synapse    Cholinergic synapse    Serotonergic synapse    Dopaminergic synapse    Long-term depression    Insulin secretion    GnRH signaling pathway    Estrogen signaling pathway    Melanogenesis    Thyroid hormone synthesis    Endocrine and other factor-regulated calcium reabsorption    Salivary secretion    Gastric acid secretion    Pancreatic secretion    Alzheimer's disease    Huntington's disease    Chagas disease (American trypanosomiasis)    African trypanosomiasis    Amoebiasis   
REACTOMEP50148 [protein]
REACTOME PathwaysREACT_604 Hemostasis [pathway]
REACTOME PathwaysREACT_111217 Metabolism [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseGNAQ
Wikipedia pathwaysGNAQ
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)GNAQ
SNP (GeneSNP Utah)GNAQ
SNP : HGBaseGNAQ
Genetic variants : HAPMAPGNAQ
1000_GenomesGNAQ 
Cancer Gene: CensusGNAQ 
CONAN: Copy Number AnalysisGNAQ 
Somatic Mutations in Cancer : COSMICGNAQ 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)9:80331190-80646365
Mutations and Diseases : HGMDGNAQ
OMIM163000    185300    600998   
MedgenGNAQ
GENETestsGNAQ
Disease Genetic AssociationGNAQ
Huge Navigator GNAQ [HugePedia]  GNAQ [HugeCancerGEM]
Genomic VariantsGNAQ  GNAQ [DGVbeta]
Exome VariantGNAQ
dbVarGNAQ
ClinVarGNAQ
snp3D : Map Gene to Disease2776
DGIdb (Curated mutations)GNAQ
DGIdb (Drug Gene Interaction db)GNAQ
General knowledge
Homologs : HomoloGeneGNAQ
Homology/Alignments : Family Browser (UCSC)GNAQ
Phylogenetic Trees/Animal Genes : TreeFamGNAQ
Chemical/Protein Interactions : CTD2776
Chemical/Pharm GKB GenePA174
Clinical trialGNAQ
Other databases
Probes
Litterature
PubMed190 Pubmed reference(s) in Entrez
CoreMineGNAQ
GoPubMedGNAQ
iHOPGNAQ

Bibliography

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PMID 8431862
 
Prognostic implications of monosomy 3 in uveal melanoma.
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PMID 8622452
 
Genomic analysis of blue nevi and related dermal melanocytic proliferations.
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PMID 16096412
 
Uveal melanoma: epidemiologic aspects.
Singh AD, Bergman L, Seregard S.
Ophthalmol Clin North Am. 2005 Mar;18(1):75-84, viii. (REVIEW)
PMID 15763193
 
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
 
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
 
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
 
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
 
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
 
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
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written03-2011Swapna Vemula, Klaus Griewank, Boris C Bastian
Department of Pathology, University of California, San Francisco, CA, USA (SV); Department of Pathology and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA (KG, BCB)

Citation

This paper should be referenced as such :
Vemula, S ; Griewank, K ; Bastian, BC
GNAQ (guanine nucleotide binding protein (G protein), q polypeptide)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(10):831-835.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/GNAQID43280ch9q21.html

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indexed on : Thu Dec 4 15:39:39 CET 2014

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