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

2011-03-01   Swapna Vemula , Klaus Griewank , Boris C Bastian 

Department of Pathology, University of California, San Francisco, CA, USA (SV); Department of Pathology, Human Oncology, Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA (KG, BCB)

Identity

HGNC
LOCATION
9q21.2
LOCUSID
ALIAS
CMC1,G-ALPHA-q,GAQ,SWS
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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.
Atlas Image
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 name
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
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 name
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
Total 65 33.2% 79 40.3% 52 26.5% 196
Uveal nevus 0 0.0% 1 100.0% 0 0.0% 1
Table representing the exon 5 mutation frequencies of GNAQ and GNA11 in uveal melanoma.
Entity name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
195515322009Somatic mutation of GNAQ gene is rare in common solid cancers and leukemias.Eom HS et al
183265042008Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans.Frey UH et al
84318621993Cytogenetic analysis of uveal melanoma. Consistent occurrence of monosomy 3 and trisomy 8q.Horsman DE et al
161825152006Cell signalling diversity of the Gqalpha family of heterotrimeric G proteins.Hubbard KB et al
199367692010Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system.Küsters-Vandevelde HV et al
197184452009Mutational profile of GNAQQ209 in human tumors.Lamba S et al
160964122005Genomic analysis of blue nevi and related dermal melanocytic proliferations.Maize JC Jr et al
187190782008Oncogenic mutations in GNAQ occur early in uveal melanoma.Onken MD et al
86224521996Prognostic implications of monosomy 3 in uveal melanoma.Prescher G et al
157631932005Uveal melanoma: epidemiologic aspects.Singh AD et al

Other Information

Locus ID:

NCBI: 2776
MIM: 600998
HGNC: 4390
Ensembl: ENSG00000156052

Variants:

dbSNP: 2776
ClinVar: 2776
TCGA: ENSG00000156052
COSMIC: GNAQ

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000156052ENST00000286548P50148
ENSG00000156052ENST00000286548A0A024R240
ENSG00000156052ENST00000411677B1AM21

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Calcium signaling pathwayKEGGko04020
Gap junctionKEGGko04540
Long-term potentiationKEGGko04720
Long-term depressionKEGGko04730
GnRH signaling pathwayKEGGko04912
MelanogenesisKEGGko04916
Alzheimer's diseaseKEGGko05010
Huntington's diseaseKEGGko05016
Calcium signaling pathwayKEGGhsa04020
Gap junctionKEGGhsa04540
Long-term potentiationKEGGhsa04720
Long-term depressionKEGGhsa04730
GnRH signaling pathwayKEGGhsa04912
MelanogenesisKEGGhsa04916
Alzheimer's diseaseKEGGhsa05010
Huntington's diseaseKEGGhsa05016
Pathways in cancerKEGGhsa05200
Vascular smooth muscle contractionKEGGhsa04270
Vascular smooth muscle contractionKEGGko04270
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
Salivary secretionKEGGko04970
Salivary secretionKEGGhsa04970
Gastric acid secretionKEGGko04971
Gastric acid secretionKEGGhsa04971
AmoebiasisKEGGko05146
AmoebiasisKEGGhsa05146
Pancreatic secretionKEGGko04972
Pancreatic secretionKEGGhsa04972
African trypanosomiasisKEGGko05143
African trypanosomiasisKEGGhsa05143
Endocrine and other factor-regulated calcium reabsorptionKEGGko04961
Endocrine and other factor-regulated calcium reabsorptionKEGGhsa04961
Glutamatergic synapseKEGGko04724
Glutamatergic synapseKEGGhsa04724
Cholinergic synapseKEGGhsa04725
Dopaminergic synapseKEGGko04728
Dopaminergic synapseKEGGhsa04728
Serotonergic synapseKEGGhsa04726
Retrograde endocannabinoid signalingKEGGhsa04723
Retrograde endocannabinoid signalingKEGGko04723
Circadian entrainmentKEGGhsa04713
Circadian entrainmentKEGGko04713
Insulin secretionKEGGhsa04911
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
Thyroid hormone synthesisKEGGhsa04918
Thyroid hormone synthesisKEGGko04918
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Adrenergic signaling in cardiomyocytesKEGGhsa04261
Adrenergic signaling in cardiomyocytesKEGGko04261
Inflammatory mediator regulation of TRP channelsKEGGhsa04750
Inflammatory mediator regulation of TRP channelsKEGGko04750
Platelet activationKEGGhsa04611
Oxytocin signaling pathwayKEGGhsa04921
Oxytocin signaling pathwayKEGGko04921
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
Sphingolipid signaling pathwayKEGGhsa04071
Glucagon signaling pathwayKEGGhsa04922
Sphingolipid signaling pathwayKEGGko04071
Glucagon signaling pathwayKEGGko04922
Renin secretionKEGGhsa04924
Renin secretionKEGGko04924
HemostasisREACTOMER-HSA-109582
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Signal amplificationREACTOMER-HSA-392518
ADP signalling through P2Y purinoceptor 1REACTOMER-HSA-418592
Thromboxane signalling through TP receptorREACTOMER-HSA-428930
Thrombin signalling through proteinase activated receptors (PARs)REACTOMER-HSA-456926
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (q) signalling eventsREACTOMER-HSA-416476
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
MetabolismREACTOMER-HSA-1430728
Integration of energy metabolismREACTOMER-HSA-163685
Regulation of insulin secretionREACTOMER-HSA-422356
Acetylcholine regulates insulin secretionREACTOMER-HSA-399997
Free fatty acids regulate insulin secretionREACTOMER-HSA-400451
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretionREACTOMER-HSA-434316
Aldosterone synthesis and secretionKEGGhsa04925
Aldosterone synthesis and secretionKEGGko04925
Apelin signaling pathwayKEGGhsa04371

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA193HTR2AGenePathwayassociated19741567
PA194HTR2CGenePathwayassociated19741567
PA27946F2RGenePathwayassociated20938371
PA27949F2RL3GenePathwayassociated20938371
PA32868P2RY1GenePathwayassociated20938371
PA33384PLCB1GenePathwayassociated19741567, 20938371
PA33385PLCB2GenePathwayassociated19741567
PA33386PLCB3GenePathwayassociated19741567
PA33387PLCB4GenePathwayassociated19741567
PA33393PLCG2GenePathwayassociated20938371
PA348TBXA2RGenePathwayassociated20938371

References

Pubmed IDYearTitleCitations
190789572009Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.417
210833802010Mutations in GNA11 in uveal melanoma.396
210833802010Mutations in GNA11 in uveal melanoma.396
248825152014Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry.158
187190782008Oncogenic mutations in GNAQ occur early in uveal melanoma.108
180968062007Structure of Galphaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs.95
156111062005beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation.80
171974452007Galphaq-TRPC6-mediated Ca2+ entry induces RhoA activation and resultant endothelial cell shape change in response to thrombin.77
176066142007Galphaq directly activates p63RhoGEF and Trio via a conserved extension of the Dbl homology-associated pleckstrin homology domain.59
241417862014Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations.50

Citation

Swapna Vemula ; Klaus Griewank ; Boris C Bastian

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

Atlas Genet Cytogenet Oncol Haematol. 2011-03-01

Online version: http://atlasgeneticsoncology.org/gene/43280/gnaq-(guanine-nucleotide-binding-protein-(g-protein)-q-polypeptide)