Alternative titles; symbols
HGNC Approved Gene Symbol: GNAQ
Cytogenetic location: 9q21.2 Genomic coordinates (GRCh38): 9:77,716,097-78,031,811 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.2 | Capillary malformations, congenital, 1, somatic, mosaic | 163000 | 3 | |
| Sturge-Weber syndrome, somatic, mosaic | 185300 | 3 |
Guanine nucleotide-binding proteins are a family of heterotrimeric proteins that couple cell surface, 7-transmembrane domain receptors to intracellular signaling pathways. Receptor activation catalyzes the exchange of GTP for GDP bound to the inactive G protein alpha subunit resulting in a conformational change and dissociation of the complex. The G protein alpha and beta-gamma subunits are capable of regulating various cellular effectors. Activation is terminated by a GTPase intrinsic to the G-alpha subunit. G-alpha-q is the alpha subunit of one of the heterotrimeric GTP-binding proteins that mediates stimulation of phospholipase C-beta (600230) (summary by Dong et al., 1995).
Dong et al. (1995) isolated and characterized cDNA clones from a frontal cortex cDNA library encoding human G-alpha-q. The encoded protein is 359 amino acids long and is identical in all but 1 amino acid residue to the mouse protein. Analysis of human genomic DNA revealed an intronless sequence with strong homology to human GNAQ cDNA. In comparison to GNAQ cDNA, this genomic DNA sequence included several small deletions and insertions that altered the reading frame, multiple single based changes, and a premature termination codon in the open reading frame, all hallmarks of a processed pseudogene. Probes derived from human GNAQ cDNA sequence mapped both chromosomes 2 and 9 in higher constringency genomic blot analyses of DNA from a panel of human/rodent hybrid cell lines. PCR primers that selectively amplified the pseudogene sequence generated a product only when DNA containing human chromosome 2 was used as the template, indicating that the authentic GNAQ gene is located on chromosome 9.
Crystal Structure
G protein-coupled receptor kinase-2 (GRK2; 109635) plays a key role in the desensitization of G protein-coupled receptor signaling by phosphorylating activated heptahelical receptors and by sequestering heterotrimeric G proteins. Tesmer et al. (2005) reported the atomic structure of GRK2 in complex with G-alpha-q and G-beta-gamma (see 139380, 606981), in which the activated G-alpha subunit of Gq is fully dissociated from G-beta-gamma and dramatically reoriented from its position in the inactive G-alpha-beta-gamma heterotrimer. G-alpha-q forms an effector-like interaction with the GRK2 regulator of G protein signaling (RGS) homology domain that is distinct from and does not overlap with that used to bind RGS proteins.
Lutz et al. (2007) determined the crystal structure of the G-alpha-q-p63RhoGEF (610215)-RhoA (165390) complex, detailing the interactions of G-alpha-q with the Dbl and pleckstrin homology (DH and PH) domains of p63RhoGEF. These interactions involved the effector-binding site and the C-terminal region of G-alpha-q and appeared to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio (601893), Duet (604605), and p63RhoGEF were shown to constitute a family of G-alpha-q effectors that appear to activate RhoA both in vitro and in intact cells. Lutz et al. (2007) proposed that this structure represents the crux of an ancient signal transduction pathway that is expected to be important in an array of physiologic processes.
Waldo et al. (2010) described how heterotrimeric guanine nucleotide-binding proteins (G proteins) activate PLC-betas and in turn are deactivated by these downstream effectors. The 2.7-angstrom structure of PLC-beta-3 (600230) bound to activated G-alpha-q revealed a conserved module found within PLC-betas and other effectors optimized for rapid engagement of activated G proteins. The active site of PLC-beta-3 in the complex is occluded by an intramolecular plug that is likely removed upon G protein-dependent anchoring and orientation of the lipase at membrane surfaces. A second domain of PLC-beta-3 subsequently accelerates guanosine triphosphate hydrolysis by G-alpha-q, causing the complex to dissociate and terminate signal propagation. Mutations within this domain dramatically delay signal termination in vitro and in vivo. Waldo et al. (2010) concluded that their work suggested a dynamic catch-and-release mechanism used to sharpen spatiotemporal signals mediated by diverse sensory inputs.
By fluorescence in situ hybridization, Dong et al. (1995) mapped the GNAQ gene to 9q21 and a pseudogene at 2q14.3-q21.
G proteins play a major role in signal transduction upon platelet activation. Rao et al. (1984) reported a patient with diminished platelet aggregation and secretion in response to multiple agonists despite presence of normal dense granule stores. The patient was a 46-year-old white female with mild lifelong mucocutaneous bleeding diathesis associated with prolonged bleeding times and normal platelet counts. The patient's daughter and father may also have had a history of easy bruising. Further studies showed that receptor-mediated release of arachidonic acid from phospholipids and calcium mobilization were impaired upon platelet activation. They postulated that these abnormal responses might be due to a defect in signal transduction mechanisms. To delineate the platelet defect in this patient, Gabbeta et al. (1997) investigated receptor-stimulated G protein function and reported an abnormality in G-alpha subunit function associated with a decrease in immunoreactive G-alpha-q in platelets. To their knowledge, this was the first description of a human platelet G protein defect.
By study of cultured neonatal rat cardiac myocytes, Adams et al. (1998) demonstrated that overexpression of wildtype GNAQ resulted in hypertropic growth. Strikingly, expression of a constitutively activated mutant of GNAQ, which further increased Gq signaling, produced initial hypertrophy, which rapidly progressed to apoptotic cardiomyocyte death. This paradigm was recapitulated during pregnancy in GNAQ overexpressing mice and in transgenic mice expressing high levels of wildtype GNAQ. The consequence of cardiomyocyte apoptosis was a transition from compensated hypertrophy to a rapidly progressive and lethal cardiomyopathy. Progression from hypertrophy to apoptosis in vitro and in vivo was coincident with activation of p38 (600289) and JUN (165160) kinases. These data suggest a mechanism in which moderate levels of Gq signaling stimulate cardiac hypertrophy, whereas high level Gq activation results in cardiomyocyte apoptosis. The identification of a single biochemical stimulus regulating cardiomyocyte growth and death suggested a plausible mechanism for the progression of compensated hypertrophy to decompensated heart failure.
Santagata et al. (2001) demonstrated that tubby (601197) functions in signal transduction from heterotrimeric G protein-coupled receptors. Receptor-mediated activation of G-alpha-q releases tubby from the plasma membrane through the action of phospholipase C-beta (see 607120), triggering translocation of tubby to the cell nucleus. The localization of tubby-like protein-3 (TULP3; 604730) is similarly regulated. Santagata et al. (2001) concluded that tubby proteins function as membrane-bound transcription regulators that translocate to the nucleus in response to phosphoinositide hydrolysis, providing a direct link between G protein signaling and the regulation of gene expression.
Using mice lacking G-alpha subunits specifically in smooth muscle cells, Wirth et al. (2008) found that G-alpha-q and G-alpha-11 (GNA11; 139313) were required for maintenance of basal blood pressure and for development of salt-induced hypertension. In contrast, lack of G-alpha-12 (GNA12; 604394) and G-alpha-13 (GNA13; 604406) and their effector, Larg (ARHGEF12; 604763), did not alter normal blood pressure regulation, but blocked development of salt-induced hypertension.
Wang et al. (2019) found that Gnaq expression was downregulated in virus-infected mouse cells. Knockdown of Gnaq reduced viral infection in vitro, whereas overexpression promoted it, indicating that Gnaq played a negative role in host defense against viral infection. Gnaq-knockout mice were more resistant to viral infection with increased postinfection survival compared with wildtype. Further analysis demonstrated that Gnaq regulated antiviral innate immune responses through the Plc-beta/Ca(2+) signaling pathway and negatively regulated production of Ifn I by dephosphorylating Tbk1 (604834).
Somatic Mutations
Van Raamsdonk et al. (2009) reported frequent somatic mutations in the heterotrimeric G protein alpha-subunit in blue nevi (603670) (83%) and ocular melanoma of the uvea (46%) (see 155720). The mutations occurred exclusively in codon 209 in the Ras-like domain and resulted in constitutive activation, turning GNAQ into a dominant-acting oncogene. Van Raamsdonk et al. (2009) concluded that their results demonstrated an alternative route to MAP kinase activation in melanocytic neoplasia, providing new opportunities for therapeutic intervention.
Van Raamsdonk et al. (2010) identified somatic mutations affecting residue Q209 of the GNAQ gene in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Somatic mutations affecting the same residue in the paralog gene GNA11 (139313) were found in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. The sample group included a total of 713 melanocytic neoplasms. Sequencing of exon 4 of these genes, affecting residue R183, in 453 melanocytic neoplasms showed a lower prevalence of mutations: 2.1% of blue nevi and 4.9% of primary uveal melanomas. The mutations were mutually exclusive, except for a single tumor that carried mutations at both Q209 and R183 in GNA11. In total, 83% of all uveal melanomas examined had oncogenic mutations in either GNAQ or GNA11. Although GNA11 mutations appeared to have a more potent effect on melanocytes than did GNAQ mutations, there was no difference in patient survival among those with GNA11 mutations compared to those with GNAQ mutations.
Populo et al. (2011) identified the GNAQ Q209 mutation in 36% of 22 enucleated uveal melanomas. No associations were found between the presence of the GNAQ mutation and prognostic parameters, the expression of ERK1/2 (MAPK3, 601795/MAPK1, 176948), phosphorylated ERK1/2, and cell cycle markers. Populo et al. (2011) suggested that GNAQ-mutated uveal melanomas do not exhibit a higher deregulation of proliferation or higher activation of the MAP kinase signaling pathway than uveal melanomas without GNAQ activation.
Shirley et al. (2013) performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 patients with Sturge-Weber syndrome (SWS; 185300) and identified 1 nonsynonymous somatic single-nucleotide variant in the GNAQ gene (R183Q; 600998.0001) that was present in all 3 affected samples and was not present in the normal-appearing samples. Screening of additional SWS patients as well as individuals with nonsyndromic port-wine stains (PWSs; CMC, 163000) revealed the presence of the R183Q mutation in either port-wine-stained skin or brain tissue from 23 (88%) of 26 SWS patients as well as in affected skin from 12 (92%) of 13 patients with nonsyndromic port-wine stains. Shirley et al. (2013) noted that the GNAQ somatic substitution R183Q, as well as a more common Q209L substitution, had previously been found in patients with uveal melanoma (Van Raamsdonk et al., 2010); functional analysis demonstrated that R183Q has a gain-of-function effect that activates downstream pathways, although to a lesser degree than the Q209L mutation.
Using tissue from a patient with sporadic nonsyndromic port-wine stain, Lian et al. (2014) screened 275 cancer genes previously implicated in tumorigenesis and detected the GNAQ R183Q mutation at an allelic fraction of 0.05 in PWS tissue; the mutation was not found in paired normal tissue. In addition, several novel somatic variants were identified in other genes, including SMARCA4 (603254), EPHA3 (179611), MYB (189990), PDGFRB (173410), and PIK3CA (171834), which were all present at an allelic fraction of less than 0.10.
Using RNA-seq followed by filtering, Ayturk et al. (2016) analyzed congenital hemangioma samples from 8 individuals and identified GNAQ as the only gene with variants in 3 or more samples that were not found in controls. Reanalysis of the samples showed that 6 of the 8 had a somatic GNAQ mutation, all involving the glutamine at amino acid 209: Q209L in 4, Q309P in 1, and Q209H in 1; the remaining 2 samples had a GNA11 (139313) mutation at the same residue, Q209L. The mutations were confirmed in 6 samples by digital droplet PCR (ddPCR) and/or molecular inversion probe sequencing (MIP-seq), and the somatic nature of the variants was verified by ddPCR testing of saliva or blood from 4 participants. Using a combination of ddPCR and MIP-seq, the authors also tested 8 archival formalin-fixed, paraffin-embedded congenital hemangioma samples and 4 chorangioma samples, and found a likely GNAQ (Q209L and Q209P) or GNA11 (Q209L) mutation in 4 of the congenital hemangioma samples. Ayturk et al. (2016) noted that the same GNAQ or GNA11 mutation (Q209L) occurred in both rapidly involuting congenital hemangioma (RICH) samples and in noninvoluting congenital hemangioma (NICH) samples, suggesting that other genetic, epigenetic, and/or environmental factors likely account for the these tumors' different postnatal behaviors.
Exclusion Studies
Oyesiku et al. (1997) screened 37 pituitary adenomas (see 102200) for activating mutations of the G-alpha-q gene. G-alpha-q specific primers were used to generate cDNA by RT-PCR. Fragments of G-alpha-q cDNA-encompassing residues (arg183, gln209) were screened by SSCP and then sequenced in both directions. No mutations were detected, and Oyesiku et al. (1997) concluded that mutations in these regions of the G-alpha-q cDNA occur infrequently, if at all, in human pituitary adenomas.
Offermanns et al. (1997) generated Gnaq-deficient mice, which suffered from ataxia with typical signs of motor discoordination. They observed that about 40% of adult Purkinje cells in the Gnaq-deficient mice remained multiply innervated by climbing fibers because of a defect in regression of supernumerary climbing fibers in the third postnatal week. Offermanns et al. (1997) hypothesized that GNAQ is part of a signaling pathway involved in the elimination of multiple climbing fiber innervation during this period.
Offermanns et al. (1997) observed that platelets from Gnaq-deficient mice were unresponsive to a variety of physiologic platelet activators. As a result, Gnaq-deficient mice had increased bleeding times and were protected from collagen and adrenaline-induced thromboembolism. Offermanns et al. (1997) concluded that GNAQ is essential for the signaling processes used by different platelet activators.
Offermanns et al. (1998) bred Gnaq-deficient mice with Gna11 (139313)-deficient mice and observed gene dosage effects between Gnaq and Gna11. Embryos completely lacking both genes died in utero with heart malformations. Mice inheriting a single copy of either gene died within hours of birth with craniofacial and/or cardiac defects. Offermanns et al. (1998) concluded that at least 2 active alleles of these genes are required for extrauterine life. Genetic, morphologic, and pharmacologic analyses of intercross offspring inheriting different combinations of these 2 mutations indicated that Gnaq and Gna11 have overlapping functions in embryonic cardiomyocyte proliferation and craniofacial development.
A new class of dominant 'dark skin' (Dsk) mutations was discovered in a screen of approximately 30,000 mice in a large-scale mutagenesis study. These result from increased dermal melanin. Van Raamsdonk et al. (2004) identified 3 of 4 such mutations as hypermorphic alleles of Gnaq and Gna11, which encode widely expressed G-alpha-q subunits, act in an additive and quantitative manner, and require endothelin receptor, type B (EDNRB; 131244). Interaction between Gq and Kit receptor tyrosine kinase (164920) signaling can mediate coordinate or independent control of skin and hair color. The results provided a mechanism that can explain several aspects of human pigmentary variation and show how polymorphism of essential proteins and signaling pathways can affect a single physiologic system.
Fan et al. (2005) found that transgenic mice selectively expressing an inducible form of G-alpha-q in cardiac myocytes were born at the expected mendelian ratio and bred normally. Following activation of G-alpha-q at 8 weeks of age, transgenic mice developed peripheral edema, heart enlargement, and increased extracellular space in cardiac myocytes compared with controls. Quantitative PCR analysis showed that heart failure was associated with increased mRNA expression of Bnp (NPPB; 600295) and beta-Mhc (MYH7; 160760) and decreased expression of alpha-Mhc (MYH6; 160710). Heart failure was also associated with decreased myocyte contractility, likely due to abnormal Ca(2+) handling in cardiac myocytes.
In a follow-up to Fan et al. (2005), Jiang et al. (2006) found that heart failure in transgenic mice selectively expressing inducible G-alpha-q in cardiac myocytes was reversed when G-alpha-q expression was turned off. The reversion occurred not only at the morphologic and histologic levels, but also at the molecular level, as altered Bnp and alpha- and beta-Mhc expression and abnormal Ca(2+) handling were reversed.
Wettschureck et al. (2006) found that mice with forebrain-specific deletion of G-alpha-q and G-alpha-11 had spontaneous epileptic seizures starting at age 3 months, with increased frequency as they aged. Histologic and immunohistochemical analyses revealed neuronal degeneration and reactive gliosis in the hippocampal CA1 region of knockout mice. Pharmacologic and electrophysiologic analyses indicated that endocannabinoid-mediated protective mechanisms were intact in knockout mice, but endogenous cannabinoid synthesis was impaired, resulting in increased seizure susceptibility and impaired neuroprotection.
Kero et al. (2007) generated mice with thyrocyte-specific Gna11/Gnaq deficiency and observed severely reduced iodine organification and thyroid hormone secretion in response to TSH, with many of the mice developing hypothyroidism within months after birth. In addition, these mice lacked the normal proliferative thyroid response to TSH or goitrogenic diet. Kero et al. (2007) concluded that the GNA11/GNAQ pathway has an essential role in the adaptive growth of the thyroid gland.
Li et al. (2019) found that mice with natural killer (NK) cell-specific deletion of Gnaq were born at the expected mendelian ratio with no alterations in organ morphology or overt pathology. Gnaq deficiency led to enhanced NK cell survival, as purified splenic NK cells from knockout mice exhibited a significant survival advantage over wildtype NK cells.
Shirley et al. (2013) performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 patients with Sturge-Weber syndrome (SWS; 185300) and identified 1 nonsynonymous somatic single-nucleotide variant, a c.548G-A transition in the GNAQ gene, resulting in an arg183-to-gln (R183Q) substitution at a highly conserved residue, that was present in all 3 affected samples and was not present in the normal-appearing samples. Screening of additional SWS patients as well as individuals with nonsyndromic port-wine stains (163000) revealed that all 9 SWS patients were positive for the R183Q mutation in port-wine-stained skin, 6 (86%) of 7 participants with SWS were negative for the mutation in visibly normal skin, and 12 (92%) of 13 participants with nonsyndromic port-wine stains were positive for the mutation. The mutation was also detected in brain samples from 15 (83%) of 18 SWS patients, whereas all 6 brain samples from normal controls were negative. Transfection studies in HEK 293T cells showed significant activation of ERK (600997) by the R183Q mutant compared to control. Overall, 23 (88%) of 26 SWS patients were positive for the gain-of-function R183Q mutation in either port wine-stained skin or brain tissue. Shirley et al. (2013) suggested that nonsyndromic port-wine stains may represent a late origin of the somatic GNAQ mutation in vascular endothelial cells, whereas in Sturge-Weber syndrome, the mutation may occur earlier in development, in progenitor cells that are precursors to a larger variety of cell types and tissues, leading to the syndromic phenotype. Five (0.7%) of 669 samples from the 1000 Genomes Project database were positive for R183Q; noting that the reported prevalence of port-wine stains is 0.3% to 0.5%, Shirley et al. (2013) hypothesized that the 0.7% prevalence in that database represented the occurrence of port-wine stains in the population.
In tissue from a patient with a sporadic long-standing unilateral facial port-wine stain, Lian et al. (2014) detected the GNAQ R183Q mutation at an allelic fraction of 0.05 in PWS tissue; the mutation was not found in paired normal tissue. The percentage of GNAQ mutation was consistent with the percentage of lesional endothelial cells in the specimen.
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