GNAQ

GNAQ is the acronym for "Guanine nucleotide-binding protein G(q) subunit alpha". In humans, it is a protein encoded by the GNAQ gene of the same name. Together with GNA11 (its paralog), the protein functions as a Gq alpha subunit.

The Gq protein (Gαq, or Gq/11) is a heterotrimeric G protein subunit that activates phospholipase C (PLC). Phospholipase C in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol trisphosphate (IP3) signal transduction pathway. DAG acts as a second messenger that activates protein kinase C (PKC). IP3 is important for the phosphorylation of various proteins.

Gq proteins are a class of G proteins that activate phospholipase C (PLC) and are involved in a variety of cellular signaling pathways. The Gq protein acts by activating phospholipase C (PLC). PLC then cleaves a phospholipid. In this process, phosphatidylinositol 4,5-bisphosphate (PIP2) is cleaved into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Diacylglycerol remains bound to the membrane and IP3 is released into the cytosol as a soluble structure. IP3 then diffuses through the cytosol and binds to IP3 receptors, specifically calcium channels in the endoplasmic reticulum (ER). These channels are specific for calcium and only allow calcium to pass through. This increases the cytosolic calcium concentration, triggering a cascade of intracellular changes and activities.

The G-protein alpha and beta-gamma subunits are able to regulate various cellular effectors. Activation is terminated by a GTPase that is part of the G-alpha subunit. Guanine nucleotide-binding proteins (G-proteins) are involved in various transmembrane signaling systems as modulators or transducers. They regulate B cell selection and survival and are required to prevent B cell-dependent autoimmunity. G proteins regulate chemotaxis of BM-derived neutrophils and dendritic cells (in vitro) (By similarity).

Related pathways include aldosterone synthesis and secretion and ADP signaling through P2Y purinoceptor 1. Gene Ontology (GO) annotations associated with this gene.

Sturge-Weber (Krabbe) syndrome: Diseases associated with GNAQ include Sturge-Weber syndrome. The somatic substitutions in GNAQ encoding p.Gln209Leu and p.Arg183Gln are also found in patients with uveal melanoma (Shirley MD et al. 2013). The more common p.Gln209Leu has been shown to overactivate the mitogen-activated protein kinase (MAPK) signaling pathway (Van Raamsdonk CD et al. 2009). However, the mutaions lead to different activities on downstream signaling pathways.

Non-syndromic port wine st ains: The non-syndromic port wine stains may represent a late origin of the somatic GNAQ mutation in vascular endothelial cells, whereas the mutation in Sturge-Weber syndrome may occur earlier in development in progenitor cells that are precursors to a wider variety of cell types and tissues, leading to the syndromic phenotype (Shirley MD et al. 2013 ).

Other: Activating somatic GNAQ mutations have been identified in blue nevi and the more extensive nevi of Ota (Van Raamsdonk CD et al. 2009). When these melanocytic nevi are colocalized with port wine stains, the disorder is termed phakomatosis pigmentovascularis , which is occasionally found in association with Sturge-Weber syndrome (Al Robaee A et al (2004).

Experimental: Mutations in GNAQ were also identified in a chemical mutagenesis screen for a dark skin phenotype in laboratory mice. Two of the dark skin alleles were identified at positions corresponding to human Gαq p.Val179Met and p.Phe335Leu. These germline amino acid substitutions cause an increase in the number of neural crest cells that differentiate into melanoblasts. The abnormal early melanocyte development resulting from these mutations in neural crest cells is mediated by endothelin, a G protein-coupled receptor (Van Raamsdonk CD et al. 2004). Because endothelin also plays an important role in vasculogenesis, dysregulation of this G protein-coupled receptor as a result of the Gαq p.Arg183Gln mutation in individuals with Sturge-Weber syndrome and those with nonsyndromic port-wine stains may also lead to vascular malformations.

Choroidal melanoma: A somatic activating mutation may have oncogenic potential. This explains that somatic mutations of GNAQ in melanocytes are associated with uveal melanoma (Shirley MD et al 2013 ). The most common mutation causing Gαq p.Gln209Leu is an activating mutation that results in increased downstream signaling via the MAPK pathway. Activation of this pathway increases cell proliferation and inhibits apoptosis (Van Raamsdonk CD et al. 2009).

A few uveal melanomas have a somatic mutation in GNAQ p.Arg183Gln , although the functional consequence of this substitution is unknown (Shirley MD et al. 2013 ). The pathogenesis of uveal melanoma is likely very different from the pathogenesis of nonsyndromic port-wine stains and Sturge-Weber syndrome. Melanomas often have multiple somatic mutations (Hodis E et al 2012).

Use of amplicon sequencing and SNaPshot assays to detect a polymorphism

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