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).