GNAQ gene

The GNAQ gene (GNAQ stands for "G Protein Subunit Alpha Q") is a protein-coding gene located on chromosome 9q21.2. This locus encodes a guanine nucleotide-binding protein (GNAQ protein). The encoded protein, an alpha subunit of the Gq class, couples a receptor with seven transmembrane domains to the activation of phospolipase C-beta.

Mutations at this locus have been associated with problems in platelet activation and aggregation.

Diseases associated with GNAQ include:

• Sturge-Weber-Krabbe syndrome
• nevus flammeus
• uveal melanoma (Van Raamsdonk CD et al. 2009)
• other capillary malformations (Galeffi F et al. (2022).

Related signaling pathways include thromboxane signaling through the TP receptor and activation of ERK by developmental angiotensin. An important paralog of this gene is GNA11.

Guanine nucleotide-binding proteins (G proteins) act as modulators or transducers in various transmembrane signaling systems. They are essential for platelet activation. Furthermore, they regulate the selection and survival of B cells and are necessary to prevent B-cell-dependent autoimmunity. Together with GNA11, they are essential for heart development.

Oncogenic driver mutations in GNAQ or GNA11 genes are found in approximately 85% of uveal melanomas. They lead to activation of the G alpha _q/11signaling pathway and its downstream effectors. Direct, targeted intervention in this dysregulated signaling pathway could therefore be a therapeutic option for patients with uveal melanoma (Gaffal E 2020).      

The diagnostic differentiation of the isolated port wine stain from the sporadically occurring Sturge-Weber syndrome (SWS) with facial nevus flammeus, intracranial and intraocular vascular malformations is prognostically significant. In Sturge-Weber syndrome, leptomeningeal angiomatosis can lead to epileptic crises as early as the first year of life, affecting psychomotor and mental development. Stroke-like episodes and glaucoma are also among the serious manifestations. Etiologically, the common port wine stain and the rare SWS are two extreme clinical manifestations of the same molecular mechanism. In malformed capillaries, a specific postzygotic point mutation in the GNAQ gene, which activates the RAS/RAF signaling pathway, is identified in the majority of cases in both clinical pictures. It is likely that non-syndromic port wine stains are caused by a late postzygotic mutation and Sturge-Weber syndrome by an early postzygotic mutation.

Remark: Mutations in RAS and other genes of the RAS/RAF signaling pathway have also been identified in sporadic vascular malformations.

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