GNAQ – Sturge-Weber Syndrome

Sturge-Weber syndrome (SWS) is a sporadic, congenital neurocutaneous disorder characterized by unilateral facial port-wine stain, leptomeningeal angiomatosis, glaucoma and seizures. It is caused by postzygotic, somatic activating mutations in GNAQ, leading to mosaicism in vascular endothelial cells and downstream hyperactivation of Gαq-dependent signaling pathways.

Genetic evidence supports a definitive association between GNAQ and SWS. Whole-genome sequencing and targeted assays identified a recurrent c.548G>A (p.Arg183Gln) variant in 23 of 26 unrelated SWS probands ([PMID:23656586]) and in 12 of 15 additional cases ([PMID:25374402]). Sensitive droplet digital PCR detected the same variant at low allele fractions in brain and skin of four of three NGS-negative patients, and in leukocyte or saliva DNA of 4/40 patients. A familial case with three affected relatives across four generations segregating c.548G>A further confirms pathogenicity ([PMID:28454448]).

Inheritance is somatic mosaicism with no germline transmission; however, rare familial occurrence demonstrates segmental dominant transmission in mosaic carriers. Segregation analysis identified three affected relatives with the same GNAQ variant in one pedigree ([PMID:28454448]). The variant spectrum in SWS is highly restricted, with >90% of cases harboring the single missense change c.548G>A (p.Arg183Gln).

Functional studies demonstrate that p.Arg183Gln disrupts GDP binding, destabilizes the inactive Gαq conformation, and increases ERK1/2 phosphorylation and downstream MAPK signaling in vitro ([PMID:23656586]). Computational modeling predicts loss of hydrogen bonding with GDP and constitutive activation of Gαq, with altered surface features in switch regions ([PMID:28779688]). Patient-derived brain endothelial cells enriched for the mutant allele (24–35% frequency) show enhanced proliferation, indicating an endothelial cell–autonomous mechanism ([PMID:27919468]).

No conflicting genetic or functional data have been reported. The convergence of robust case series, a recurrent activating variant, and concordant mechanistic data establishes GNAQ c.548G>A (p.Arg183Gln) as the causative lesion in SWS.

Key Take-home: Somatic GNAQ c.548G>A (p.Arg183Gln) has a definitive gene-disease association with Sturge-Weber syndrome and provides a diagnostic biomarker and potential therapeutic target.

References

• The New England journal of medicine • 2013 • Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. PMID:23656586
• Journal of human genetics • 2014 • The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome. PMID:25374402
• Oncology letters • 2017 • GNAQ mutation R183Q as a potential cause of familial Sturge-Weber syndrome: A case report. PMID:28454448
• Journal of molecular graphics & modelling • 2017 • Computational analysis for GNAQ mutations: New insights on the molecular etiology of Sturge-Weber syndrome. PMID:28779688
• Pediatric neurology • 2017 • Somatic GNAQ Mutation is Enriched in Brain Endothelial Cells in Sturge-Weber Syndrome. PMID:27919468

Evidence Based Scoring (AI generated)