The GNAQ R183Q mutation was present in the patient's choroidal vessels (21.1%) at a frequency similar to that found in brain tissue from a different patient with Sturge-Weber syndrome (25.1%).
Further, the mechanisms by which the R</span>183Q mutation alters microvascular architecture and blood flow must be uncovered to develop new treatment strategies for SWS in particular, a devastating disease for which there is no cure.
In 2013, the causative mutation underlying SWS (p.R183Q somatic activating mutation in the guanine nucleotide-binding protein alpha-q (GNAQ) gene) was identified.
Our study provides evidence that GNAQ p.R183Q mutation is enriched in endothelial cells in SWS brain lesions and thereby reveals endothelial cells as a source of aberrant Gαq signaling.
Here, we reported a case of Sturge-Weber Syndrome (SWS) manifesting cutaneous vascular malformations (hemifacial Port-wine stain), cerebral and ocular vascular abnormalities (including epilepsy and glaucoma) and harboring a c.548G>A (p.R183Q) somatic mosaic mutation in GNAQ.
These findings suggest that the recurrent somatic GNAQ mutation c.548G>A is the major determinant genetic factor for SWS and imply that other mutated candidate gene(s) may exist in SWS.
We identified a nonsynonymous single-nucleotide variant (c.548G→A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge-Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls.
We identified a nonsynonymous single-nucleotide variant (c.548G→A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge-Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls.
Our findings reveal that the molecular properties of Gα<sub>q</sub> Q209P are fundamentally different from those in other active Gα<sub>q</sub> proteins and could be leveraged as a specific vulnerability for the ∼20% of UMs bearing this mutation.
Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma.
Overall, this model offers a new tool to dissect signaling by oncogenic GNAQ and to test potential therapeutics in an in vivo setting where GNAQ(Q209L) mutations contribute to both the initiation and metastatic progression of uveal melanoma.
Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma.
Whereas Q209L accounts for approximately half of GNAQ mutations in UM, Q209P is as frequent as Q209L and also promotes oncogenesis, but has not been characterized at the molecular level.
Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma.
Overall, this model offers a new tool to dissect signaling by oncogenic GNAQ and to test potential therapeutics in an in vivo setting where GNAQ(Q209L) mutations contribute to both the initiation and metastatic progression of uveal melanoma.
Intriguingly, enforced expression of GNAQ(Q209L) progressively eliminated melanocytes from the interfollicular epidermis in adults, possibly explaining the near absence of GNAQ(Q209) mutations in human epithelial melanomas.