A somatic missense mutation in GNAQ causes capillary malformation

Abstract

Purpose of review: Capillary malformations, the most common type of vascular malformation, are caused by a somatic mosaic mutation in GNAQ, which encodes the Gαq subunit of heterotrimeric G-proteins. How the single amino acid change - predicted to activate Gαq - causes capillary malformations is not known but recent advances are helping to unravel the mechanisms.

Recent findings: The GNAQ R183Q mutation is present not only in endothelial cells isolated from skin and brain capillary malformations but also in brain tissue underlying the capillary malformation, raising questions about the origin of capillary malformation-causing cells. Insights from computational analyses shed light on the mechanisms of constitutive activation and new basic science shows Gαq plays roles in sensing shear stress and in regulating cerebral blood flow.

Summary: Several studies confirm the GNAQ R183Q mutation in 90% of nonsyndromic and Sturge-Weber syndrome (SWS) capillary malformations. The mutation is enriched in endothelial cells and blood vessels isolated from skin, brain, and choroidal capillary malformations, but whether the mutation resides in other cell types must be determined. Further, the mechanisms by which the R183Q 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.

Figure 1.

Leptomeningeal blood vessels, stained for endothelium with Ulex Europaeus Agglutinin I (red) and nuclei with Hoechst (blue). Left: Sturge-Weber brain. Right: normal brain, with leptomeningeal vessels in a sulcus seen on the left side of the image, adjacent to a molecular layer and dentate gyrus on the right. Scale bars: 50 μm.

Figure 2.

The human Gαq polypeptide is 359 amino acids in length. It contains three α-helical domains called switch I (SWI), switch II (SWII) and switch III (SWIII) shown as patterned boxes. The location of amino acid residues R183 in SWI and Q209 in SWII are shown. The amino-terminal domain of Gαq interacts with PLCβ3[33]; Gαq activates PLCβ3 to hydrolyze PIP2 into inositol 1, 4, 5 triphosphate (IP3) and diacylglycerol (DAG). The SWI region changes conformation upon receptor binding; the SWII region interacts with the βγ subunits of the heterotrimer G-protein; and putative G-protein coupled receptor (GPCR) binding is located in the C-terminal region.