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A novel somatic mutation in GNAQ in a capillary malformation provides insight into molecular pathogenesis. Angiogenesis 2022 Nov;25(4):493-502



Pubmed ID


Pubmed Central ID




Scopus ID

2-s2.0-85131102273 (requires institutional sign-in at Scopus site)   6 Citations


Sturge-Weber syndrome (SWS) is a sporadic, congenital, neuro-cutaneous disorder characterized by a mosaic, capillary malformation. SWS and non-syndromic capillary malformations are both caused by a somatic activating mutation in GNAQ encoding the G protein subunit alpha-q protein. The missense mutation R183Q is the sole GNAQ mutation identified thus far in 90% of SWS-associated or isolated capillary malformations. In this study, we sequenced skin biopsies of capillary malformations from 9 patients. We identified the R183Q mutation in nearly all samples, but one sample exhibited a Q209R mutation. This new mutation occurs at the same residue as the constitutively-activating Q209L mutation, commonly seen in tumors. However, Q209R is a rare variant in this gene. To compare the effect of the Q209R mutation on downstream signaling, we performed reporter assays with a GNAQ-responsive reporter co-transfected with either GNAQ WT, R183Q, Q209L, Q209R, or C9X (representing a null allele). Q209L showed the highest reporter activation, with R183Q and Q209R showing significantly lower activation. To determine whether these mutations had similar or different downstream consequences we performed RNA-seq analysis in microvascular endothelial cells (HMEC-1) electroporated with the same GNAQ variants. The R183 and Q209 missense variants caused extensive dysregulation of a broad range of transcripts compared to the WT or null allele, confirming that these are all activating mutations. However, the missense variants exhibited very few differentially expressed genes (DEGs) when compared to each other. These data suggest that these activating GNAQ mutations differ in magnitude of activation but have similar downstream effects.

Author List

Galeffi F, Snellings DA, Wetzel-Strong SE, Kastelic N, Bullock J, Gallione CJ, North PE, Marchuk DA


Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Endothelial Cells
GTP-Binding Protein alpha Subunits, Gq-G11
Protein Subunits
Sturge-Weber Syndrome
Vascular Malformations