Abstract
Sturge–Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK signalling. In this study of six Norwegian patients with classical SWS, we aimed to identify somatic mutations through deep sequencing of DNA from skin biopsies. Surprisingly, one patient was negative for the GNAQ mutation, but instead harbored a somatic mutation in GNB2 (NM_005273.3:c.232A>G, p.Lys78Glu), which encodes a beta chain of the same G-protein complex. The positions of the mutant amino acids in the G-protein are essential for complex reassembly. Therefore, failure of reassembly and continuous signalling is a likely consequence of both mutations. Ectopic expression of mutant proteins in endothelial cells revealed that expression of either mutant reduced cellular proliferation, yet regulated MAPK signalling differently, suggesting that dysregulated MAPK signalling cannot fully explain the SWS phenotype. Instead, both mutants reduced synthesis of Yes-associated protein (YAP), a transcriptional co-activator of the Hippo signalling pathway, suggesting a key role for this pathway in the vascular pathogenesis of SWS. The discovery of the GNB2 mutation sheds novel light on the pathogenesis of SWS and suggests that future research on targets of treatment should be directed towards the YAP, rather than the MAPK, signalling pathway.
Highlights
Sturge–Weber syndrome [Mendelian Inheritance in Man (MIM): 185300] is a rare neurocutaneous disorder of dilated postcapillary venules in the eye, skin and the leptomeninges of the brain
Samples from affected and unaffected dermis, available cell cultures of endothelial cells, keratinocytes and fibroblasts, as well as laser capture microdissected material and a mutation positive control sample were subject to targeted amplicon sequencing covering the GNAQ:c.548G>A variant
As the identified mutation GNB2 K78E is associated with a classical Sturge–Weber syndrome phenotype similar to the one caused by GNAQ R183Q [2], and as there is a well-characterized interaction of these G-protein subunits in G-protein-coupled receptor (GPCR)-dependent intracellular signalling, it appears likely that the two mutations cause Sturge–Weber syndrome through the same downstream pathways
Summary
Sturge–Weber syndrome [Mendelian Inheritance in Man (MIM): 185300] is a rare neurocutaneous disorder of dilated postcapillary venules in the eye, skin and the leptomeninges of the brain. Due to its well-circumscribed borders, absence of systemic symptoms and a generally unilateral location, it has been believed to be caused by a somatic mutation [1] This hypothesis was confirmed in 2013 by Shirley et al [2], who found a single somatic missense mutation in the GNAQ gene (MIM: 600998) in 23 out of 26 patients with Sturge–Weber syndrome and in 12 out of 13 patients with port-wine birthmarks. A longstanding hypothesis has been that Sturge–Weber syndrome results from aberrant early vascular development, due to a somatic mutation originating in a subset of angioblasts [9] Support for this assumption was found in a study by Couto et al who sequenced DNA from purified dermal endothelial cells from patients with sporadic capillary malformations and revealed that 10 out of 13 samples harboured the c.548G>A mutation in GNAQ [3]. Other studies have later corroborated this finding in brain endothelial cells [6]
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