SWS is a rare, sporadic neurocutaneous disorder classically presenting with a facial port-wine birthmark on the upper part of the face, glaucoma and vascular eye abnormalities, and an occipital leptomeningeal angioma (which is a vascular malformation, not a tumor). SWS occurs sporadically and with equal frequency in the sexes. The genetic, environmental, and/or prenatal factors resulting in the disorder are unknown. Because of the impaired blood flow in the brain, children with Sturge-Weber syndrome often develop progressive neurologic problems including seizures, migraines, stroke-like episodes, learning difficulties or intellectual disabilities, visual field cuts and hemiparesis (weakness on one side of the body). A major focus of our laboratory work has been to identify the underlying cause(s) of SWS in order to develop novel treatment and prevention strategies.
Somatic Mutation Causing Sturge-Weber Syndrome and Port-Wine Birthmarks
Recently our lab (with collaborators Dr. Anne Comi, who directs the Hunter Nelson Sturge-Weber Clinic at Kennedy Krieger Institute, and Doug Marchuk at Duke University) discovered that Sturge-Weber syndrome and port-wine birthmarks are cause by a somatic mutation in the gene GNAQ. This somatic mosaic mutation was hypothesized in the 1980s by Happle but now has been proven to be the causative mechanism. GNAQ encodes a guanine nucleotide associated protein (q polypeptide; Gaq) that forms the a subunit of a heterotrimeric Gq protein complex essential to the intracellular signaling of a subset of G protein coupled receptors (GPCRs). The somatic mutation GNAQ p.Arg183Gln amino acid substitution, found to be the cause of port-wine stains (prevalence 1 in 300) and Sturge-Weber syndrome (prevalence approximately 1 in 20,000), results in a glutamine substitution at GaqArg183. Substitution of glutamine at this position causes constitutive activation of the downstream pathways. Confirmation of this was found in increased phosphorylated-ERK and phosphorylated-JNK in cells transfected with mutated constructs, compared to wild-type. Together we published these findings recently in the NEJM. The first author, Matt Shirley identified the mutation (see his blog here). Other lab members were Joseph Baugher and Larry Frelin.
A somatic mutation model of SWS
The localized abnormalities of blood vessel development and function affecting the facial skin, eye, and brain suggest a developmental disruption occurring in the first trimester of pregnancy. The angioma found in classic Sturge-Weber syndrome has been suggested to result from the failure of the primitive cephalic venous plexus to regress and properly mature in the first trimester of development. We hypothesize that a somatic mutation in the GNAQ gene involving these embryological tissues results in SWS. We also hypothesize that a somatic mutation occurring later in pregnancy results in a port-wine birthmark rather than SWS.
A current major focus of the lab is on determining the cell type(s) affected by the somatic mutation in SWS, port-wine birthmarks and in other capillary malformation related disorders. With our collaborators, we are also currently working on developing in vitro models for drug screening and are engaged in developing novel and specific treatment strategies for SWS and port-wine birthmarks based upon the knowledge of the underlying pathway affected by the somatic mutation.
Reference: Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, M.D., North PE, Marchuk DA, Comi AM, Pevsner J. A GNAQ Somatic Mutation Causes Sturge-Weber Syndrome and Port-wine Stains. New England J Medicine. PMID: 23656586