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DURHAM, N.C. – A non-inherited genetic mutation that arises during fetal development has been shown to be the cause of port-wine stains, one of the most common birth defects, as well as a related, but rare disorder called Sturge-Weber Syndrome (SWS).
 
In a study published May 8, 2013, in the New England Journal of Medicine, Duke Medicine scientists, in collaboration with researchers at Kennedy Krieger Institute, Johns Hopkins School of Medicine, and the Medical College of Wisconsin, have identified a variant of the gene GNAQ as the mutation that causes the defects.
 
Sturge-Weber Syndrome occurs in approximately 1 in 20,000-50,000 live births, and is characterized by seizures, developmental delays and glaucoma, among other health problems. Researchers believe that the earlier the mutation in GNAQ happens during fetal development, the more likely it will lead to the more severe SWS outcome.
 
The findings confirms a hypothesis posited by German dermatologist Rudolf Happle in 1987, who observed that the conditions did not appear to be inherited, suggesting they resulted from a somatic mutation – a mutation that happens during development.
 
“What was really exciting was that Happle was right,” said co-senior author Douglas Marchuk, Ph.D., professor and vice chair of the Department of Molecular Genetics and Microbiology at Duke. “If he was right, people with Sturge-Weber and people with port-wine stains would have a mutation in the same gene, because they’re really the same thing, with the difference being when the mutation happens during development. Sure enough, we found the same mutation in both affected tissues, and not only was it the same gene, it was exactly the same mutation.”
 
The researchers performed whole genome sequencing on both affected and non-affected tissue samples from individuals with SWS and port-wine stains, and from normal subjects. Advanced sequencing technology and bioinformatics were critical to identifying the gene, the mutation, and the protein involved in the disease process, which is called G-alpha(q) (Gαq). The Gαq protein is a highly studied compound associated with G-protein-coupled receptors, the family of signaling receptors involved in a wide variety of physiological processes. The receptors are the subject of research that led to Duke’s Robert Lefkowitz winning the 2012 Nobel Prize in Chemistry.
 
Marchuk said the association may bode well for development of new therapies for SWS and port-wine stains. “Gαq is an important protein in a lot of processes, so people are already studying drugs that might inhibit the receptor,” he said.
 
Although the research team has not yet isolated which specific cell type is involved, they suspect the mutation occurs in endothelial cells in the blood vessels in the region of the eye and nearby brain. Now that the gene and the mutation have been identified, the next step will be to develop an animal model to characterize the tissue and cell types.
 
Marchuk and his colleagues worked closely with the patient advocacy group Sturge-Weber Foundation. Karen Bell, Sturge-Weber Foundation president and CEO, said identifying the gene and mutation is a major milestone toward eradicating the condition.
 
“I think the first emotional wave is to just be dumbstruck – and then the ‘wow’ moment will come and they’ll be giddy,” she said. “Then I hope individuals affected by Sturge-Weber will be even more united to drive home therapies that can help their loved ones. It’s an opportunity to educate the public and the members, and to have a rallying point for more significant change, personally and medically.”
 
The study was funded by Hunter’s Dream for a Cure Foundation and the Brain Vascular Malformation Consortium (U54NS065705). The Brain Vascular Malformation Consortium is part of the National Institutes of Health Rare Disease Clinical Research Network, supported through the NIH Office of Rare Diseases Research at the National Center for Advancing Translational Science and the National Institute of Neurological Disorders and Stroke.
 
In addition to Marchuk, study authors at Duke include Hao Tang and Carol Gallione; along with Jonathan Pevsner, Anne Comi, Matthew D. Shirley, Joseph D. Baugher and Laurence Frelin of Kennedy Krieger Institute; Bernard Cohen of the Johns Hopkins; and Paula E. North of the Medical College of Wisconsin.
 
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