We Are Not Alone

In the last topic we saw GNAQ as a protein that sits inside a cell. There was a complicated picture showing dozens of proteins that are all parts of various pathways. The main points were that

·      GNAQ is normally either “off” or “on”;

·      In Sturge-Weber syndrome it stays slightly on all the time;

·      That in turn could disturb pathways inside of cells;

·      Perhaps a strategy to treat Sturge-Weber syndrome could include fixing those pathways, rather than directly fixing Gaq.

Sturge-Weber syndrome before and after GNAQ

Sturge-Weber Syndrome was first described in the late 1800s, and named in the early 1900s. If we look at old books on Sturge-Weber syndrome we can see that they describe features that may occur such as port-wine birthmarks, calcification of the brain, seizures, and glaucoma.

In 2013 we reported the mutation in GNAQ that causes SWS. Knowing the cause means that we can search for treatments (and hopefully even a cure some day) based on trying to fix what’s not working right.

There’s another benefit to knowing that mutations in GNAQ cause SWS. It’s that we’re now “connected” with dozens of other diseases. I’d like to explain that connection and why that’s a good thing.

Genes and Disease

There are about 20,000 genes that make proteins. And there are thought to be over 5,000 single gene disorders, referring to diseases that occur primarily because one single gene is not working correctly. The first time a gene was linked to a disease was in 1949 when mutations in hemoglobin were shown to cause sickle cell disease. This finding makes sense: hemoglobin carries oxygen in red blood cells, and in the disease red blood cells don’t work properly.

We now know that lots of diseases are “complex” and involve multiple genes. Examples are bipolar disorder and schizophrenia.

We know that some single gene disorders also make sense. A gene may have a function of making an enzyme, and a child is born with a defective gene so the enzyme doesn’t work. That results in a pathway that doesn’t work properly. An example is phenylketonuria (PKU), a condition that all newborns in the U.S. are screened for. If a child has PKU then the body can’t handle a particular amino acid, and by keeping that amino acid out of the diet that child can be fine.

Some single gene disorders make no sense (yet). The function of the gene is completely unknown to us. There’s no known connection to other diseases, or to the functions of a cell or an organ.

How does GNAQ fit into this picture? I’d like to suggest five ways.


[1] GNAQ connects to cancer

Sturge-Weber syndrome and port-wine birthmarks are caused primarily by an R183Q mutation in the GNAQ gene. The same mutation in the same gene is a cause of melanoma of the eye (uveal melanoma). Uveal melanoma involves a different cell type (melanocytes instead of endothelial cells) and a different time of life. So it matters when and where the mutation occurs. But we can see what the uveal melanoma community is doing to make progress and see if that applies to us. One scientist, Silvio Gutkind at UCSC, discovered that GNAQ is an oncogene (a type of cancer gene) and his lab has now turned to do research on SWS.

[2] GNAQ connects to GPCRs

Cells have receptors on their surface to let materials in and to instruct the cell how to respond to whatever is happening on the outside. The human genome has about 20,000 genes that make proteins, and some of these proteins are related to each other in protein “families.” The largest family in the human genome is G protein coupled receptors (GPCRs). Our GNAQ connects to several different GPCRs (one is called the endothelin receptor). We immediately tap into a wealth of knowledge. Several researchers recently shared a Nobel Prize for figuring out details of how GPCRs work. That helps us as we try to figure out the role of GPCRs in SWS.

[3] GNAQ connects to G proteins

GNAQ is a gene that encodes (makes) a protein called GNAQ. GNAQ is a G protein that sits inside a cell and sends signals. There are 24 G protein genes in the human genome, some involved in disease. We understand how G proteins work at the atomic level, meaning that we can “see” how the protein works and we can see what the mutation does to GNAQ as it turns it on inappropriately.

[4] GNAQ connects to famous signaling pathways

When GNAQ is turned on, either under normal conditions or too actively in SWS, it tells other proteins in a cascade to jump into action. These other proteins are parts of pathways that might typically have a dozen members. If you’d like to see lists of proteins and/or pictures of some of these pathways visit these sites:



            Many labs have tried to discover drugs that can modulate these pathways, and we hope that could lead us to new treatments for SWS someday.

[5] GNAQ connects to childhood brain diseases

Many other genes make proteins that when mutated cause cancer and/or childhood diseases. Here are a couple other proteins.

·      mTOR is an oncogene. Mutations can also cause a condition called focal cortical dysplasia.

·      AKT1. (Look to the left of phosphoERK then up one protein.) Mutations in AKT1 cause the Proteus syndrome, a rare overgrowth syndrome. Bones, skins, and other body parts can grow too much. It’s well known as an oncogene: it is mutated in various cancers including breast cancer, colorectal cancer, and ovarian cancer. 

·      PIK3CA is also an oncogene. Mutations can cause a variety of cancers (breast, colorectal, gastric, other) and megalencephaly-capillary malformation-polymicrogyria syndrome.


Conclusions: We’re in this together

Those of us who care about SWS, port-wine birthmarks and related conditions are not alone. Our mission is to improve diagnosis and treatment, and hopefully to find a cure.

            We’re all in this together. As scientists we’re all closely following each other’s progress to make an impact on SWS as soon as possible.