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Medicine & Science
UTMB-led research finds genetic variant links to multiple sclerosis
by Lora-Marie Bernard
Monday, April 17, 2017

UTMB Garcia-BlancoGuidry News recently met with a University of Texas Medical Branch researcher whose team found two particular gene variants that could make a person three times more likely to develop multiple sclerosis.

Mariano Garcia-Blanco, professor and chair of biochemistry and molecular biology at UTMB, has been collaborating with scientists from UTMB, Duke University, University of California, Berkeley and Case Western Reserve University to study two DNA variants in a person’s genetic code.

He said his research began when a colleague came to him ten years ago to discuss the mutations in certain genomes. Listen  (25:59)

“(My colleague) said to me, ‘We have found a variant in this gene called the (abbreviated) IL7R and this is the first variant we found associated with multiple sclerosis,’ ” Garcia-Blanco said.

He said they began working together because he knew how the unique way the variant, IL7R, created protein.

“We know how to decode this information,” he said. ”You translate the information from the gene to proteins. But if you were actually trying to decode it by looking at...if you can imagine…a filmstrip and every frame gives you a frame of the protein. If you looked at IL7R, it would make absolutely no sense. It would be like before the editor cut it.” 

He said the “film editing” process in human bodies is different for IL7R. It has a specific way that it acts which is similar to “splicing film”.

As a result, IL7R can make one of two forms of protein.

UTMB Garcia-Blanco“One form of the receptor sits on the cells,” he said. “In the other form the receptor becomes soluble and it becomes soluble IL7R.  So this soluble IL7R is a protein.”

The soluble IL7R, or “the alternative splicing protein,” makes a piece of the receptor that can move around, he said.  He added that identifying how it operates was important to the team.

“We don’t completely understand why having too much of that soluble IL7R is bad, but it is,” he said.  “So having too much soluble IL7R floating around in the circulation predisposes you to autoimmunity.  We have very strong suspicions that it is not only multiple sclerosis but several other autoimmune disorders.”

With that information, Garcia-Blanco said he and the research team were able to publish information in 2007 that showed an association between the IL7R variant and multiple sclerosis.

‘It was significant enough that we believed there was a true association with the disease,” he said. “Then we became fascinated with the splicing effects on IL7R and thought that, if we study, we may understand more. We went into a deep analysis of how you manipulate the splicing.”

Splicing studies led researchers to find a second variant, he said.

“We wanted to know the genetic “editors” but we also wanted to know what were the “editors”, or proteins, that actually were involved in deciding whether to make more of this soluble IL7R.”

The researchers tested 150 proteins to find specific ones that were linked with the variant.

“The one that was the master – because it had the biggest effect – was one named DDX39B,” he said. “Now, it has a weird name because it is a part of a long family of proteins.”

After they identified the protein, they began trying to find a connection with the variants.

“The prediction was that if you had high levels of it in your T-cells…and had low levels of this protein, I would expect it to make more of the soluble IL7R,” he said.

“That is because the protein DDX39B represses the ability to perform the variant splicing that creates soluble IL7R.  We could - by manipulating the level artificially - show that that was exactly what was the case,” he said.

He and the team then had two independent analyses done to test their case.  Both came back with the same result as Garcia-Blanco and his team. 

“At that point we knew we were onto something fantastic,” he said. “We now know that this protein is not only functionally important, but it must be important to the cause and to the association with the disease.”

Garcia-Blanco concluded by saying that the findings are important to the scientific community, but also to the public, because they could eventually help identify persons vulnerable to multiple sclerosis and provide new interventions and treatments.

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