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Genetic Cause of Rare Condition Uncovered by Oklahoma Researchers

Friday, April 18, 2014 - Campus News - Contact Theresa Green, (405) 833-9824

It is a condition so rare that it has been diagnosed in only a handful of families and individuals worldwide. Now, researchers at the University of Oklahoma Health Sciences Center and the Oklahoma Medical Research Foundation have discovered that a mutation in a single gene is responsible for Stormorken syndrome as well as how that mutation causes the condition

The groundbreaking work appears in Proceedings of the National Academy of Sciences. It all started about a year ago when OU Children's Physicians' pediatric hematologist-oncologist William Meyer, M.D., referred Isabel, a 10-year-old Oklahoma girl, to his colleague Klaas Wierenga, M.D., a medical geneticist with OU Children's Physicians.

"When she was just a baby, she would bleed spontaneously from the mouth. She didn't act sick, but she would bruise so easily. She as a beautiful little baby, but we didn't understand what was going on," said Linda Hammond, Isabel's grandmother.

"Until our case, there were only six reported families with this syndrome," Wierenga said. "The syndrome is diagnosed if the patient meets three criteria. The first is a muscle disorder, typically weakness in the proximal muscles. The thigh muscles are usually the weakest. The second is a bleeding disorder, for which she was seeing Meyer, and the third is congenital miosis, which means the eyes are always pinpointed, unable to dilate in a dark room."

The condition is inherited in a dominant manner, which means it is passed on from a parent to half of his or her children. Interestingly, though, Wierenga quickly discovered that, unlike other families with this condition, Isabel's parents did not have Stormorken syndrome. That meant it was not inherited, but instead, the result of a spontaneous mutation at conception.

"That's when a geneticist's heart starts beating faster, because we think this might be something we can more easily solve," he said.
Wierenga partnered with Patrick Gaffney, M.D., at the Oklahoma Medical Research Foundation to begin trying to pinpoint the exact genetic cause. Gaffney, staff scientist Graham Wiley, Ph.D., and the team set to work trying to solve the genetic underpinnings of the condition.

They utilized a process called exome sequencing. It provides a more efficient, yet still effective, alternative to whole genome sequencing. Exome sequencing looks at the exons or snippets of genes that code for proteins. In the human genome, there are about 180,000 exons.

Comparing genetic samples of the patient with Stormorken syndrome to that of her unaffected relatives through exome sequencing, researchers hit upon three possible genetic targets initially. Next, they compared the Oklahoma patient to another with the same syndrome from Switzerland. This time, they uncovered a single mutation present in both, in the gene named STIM1.

"This is significant because the genetic cause of the syndrome was previously unknown. Now, we know what the gene is and what the mutation is," Gaffney said.

STIM1 is part of the cellular machinery that controls calcium inflow in the cells of the body. The next step for researchers was to determine exactly how the newly discovered mutation triggered changes in the body that cause the syndrome. For those answers, researchers turned to another Oklahoma colleague, Leonidas Tsiokas, Ph.D., researcher and professor of cell biology at the OU College of Medicine.

Tsiokas, post-doctoral scholar Vasyl Nesin, Ph.D., and their team set to work. They focused on how ionized calcium enters the cell in unaffected individuals and in patients with Stormorken syndrome. Calcium inflow was measured as a tiny electrical current.

The team learned the STIM1 mutation works much like a faulty electrical switch that gets stuck in the "on" position. Normally, when calcium levels in the cell drop, STIM1 activates calcium entry into the cell from the outside. When sufficient calcium has entered, STIM1 closes the channel. With the mutation, however, the channel opens and stays open. So the calcium keeps flowing.

"The calcium activates the platelets in the blood and keeps activating them. Eventually, the platelets are exhausted and destroyed," Tsiokas said.

With the help of colleagues at Duke University, the OU team tested their findings in a zebra-fish model. Again, the single mutation in STIM1 caused the same over-function of the "calcium switch" and destroyed platelets. That confirmed the mutation as the cause of the bleeding problems found with Stormorken syndrome.

The team believes it is the same errant signaling that causes the other hallmark symptoms of Stormorken syndrome – proximal muscle weakness and miosis. In fact, the finding may hold promise for a better understanding of more common conditions too.

"Stormorken syndrome is extremely rare, but the pathologies of the syndrome are not rare," Tsiokas said. "Too much calcium in the cell may also play a role in dyslexia, muscle defects and asplenia (the absence of normal spleen function)."

Because STIM1 is important for regulating free calcium levels in the cells of the body, researchers believe it is probable that, in fact, every cell in the body suffers when the gene is over activated. However, the damage is more apparent in tissues most sensitive to calcium channel over stimulation, including the pupils, platelets and muscles.

"We hope this research puts new attention into this aspect of calcium channel activation, which may be more common that we currently suspect," Wierenga said. "If there were a drug that targeted this over-activation, this would be a rational form of therapy. Of course, we don't know of such a drug; but until recently, we did not even know the cause of this syndrome."

Researchers say the research discovery highlights the importance of collaboration and the benefits gained through the advancement of the science of modern medicine.

"New advances in genetic sequencing provide an unprecedented opportunity to understand the genetic basis of poorly understood genetic disorders," Gaffney said. "We hope that this will eventually lead to new therapies for treating rare diseases and add to our understanding of gene/protein function, stimulating further breakthroughs down the road."

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