Discovery may boost understanding of other more common conditions, too
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.”
Often people are afraid to talk about mental health because there are many misconceptions about mental illnesses. This week on the OU Medicine Webchat, Britta Ostermeyer, M.D., chair of psychiatry at the OU College of Medicine, will break down the myths and facts about mental illness.
Researchers at the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma for the first time have shown a drug commonly used for infertility also effectively inhibits colorectal cancer. The findings point to potential new preventive and treatment therapies for those at highest risk.
The research is prominently displayed on the front cover of the latest issue of the Cancer Prevention Research Journal of the American Association for Cancer Research.
“It is really a great honor for me to have my work featured on the cover of this prestigious publication,” said Cancer Center researcher Naveena Janakiram, Ph.D., who also holds a faculty position within the department of Internal Medicine at the OU Health Sciences Center.
More than 1.2 million people are diagnosed with colon cancer, and 600,000 die every year worldwide. Colon cancer is the fourth most common cause of cancer death, after lung, liver and stomach cancer.
Janakiram and her team focused on how to mitigate the role high estrogen levels play in colorectal cancers.
"We know that estrogen is having a pivotal role in colorectal cancer," she said. “Women with high levels of estrogen have a 60 percent higher risk of colon cancer.”
Women with high levels of estrogen are at increased risk for colorectal cancer because higher estrogen levels suppress the body's tumor-killing response during the formation of colon tumors.
When the body detects cancer cells, Janakiram explained it normally responds by dispatching its own army of cancer fighters known as natural killer cells.
“The more natural killer cells, the better the patient’s prognosis,” she said.
However, when high estrogen levels are present, the body’s natural killer cells are essentially blocked. The OU team set out to determine if they could counteract the effects of high estrogen levels.
Janakiram and her team found the drugs effectively suppressed the tumor-forming effects of estrogen by increasing the presence of the natural killer cells. In addition, the drugs also appear to suppress various other tumor-promoting genes and increase the body’s innate immune response against tumors.
The findings may help advance the treatment and prevention of colorectal cancer in humans, especially for those at highest risk. Fellow researchers believe the findings are interesting and significant as they work to advance the fight against colorectal cancer.
“These laboratory studies reveal how high estrogen levels impact the immune system, suppressing the natural killer cells and allowing tumor-initiating cells, much like stem cells, to grow into tumors in the colon. The work also reveals how these two drugs, which suppress the negative effects of high estrogen, potentially may have a positive impact on tumor treatment and prevention,” said C. V. Rao, Ph.D., director of the Center for Cancer Prevention and Drug Development at the OU Health Sciences Center.
The research also garnered significant attention as thousands of cancer researchers and specialists from around the world gathered this month for the annual conference of the American Association for Cancer Research in San Diego.
Janakiram’s research was supported by a COBRE grant from the National Institutes of Health (1P20GM103639-01).
Oklahoma City— Time and treatment are critical when a person is having a heart attack or serious cardiovascular issue, and a new $20 million state-of-the-art cardiac catheterization and electrophysiology(EP) laboratory at OU Medical Center well help provide even more life-saving diagnoses and treatments for Oklahomans needing urgent cardiac and vascular care.
The 20,000-square-foot cardiac catheterization/EP laboratory has five rooms and state-of the-art technology, providing faster and more efficient treatments to unclog blocked arteries during a heart attack. Innovative hybrid technology also allows OU Medicine experts to treat a wide range of cardiovascular and electrophysiology needs—This includes serious heart arrhythmias (irregular heartbeats), blood vessel problems and issues requiring devices such as pacemakers and implantable defibrillators.
OU Medical System CEO Chuck Spicer said the lab’s design and the collaborative involvement between cardiology and electrophysiology services will enhance quality of care for patients.
“It’s about bringing cardiology, vascular and heart-rhythm services as well as their surgical associates together to provide the finest, safest and most effective environment to save lives—It’s what patients expect from OU Medicine,” Spicer said.
The lab has several suites, including three cutting-edge hybrid operating rooms designed to accommodate a variety of procedures performed by six medical specialties.
“The hybrid suites allow us incredible flexibility to perform the simplest of procedures to open heart surgery—all in one place. This means the patient won’t have to be moved—allowing safer and quicker access to care,” said Dwight Reynolds, M.D., chief of cardiovascular services at the University of Oklahoma.
Advanced equipment in the lab will keep patients and staff safer with imaging systems designed to deliver the lowest doses of X-rays of any machine on the market, while at the same time delivering superb, crystal-clear details.
M. Dewayne Andrews, M.D., senior vice president and provost executive dean of the OU College of Medicine, said the lab is yet another example of OU Medicine’s commitment to advancing health care.
“The creation and opening of this advanced care center is another demonstration of the commitment of OU Medicine and its partners to becoming the premier destination for health care in Oklahoma and this region,” he said. “This enhances opportunities to bring discoveries of new treatments to the patients we serve.”
The lab is one component of the new OU Medicine Cardiovascular Institute, which will bring together services found across the OU Medicine entities. The institute includes an enhanced heart-lung vascular clinic, a fully accredited echo and vascular lab, a dedicated cardiovascular inpatient specialty unit and an electrocardiogram (EKG) unit.
From conception to completion, the Cardiovascular Institute and the cardiac catheterization/EP laboratory have been more than a decade in the making. The lab will open its doors to patients later this month.
For more information, please visit oumedicine.com/cath.
OU MEDICAL CENTER OU Medical Center, including The Children's Hospital at OU Medical Center, is Oklahoma's largest and most comprehensive hospital. It is located in the heart of Oklahoma City. We provide a full range of hospital services for every patient, from the smallest neonate to the most critically ill senior.
OU MEDICINE OU Medicine is the collective brand for OU Medical Center, OU Physicians and the University of Oklahoma College of Medicine. Headquartered at the Oklahoma Health Center campus near downtown Oklahoma City, OU Medicine is the state’s largest academic medical complex. Among other things, it provides health care, conducts medical research and educates the physicians of tomorrow.
OU Medical Center is home to the state’s only level one trauma center and The Children’s Hospital, Oklahoma’s most comprehensive pediatric facility. Members of OU Physicians, the state’s largest physicians group, provide care at the hospital facilities and at OU Physicians clinics in Oklahoma City and across the state. The practice includes almost every adult and child specialty, and some of its physicians have pioneered treatments or procedures that are world-firsts.