A Groundbreaking Discovery: Researchers Identify Gene Mutation Linked to Deadly Brain Aneurysms
New Study Finds Loss-of-Function THSD1 Gene Mutations in Affected Patients, Notes Cerebral Bleeding in Animal Models, and Provides New Understanding Into Intracranial Aneurysm Pathogenesis
Dec 12, 2016, 01:18 ET
HOUSTON, Dec. 12, 2016 /PRNewswire-USNewswire/ -- A team led by researchers at McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth) has discovered a genetic mutation linked to patients with intracranial aneurysms (a lesion that can kill without warning) and found that the same mutation caused brain bleeding in two separate animal models.
In the study published Nov. 17, 2016 in Stroke, an AHA/ASA Journal, researchers studied more than 500 people, including many with a family history of intracranial aneurysms, and identified a specific protein coding gene, THSD1, whose mutation is suspected to lead to the formation of weak or thin spots in cerebral arteries. This defect can cause the artery to rupture, leading to bleeding in subarachnoid space, or the area between brain and the tissue covering the brain, which often results in disability or death.
After pinpointing the genetic mutation linked to intracranial aneurysms, the research team, led by Dr. Dong Kim, director of Memorial Hermann Mischer Neuroscience Institute at the Texas Medical Center and chair of the Vivian L. Smith Department of Neurosurgery at McGovern Medical School, then investigated the consequences of a loss-of-function of THSD1 using genetically modified mice and zebrafish. The researchers discovered that both animal models experienced cerebral hemorrhage and increased mortality when the gene's function was switched off. In mice, the bleeding was located in the subarachnoid space, providing new insight and understanding into the function of a gene that has not been widely studied.
In the United States alone, about 30,000 people every year suffer subarachnoid hemorrhages. That is about one person every 18 minutes. Despite advances in treatment, ruptured brain aneurysms are fatal in about 40 percent of cases. Those who survive typically struggle with lifelong neurological impairments.
The results of the study marked a pivotal moment in a 15-year quest by Dr. Kim to uncover the gene responsible for brain aneurysms that strike multiple generations of families. The condition occurs in about 3 percent of the adult population, and the risk is even higher for those with a family history of brain aneurysms. Screening is recommended for people with two or more immediate relatives with intracranial aneurysms. Two non-invasive diagnostic tools are available – MRI with MRA (Magnetic Resonance Imaging with angiography) and CT with CTA (Computed Tomography with Angiography) – which can detect aneurysms as small as 2 millimeters. If discovered early enough, brain aneurysms can be treated through a variety of cutting-edge technological treatment options.
"We have known for quite a while that aneurysms can run in families, so we knew there had to be a genetic variant responsible, but it took several years of painstaking genetic detective work to get to the point where we could identify this specific mutation," Dr. Kim said. "The clue that unlocked this mystery came from sequencing the genome of a specific large family in which multiple members had suffered brain aneurysms, and the evidence linking THSD1 to this disease began to build from there. It's truly a fascinating discovery because, prior to this research, hardly anyone knew what this gene did or how it worked."
The family, which served as one of many included in the study, had a tragic history of the disease, including a total of nine members diagnosed with intracranial aneurysms. The mutation of THSD1 was found in all affected members of the family, including three that ultimately experienced subarachnoid hemorrhage, but was absent in unaffected relatives.
Dr. Kim said that the genetic evidence collected from those affected by intracranial aneurysms, coupled with the outcomes that were noted in the loss-of-function studies in animals, suggests that the mutation of THSD1 disrupts the ability of endothelial cells, which form a thin layer on the interior wall of an artery, to adhere to the extracellular matrix in cerebral arteries. That disruption causes blood to leak from the middle of the artery, leading to bulging and weakening of the cerebral artery that can worsen over time.
"As blood continues to rush through that artery, it bulges more and more, until at some point it can rupture," Dr. Kim said. "By identifying the role this high-risk genetic variant of THSD1 plays in leading to the formation of intracranial aneurysm, we now have a better grasp from a molecular level of why aneurysms occur. This research serves as a solid foundation on which to continue building our scientific understanding of a disease that, until now, has been somewhat of a genetic enigma."
This research was made by possible thanks to the collaboration of a team of UTHealth researchers led by Dr. Kim, Teresa Santiago-Sim, Ph.D., and Xiaoquian Fang, Ph.D., in partnership with scientists from Harvard Medical School, Brigham and Women's Hospital and the Howard Hughes Medical Institute in Maryland.
Read the full paper in Stroke.
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SOURCE Memorial Hermann Mischer Neuroscience Institute at the Texas Medical Center