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Single gene defect can lead to stroke and deadly diseases of the aorta and coronary arteries

For the first time, scientists have discovered a single gene defect that causes thoracic aortic aneurysms and dissections as well as early onset coronary artery disease, ischemic stroke and Moyamoya disease. The research is led by scientists at The University of Texas Health Science Center at Houston.

The study, “Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Early Onset Coronary Artery Disease, Stroke and Moyamoya Disease, Along with Thoracic Aortic Aneurysms and Dissections,” is published early online today in the American Journal of Human Genetics.

“If someone is found to have an alteration or mutation in this gene, we can do screening for vascular diseases, and if diagnosed with disease, they can take medications and undergo surgical approaches to prevent premature death or disability,” said senior author and principal investigator Dianna Milewicz, M.D., Ph.D., professor and director of the Division of Medical Genetics at The University of Texas Medical School at Houston.

The discovery of the causal relationship between the mutated gene ACTA2 and artery diseases has opened the door to a new way of thinking about the vascular system, Milewicz said.

“We need to look at the artery system as a continuous system or organ,” said Milewicz, the President George Bush Professor in Cardiovascular Medicine. ”We’ve been looking at it the wrong way. If you have this particular genetic mutation, it can present in several different diseases affecting different arteries.”

Milewicz and her team studied 127 members of 20 families from around the world who had ACTA2 mutations. They were phenotyped for premature vascular diseases, defined as an age of onset less than 55 years in men and less than 60 years in women.

Premature thoracic aortic aneurysms and dissections were the main vascular disease for 76 mutation carriers, while 26 had premature coronary artery disease, 15 had ischemic stroke, including Moyamoya disease, and 15 had more than one vascular disease.

In thoracic aortic disease, the wall of the aorta, the main blood vessel leading out of the heart, weakens and forms an aneurysm that can ultimately lead to an aortic dissection and death. Coronary artery disease, the most common type of heart disease, is the leading cause of death for both men and women in the United States. Stroke is the third leading cause of death in the country.

In the study, none of the family members without the ACTA2 defect had any vascular disease, helping to rule out other genetic or environmental causes. In four families, members younger than age 20 suffered a stroke and five strokes resulted from Moyamoya disease, a rare stroke disease in which the internal carotid arteries become occluded.

The main function of smooth muscle cells is to contract in response to the stretching from pulsing blood flow. Vascular pathology from mutant aortas and analysis of smooth muscle cells removed from patients and grown in the laboratory suggest that persons with ACTA2 have increased multiplication of smooth muscle cells that contribute to blocked or enlarged arteries, according to the study.

Milewicz and her team previously discovered the role of the mutated ACTA2; mutations in ACTA2 account for 14 percent of the inherited form of thoracic aortic aneurysms and dissections, making it the major gene identified for the condition.

During the research, Milewicz identified a large family with persistent livedo reticularis, a purplish mesh-like skin discoloration caused by the occlusion of arteries in the skin. This family also had a history of premature onset coronary artery disease and premature stroke without the risk factors know to cause these diseases (smoking, high cholesterol)

“Family members asked if it all could be related and I told them at the time that they just had really bad luck with several mutated genes,” Milewicz said. “It didn’t occur to me until later that it might be from the same genetic defect.”

The study results from collaborative efforts of physicians and scientists in the Texas Medical Center including surgeons Hazim Safi, M.D., professor and chairman of the Department of Cardiothoracic Vascular Surgery at the UT Houston Medical School; Dong Kim, M.D., chairman of the medical school’s Department of Neurosurgery and director of the Mischer Neuroscience Institute at Memorial Hermann—Texas Medical Center; and Anthony Estrera, M.D., associate professor of cardiothoracic vascular surgery.

Genetic statistics for the study were completed by Sanjay Shete, Ph.D., at The University of Texas MD Anderson Cancer Center and sequencing of the gene was done in part through collaboration with Steve Scherer, Ph.D., at the Human Genome Center at Baylor College of Medicine. C.S. Raman, Ph.D., assistant professor in the Department of Biochemistry and Molecular Biology at UT Medical School, provided assessment of the effect of the mutations on alpha-actin protein structure and fiber formation. Samples were collected, de-identified and banked as part of TexGen Research.

Co-authors of the study from the UT Health Science Center at Houston include: Dong-Chuan Guo, Ph.D., assistant professor of medical genetics; Christina Papke, graduate research assistant, The University of Texas Graduate School of Biomedical Sciences at Houston (GSBS); Hariyadarshi Pannu, Ph.D., assistant professor of medical genetics; Nili Avidan, Ph.D., instructor of medical genetics; Ellen Regalado, M.S., instructor of medical genetics; Ralph J. Johnson, Ph.D., assistant professor of medical genetics; James C. Grotta, M.D., professor and chair of the Department of Neurology; Eric Boerwinkle, Ph.D., director of the Division of Epidemiology and Kozmetsky Family Chair in Human Genetics at The University of Texas School of Public Health and The Brown Foundation Institute of Molecular Medicine (IMM); Ali J. Marian, M.D., professor and director, Center for Cardiovascular Genetic Research at the IMM; Sudha Veeraraghavan, Ph.D., assistant professor of biochemistry and molecular biology at the medical school and GSBS; Maximilian Buja, M.D., executive vice president of academic affairs; Lorraine Q. Frazier, Ph.D., professor of nursing at the health science center’s School of Nursing; and James T. Willerson, M.D., professor of internal medicine at the medical school and president of the Texas Heart Institute

Other co-authors are researchers from: The University of Texas MD Anderson Cancer Center; The Texas Heart Institute; The Ohio University, Columbus; Genetic Health Services Victoria at Royal Children’s Hospital, Australia; Children’s Hospital at Westmead, Sydney, Australia; Ireland Regional Genetics Services, Belfast, Northern Ireland; Queens University Belfast; Rhode Island Hospital, Providence; The University of Iowa Hospitals and Clinics, Iowa City; Baylor College of Medicine; and Brigham and Women’s Hospital/Harvard Medical School, Boston.

Funding for the research comes from a grant from the Doris Duke Charitable Foundation and the National Institutes of Health, including an $11.6 million grant from the National Heart, Lung and Blood Institute, which created the multi-institutional Specialized Center for Clinically Oriented Research in Thoracic Aortic Aneurysms and Dissections.

Deborah Mann Lake | EurekAlert!
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