Studying the molecular mechanisms of arterial disease from the left are Dianna Milewicz, M.D., Ph.D., and Dongchuan Guo, Ph.D.
Studying the molecular mechanisms of arterial disease from the left are Dianna Milewicz, M.D., Ph.D., and Dongchuan Guo, Ph.D.

A genetic discovery by a team led by Dianna Milewicz, M.D., Ph.D., could help explain a cause of a mysterious artery-damaging disease that may affect up to an estimated 5 million Americans and often strikes without warning.

Scientists at McGovern Medical School have identified gene alterations that cause this arterial disease called fibromuscular dysplasia or FMD. The research appeared in The American Journal of Human Genetics.

“This is an important step in understanding the underlying molecular mechanisms of this unexplained and puzzling condition that often affects women,” said Milewicz, the study’s senior author, and director of the Division of Medical Genetics in the Department of Internal Medicine. “The finding is a critical step in developing treatments.”

The study involved a family with a rare genetic disorder, Grange syndrome, that is also characterized by abnormal cell development on arterial walls. Grange syndrome is characterized by severe and early onset FMD-like arterial disease.

“When we compared the chromosome sequence of family members with and without Grange syndrome, we identified mutations in a gene, called YY1AP1, in affected individuals,” said Dongchuan Guo, Ph.D., the study’s lead author and an associate professor of medical genetics in the Department of Internal Medicine.

Mutations in YY1AP1 causing Grange syndrome were confirmed in additional unrelated families. Scientists also confirmed their findings through cell biology studies and performed genetic testing involving 282 people with FMD and a control cohort.

“This is a good example of how the investigation of a very rare genetic condition that has been identified in only a few individuals can lead to a better understanding of a more common medical problem such as FMD, which may benefit a broader population,” said Dorothy K. Grange, M.D., one of the study’s co-authors and a professor of pediatrics at Washington University School of Medicine.

FMD can involve the arteries going to and within the brain, leading to strokes and transient ischemic attacks. It can affect the arteries going to the kidneys, leading to high blood pressure.

When doctors suspect a person has FMD, they typically order imaging to see if they can locate the narrowed artery or arteries. While there is no cure, in severe cases, doctors insert tiny wires or catheters into the blood vessels to widen them.

“Diagnosis and treatment of patients with FMD remains a clinical challenge. The recent discovery of Dr. Milewicz and her team is a significant leap toward better understanding of the causative factors in this mysterious disease,” said Ali Azizzadeh, M.D., chief of vascular and endovascular surgery  and a member of the Memorial Hermann Heart & Vascular Institute-Texas Medical Center.

“YY1AP1 mutations predispose to vascular lesions characteristic of FMD, thus indicating that FMD can result from mutations in a single gene,” the authors wrote. “Thus, these data provide insight into the pathogenesis of FMD, an unusual and poorly understood vascular disease.”

McGovern Medical School co-authors include Xue-Yan Duan, Ph.D., Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Ph.D., and Dong Kim, M.D., professor and chair of the Department of Neurosurgery and director of the Memorial Hermann Mischer Neuroscience Institute at the Texas Medical Center.

Milewicz is the President George Bush Chair in Cardiovascular Medicine and the director of the John Ritter Research Program in Aortic and Vascular Diseases. She is also the co-director of the M.D./Ph.D. Program at The University of Texas Graduate School of Biomedical Sciences at Houston, which is operated by UTHealth and The University of Texas MD Anderson Cancer Center.

Additional co-authors include Kenneth Lieberman, M.D., of Joseph M. Sanzari Children’s Hospital, New Jersey; Bert B.A. de Vries, M.D., Ph.D., and Rolph Pfundt of the Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; Albert Schinzel of the University of Zurich, Switzerland; Dieter Kotzot of the Medical University of Innsbruck, Austria; Michael J. Bamshad, M.D., and Deborah A. Nickerson, Ph.D., of the University of Washington, Seattle; Heather L. Gornik, M.D., of the Cleveland Clinic Heart and Vascular Institute; Santhi K. Ganesh, M.D., of the University of Michigan; and Alan C. Braverman, M.D., of the Washington University School of Medicine.

The paper is titled “Loss-of-function Mutations in YY1AP1 Lead to Grange Syndrome and Fibromuscular Dysplasia-Like Vascular Disease” and was supported by the National Heart, Lung and Blood Institute (RO1 HL109942), the Vivian L. Smith Foundation, Henrietta B. and Frederick H. Bugher Foundation, National Institutes of Health (UL1 RR024148) and National Human Genome Research Institute.