Public Release: 

Discovery yields answers for family with thoracic aortic aneurysm and dissection

New genetic mutation identified as the cause of undiagnosed disease illuminates biological mechanism, possible therapeutic targets

Brigham and Women's Hospital

A new finding by clinicians and geneticists may solve a medical mystery that one family has faced for the last 15 years and help identify the cause of a rare aortic disease in other patients as well. Through genetic analysis of a family with a history of thoracic aortic aneurysm and dissection (TAAD), investigators at Brigham and Women's Hospital and Washington University School of Medicine in St. Louis have identified mutations in the LOX gene, a gene associated with the integrity of the arterial wall, in human subjects for the first time. Strong evidence from a mouse model of the disease further confirms these mutations as a cause of aortic disease, and, together, the results point toward possible strategies for managing this inherited form of TAAD. The new findings are published online this week in The Proceedings of the National Academy of Sciences.

"This discovery demonstrates that it's possible for clinical research to have a big impact on diagnostics for patients with undiagnosed disease and influence the clinical management of patients and family members," said study author Dana Vuzman, PhD, co-director of the Brigham Genomic Medicine Program.

TAAD is a relatively rare condition (affecting about 15,000 people in the U.S. each year) in which the walls of the aorta, which carries blood from the heart to the rest of the body, become weakened. As blood is pumped through, the aorta may bulge, causing an aneurysm, or tear, causing a dissection and life-threatening internal bleeding. Certain risk factors - such as smoking, age and weight gain - can increase a person's risk for TAAD, but in some cases, TAAD is caused by an underlying genetic condition, such as Marfan syndrome (a connective tissue disease) and can occur when a patient is young.

In the case of the family examined by the Brigham Genomic Medicine Program (BGMP), the primary patient tested negative for the genetic mutations that cause Marfan syndrome as well as all other mutations known to cause TAAD. In November 2013, BGMP performed whole-genome sequencing on two first cousins in the family with TAAD to identify a causal gene.

The study's senior author, Nathan O. Stitziel, MD, PhD, a cardiologist and Assistant Professor of Medicine and Genetics at Washington University in St. Louis, performed the co-segregation analysis (comparing genetic mutations shared and not shared by family members with and without the disease) that identified seven candidate mutations, including a mutation in the gene for lysyl oxidase (LOX), an enzyme that links collagen and elastin -- two structural components that comprise the arterial wall.

Stitziel then developed a collaboration with Robert P. Mecham, PhD, a Professor of Cell Biology and Physiology at Washington University in St. Louis to use CRISPR/Cas9 to replicate the same LOX mutation in mice. The Washington University investigators showed that mice with two copies of the mutated gene died of aortic rupture. Mice with one copy of the gene showed evidence of disrupted collagen and elastin fibers.

"We took advantage of CRISPR/Cas9 technology to study the effects of this specific mutation," said Stitziel. "We now have an animal model where we can test therapies relevant to this form of TAAD and understand the behavior of this enzyme in a very specific model of a human disease."

The LOX gene has another property of great interest to the research team: it's known to bind copper. The family's mutation may mean that they do not bind copper well. Clinicians and researchers will work together to evaluate possible treatment opportunities based on this insight, including whether supplementing copper in the diet could change risk for those who carry the mutation. They are also following up on next steps to add LOX to the panel of genes that are tested when an inherited form of TAAD is suspected.

"When we found this causal gene and were able to reveal it to the family, it was an emotional moment," said Natasha Frank, MD, the clinical geneticist at BWH who treated several members of the family. "Using genetic sequencing, we were able to answer the kind of question that hasn't been possible to address before and potentially change the lives of family members who can now be tested for mutations in this gene."

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This work was supported, in part, by the Hope Center Transgenic Vectors Core and Mouse Genetics Core at the Washington University School of Medicine. Funds supporting this work were provided by National Heart Lung and Blood Institute Grants R01HL105314,

R01HL53325, K08HL114642, and R01HL131961; Training Grants T32EB18266-1 and T32HL07873; the Child Health Research Center at Washington University School of Medicine (K12-HD076224); the Foundation for Barnes-Jewish Hospital; Center for Integrated Approaches to Undiagnosed Diseases (U01 HG007690-01 NIH/NHGRI); and a Brigham Research Institute (BRI) Director's Transformative Award.

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits and nearly 46,000 inpatient stays, is the largest birthing center in Massachusetts and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 3,000 researchers, including physician-investigators and renowned biomedical scientists and faculty supported by nearly $666 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom.

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