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February 01, 2018 (Vol. 38, No. 3)

Gene Variant in Amish a Clue to Better Aging

Mutation Reveals Unexpected Links That Could Contribute to Diseases of Aging

Source: Laura Baran

  • The horse and buggies arrived early, carrying modestly dressed men, women, and children to a recreation center in eastern Indiana. Nearly 200 members of nearby Amish communities somberly entered the center, which had been turned into a makeshift medical clinic for two days in early May 2015.

    Their blood was drawn, echocardiograms were run to examine their hearts, and fasting blood sugar levels were measured. It took 7–8 hours to pass through each of the medical stations.

    Douglas Vaughan, M.D., who was helping run the operation, characterized the medical marathon as intense, strenuous, and exciting, describing it as the most unusual experience he’s ever had.

    Dr. Vaughan, a cardiologist at Northwestern University, has spent his entire professional career studying a protein called plasminogen activator inhibitor type 1, or PAI-1. Because of a genetic fluke, an Amish woman  who came that day lacks PAI-1 (pronounced pie-1), leaving her with a life-threatening blood-clotting disorder.

    In mice, in addition to being instrumental in proper blood clotting, PAI-1 seems to be involved in heart and lung function, metabolism, basic cellular activities, hair loss, and even aging.

    Dr. Vaughan wanted to evaluate whether PAI-1 is as powerful in people, which was why he recruited this particular woman and her kindred community members to the recreational center.

  • A Suspect Mutation

    The Amish woman in question is in her 30s now. She is married and planning for children. Dr. Vaughan first took interest in her case when she was 9 years old and the subject of a 1992 paper in the New England Journal of Medicine. Her troubles first began when she was 3 and got a bump on her head that led to surgery and uncontrolled bleeding.

    But her blood-clotting disease didn’t fit the typical pattern. She couldn’t have hemophilia, which almost exclusively affects boys, and causes the kind of joint and muscle bleeds she’d never had. Her symptoms didn’t fit other well-known blood disorders, either.

    Amy Shapiro, M.D., a pediatric hematologist, went to visit the girl. She conducted an examination and took a blood sample. After initially chasing several dead ends, Dr. Shapiro convinced a colleague to scan for a mutation on the girl’s SERPINE1 gene, which when defective, is believed to cause PAI-1 deficiency and, potentially, clotting problems.

    Dr. Shapiro told GEN that her colleague doubted the Amish girl had the uncommon mutation. In fact, Dr. Shapiro had to hound her colleague to actually run the test. But the test confirmed the genetic deficiency; there was a mutation in the girl’s SERPINE1 gene, which prevented the proper production of the protein PAI-1.

    Armed with the knowledge that sometimes people in Amish communities marry their distant relatives, Dr. Shapiro tested and found a handful of other individuals in the Berne, Indiana community with the same unusual bleeding condition and complete PAI-1 deficiency.

  • A Possible Connection to Aging

    By this point, PAI-1 had already been beguiling Dr. Vaughan for several years.

    The stroke-busting drug tPA, or tissue plasminogen activator, had just been developed in 1988 when Dr. Vaughan began a postdoctoral stint in the lab of Désiré Collen, Ph.D., the founder of Thrombogenics and Life Sciences Research Partners, and one of the drug’s inventors. Dr. Collen told him that the PAI-1 protein rapidly inhibited tPA, and he wanted to learn more about the protein. In Dr. Vaughn’s recollection, Dr. Collen said, “No one knows what else it does, but we have a bunch in the freezer. Why don’t you work on that?”

    By the early 1990s, Dr. Vaughan had already confirmed that PAI-1 could be involved in cardiovascular disease. And Dr. Shapiro’s research on the Amish girl made him realize the protein probably played a role in blood clotting, too.

    Further research showed that PAI-1 is also involved in what’s called cellular senescence. When a cell undergoes damage, it may self-destruct, or it may go into senescence, essentially going to sleep. This helps to slow the development of cancer in young people—when a cell is multiplying too fast, the body puts it on pause to prevent uncontrolled growth. But as these senescent cells build up in the body over time, they play, scientists believe, a key role in many of the diseases of aging.

    “We connected those intellectual dots between PAI-1 and senescence, and between senescence and aging,” Dr. Vaughan said of his lab’s work.

    About 15 years ago, Dr. Vaughan also noticed that mice bred to have too much PAI-1 seemed “older” than they should. They were born bald and never grew hair. “They don’t quite look right,” he added.

    To test this link between PAI-1 and aging, he bred mice deficient in PAI-1 with mice that age rapidly. Among the offspring, lower levels of PAI-1 appeared to provide protection against rapid aging, Dr. Vaughan found.

    This work on mice left him with a question: If such relatively low levels of PAI-1 could slow biological decline in mice, could it do the same thing in people?

    The Amish group studied by Dr. Shapiro offered a real-world testing ground. 

  • A Risky Double Mutation

    The woman affected by the blood disorder inherited two mutated copies of the SERPINE1 gene—one from each parent—which led to the complete absence of PAI-1. Family members with just one changed copy of the gene did not have the bleeding disorder. In a typical population, two people with such SERPINE1 changes are not likely to meet and marry. But among the Amish, the small size of the community increases the odds of such double mutations.

    Drs. Shapiro and Vaughan published the results of their findings from the Berne community members in November 2017 in the journal Science Advances, confirming that 12 of the kindred carried the dangerous double mutations.

    Unexpectedly, not all of them had blood-clotting disorders.

    One young man in his early 30s was found to have a type of heart disease caused by scarring from an excess of fibrous tissue built up in his heart. Unfortunately, his disease was too far along by then. The man died in the Winter of 2017 at age 34. Prior to his death, fibrotic heart disease had been described in PAI-1-deficient mice, but had never before been linked to mutations in PAI-1.

    The researchers are now checking other members of the Amish community for similar heart problems, said Sweta Gupta, M.D., a paper coauthor and colleague of Dr. Shapiro’s at the Indiana Hemophilia & Thrombosis Center. She, Dr. Shapiro, and their colleagues are also working on finding drug therapies to help affected community members manage fibrotic heart disease associated with the mutation.

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