A New Gene Linked to the Aging Process and Heart Development

June 2011

Cell Nuclei
The cell nuclei (circular objects) contain the cellular DNA, shown in light blue. The yellow border is the nuclear envelope containing the newly discovered gene MLIP alongside another protein called lamin. Researchers at the University of Ottawa Heart Institute identified MLIP, which affects heart development and the aging process.

It was the very uniqueness of the gene that first drew the attention of molecular biologist Patrick Burgon, PhD. “The striking thing about this gene is that it has no other family members,” he said. “That’s what drove my curiosity.”

The gene is muscle enriched A-type lamin interacting protein, or MLIP. Burgon’s team has been the first to identify and describe it. Findings in the Journal of Biological Chemistry were published electronically in April 2011 and formally in June 2011. The gene appears to play a role in heart development and the aging process, bringing the promise of new treatments for an old and failing heart.

Normally, genes exist in families, a hallmark of evolutionary development. A gene gets duplicated and, as time moves on, the duplicates evolve in different directions. But they still share several common factors or—as Burgon put it— they share “a common fingerprint.” This gene did not.

“At first we thought it too good to be true. But as our findings accumulate, I think we’re on to something.” – Patrick Burgon, Molecular Biologist and Principal Investigator, UOHI

Two blue cell nuclei
The two blue cell nuclei house hereditary information, or DNA. The green spots in and around the DNA show the newly discovered gene MLIP, which researchers at the Heart Institute have identified and tied to the aging process of the heart.

Burgon found the gene when he went looking for proteins that interact with lamin A, one of the best-studied genes among those known to cause a variety of diseases in humans. In the case of lamin A, these include dilated cardiomyopathy (better known as an enlarged heart) and some forms of muscular dystrophy, a degenerative muscle disease. Known as laminopathies, these diseases strike muscles, whether they are heart or skeletal muscle (the muscles in the arms, legs and the rest of the body). But just how lamin A causes these diseases is not clear. Not yet, anyway.

Burgon and his team are looking at MLIP as the possible mechanism, or the hammer—as they call it—that tells lamin A to express more of itself. MLIP, he said, is a relatively new gene that appeared “sometime around the time when animal groups, such as reptiles, birds and mammals, became terrestrial creatures, leaving the water in the order of 165 million years ago.”

 

Patrick Burgon, PhD
Patrick Burgon, PhD

 

“Understanding this gene and how it functions could help us to understand how the heart ages.”

  • Molecular Biologist and Principal Investigator, University of Ottawa Heart Institute
  • Assistant Professor, Department of Medicine (Cross-appointed with Biochemistry, Microbiology and Immunology), University of Ottawa
  • Research: Genetic determinants of fetal heart development and disease; mechanics involved in the transition from hyperplastic to hypertrophic-based myocardial growth during fetal development

 

The gene is found most abundantly in the nuclei of heart, skeletal muscle and smooth muscle cells, where it interacts with lamin A. The new gene MLIP is also found in the brain cells that affect heart development and the aging process.

Burgon has for the past several years focused his investigation on the fetal heart to understand the changes that take place as the heart ages, grows frail and fails. The research leading to the discovery of MLIP is part of that undertaking.

Since he first identified and described MLIP, Burgon has begun to focus on MLIP’s function, which will be the subject of future research publications. These findings are not yet public, but he offers some tantalizing hints about what MLIP might actually do. Through experiments on knockout mice—mice at different ages and with MLIP removed—Burgon is examining what happens when a mouse has either no MLIP at all or only one copy. Mammals usually have two copies—one from each parent. Already the results are showing some dramatic effects, Burgon said.

In the longer term, knowing more about the role of MLIP in causing lamin-related diseases may lead to new ways to fight these diseases, including identifying targets for drug development. For instance, many laminopathies are related to aging and, as we age, we express less lamin A. Or we might have a genetic mutation that results in less lamin A being expressed at a younger age. In extreme cases (one in 8 million births), people without any lamin at all are born old and age rapidly, dying generally by age 8. It is a condition called progeria.

If MLIP does, indeed, regulate the expression or function of lamin A, then learning how to increase levels of MLIP in the body might lead to greater expression of lamin A, lowering the incidence of laminopathy-related diseases, said Burgon.

He believes that if MLIP can express more lamin, it might even offset the aging process—and that could have a significant impact on heart health.

“The major predictor of a cardiovascular event is age, and the outcome after a heart attack is greatly affected by age,” he explained.

MLIP might also play a role in repairing the damage after a heart attack, Burgon suggested. It may be able, for instance, to encourage the regeneration of new heart tissue after a heart attack by telling stem cells to differentiate into precursor heart cells (normally, the heart stops producing new cells about two weeks after birth). Also, it could serve to stabilize damaged tissue to prevent further injury and possibly allow lost heart function to be regained.

“Given how unique MLIP is, there’s been a very strong natural selection in terms of evolution to keep it that way,” said Burgon. To him, this is a sign of MLIP’s potential importance and what gives him the motivation to continue investigating this previously unknown gene.

“At first we thought it too good to be true. But as our findings accumulate, I think we’re on to something,” he said. “Once we understand what MLIP does, we can come up with strategies to improve healing and general health.”

From Australia to Ottawa: A Cardiac Researcher’s Journey

Patrick Burgon was set to follow the traditional Australian career path for a researcher. After finishing his doctorate at Monash University in Melbourne, Australia, he left for a post-doctoral fellowship at Harvard University. One fellowship led to another. The only problem is, he forgot the next step—returning to Australia to take up a faculty position there.

It is not that he did not have the opportunity. He was juggling offers from the University of New South Wales in Sydney, Australia, and the University of Chicago. But it was the additional offer that caught his attention—from a research institute whose reputation was growing by leaps in the field of molecular biology: the University of Ottawa Heart Institute.

“I came here because I felt it had the greatest potential in terms of starting up a new research program,” he said.

The Heart Institute provided start-up funding to get his lab going, along with space and infrastructure in which to operate. The most important factor though, he said, is mentorship—the opportunity to work with people who are hungry to learn and with the zeal to find new clues to defeating heart disease. Today, Burgon is a Principal Investigator at the Heart Institute, where his research program focuses on the genetic determinants of heart development and disease—in particular, how hearts develop in utero.