Progeria progress: Studies show how mutant protein hurts hearts

In children with progeria, a mutant protein accumulates in blood vessel cells, hampering their ability to grow and multiply or killing them outright. In mice that produce this same toxic protein, the effect is similar: These vascular cells become damaged or die.

These are the findings of two research reports published in the Proceedings of the National Academy of Sciences. Both shed important new light on the progression of progeria, a rare and fatal genetic condition that causes accelerated aging in children. But they may also illuminate the cause of atherosclerosis in adults. Also known as hardening of the arteries, atherosclerosis is a leading cause of heart attacks and strokes.

"These are very important findings not only for children with progeria but potentially for millions of adults," said Leslie B. Gordon, M.D., Ph.D., assistant professor of pediatrics research at Brown Medical School and a co-author on both research papers.

"We now know there is a brand-new culprit molecule that plays a pivotal role in causing heart disease," Gordon said. "We know this is true with progeria. Now we can explore a bigger question: Does this molecule play the same role in heart disease in all of us?"

A Brown Medical School graduate, Gordon created the Progeria Research Foundation in 1999, one year after her son, Sam, was diagnosed with the condition. The foundation raises public awareness and bankrolls research about the rare disorder, which causes hair loss, osteoporosis, and other signs of premature aging in children. Children with the disorder die almost exclusively of atheroscleroris at an average age of 13. This form of heart disease is typically seen in people over 60.

Progeria is extremely rare. The foundation reports that there are 42 known cases worldwide. Atherosclerosis, however, is quite common, affecting millions of adults. It prompts the build-up of fats, cholesterol, calcium and other substances in arteries. These plaques reduce blood flow and can cause clots that block blood vessels to the heart or brain, triggering a heart attack or stroke.

To better understand progeria, and find a cure, the foundation runs a medical and research database through Brown's Center for Gerontology and Health Care Research and operates a cell and tissue bank at Rhode Island Hospital. It also funds research, providing partial funding for one of the new research studies.

Here are summaries of those reports:

  • Using human skin tissue from the Rhode Island Hospital bank, researchers from the College of Physicians and Surgeons at Columbia University found that progerin, a mutant form of the protein lamin A, builds up in the nucleus of cells, particularly those of blood vessels. As a result of this build-up, the nucleus becomes deformed and these cells stop growing, moving and multiplying. Some cells die. Blood vessel cells most affected were those in smooth muscle. The result is support for a direct relationship between progerin and atherosclerosis. The results of this study replicate findings included in previous research on the use of FTIs in progeria research.
  • A research team, led by scientists at the National Human Genome Research Institute at the National Institutes of Health, created and studied mice that carried the human form of the mutant lamin A gene. The gene, harbored in an artificial chromosome, produced the same toxic protein that harms or kills cells in children with progeria. In parallel with the Columbia and Brown team, scientists found that these mice lost blood vessel cells in smooth muscle.

"This mouse model should prove valuable for testing experimental therapies for progeria, such as anti-cancer drugs and bone marrow transplants," said Francis S. Collins, M.D., director of the National Human Genome Research Institute and senior scientist on the NIH paper. "Now that we're armed with a better understanding of the underlying causes of atherosclerosis, we can also use this model to explore cardiovascular disease in general."

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The Progeria Research Foundation and the National Institutes of Health funded the Columbia-led research. The National Institutes of Health, the Tore Nilsson Foundation, the Ake Wiberg Foundation, the Hagelen Foundation, the Loo and Hans Osterman Foundation, the Torsten and Ragnar Soderberg Foundation, the Jeansson Foundation, the Swedish Research Foundation and the Swedish Foundation for Strategic Research funded the experiments overseen by the National Human Genome Research Institute.

Copies of both articles can be found at the website of the Proceedings of the National Academies of Science at www.pnas.org. For more information on progeria, visit genome.gov/11007255 or www.progeriaresearch.org.


Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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