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Defective Gene in Mitochondria Linked to Heart Disease

By Cheryl Simon Silver

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Heart Disease

A team of researchers intrigued by a family whose members all have low magnesium levels may have stumbled upon a metabolic defect that leads people to develop a constellation of health problems, including hypertension, diabetes, and high fat levels in blood.

People who have one of these disorders tend to have others, but rarely all of them, and the relationship between the disorders has not been clear. Together the disorders are called metabolic syndrome. They add up to potent risk factors for heart disease and stroke. Metabolic syndrome, in its various combinations, affects an estimated 47 million people living in the United States.

Now, researchers led by Richard P. Lifton of the Howard Hughes Medical Institute and the Yale University School of Medicine in New Haven, Connecticut, have tied the conditions in a large family group to a specific mutation that affects the genes of mitochondria. These are the parts of the cell that produce energy, and they are inherited from the mother.

The defect identified occurs in the gene for a carrier molecule called transfer RNA, or tRNA. The particular tRNA molecule transports the amino acid isoleucine into the cell. When the transport is faulty, a number of proteins that should contain isoleucine are affected, thereby contributing to a range of cellular malfunctions.

The mutation is rare, but, says Daniel Levy, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, “it may allow us to target new therapies for the future by understanding the means by which that variant may promote disease.”

The study, published in Science, began when the team evaluated a woman with low levels of magnesium in her blood. When they learned that her extended family also had low blood magnesium, which is unusual, and also hypertension and high cholesterol, they expanded the study.

Ultimately, the researchers evaluated 142 blood relatives who were highly cooperative and easy to study because they lived in close proximity to one another.

The researchers zeroed in on low magnesium because it is the least common of the traits among the general population. The thirty two family members with the condition spanned four generations, and the trait could be traced, in every case, through the maternal line. The mutation was found only in affected family members and has not been identified in other studies of mitochondrial genomes.

The study draws attention to the mitochondria, which have their own genomes. Because the mitochondrial is miniscule compared to the human genome, it is comparatively easier to search for and decipher variants that may be associated with a particular trait, such as high blood pressure.

The finding opens the door to still more questions, such as why problems including hypertension and cholesterol levels increase with age. In members of the study family, blood pressure and fat levels in blood began to increase at about age 30, suggesting that mitochondrial function, which declines with age, may play a role in these and other metabolic syndrome disorders. Other research has shown mitochondria malfunction may also be involved in type 2 diabetes, which is also part of the metabolic syndrome.

In the Science paper, the authors write, “Given the known loss of mitochondrial function with aging, these findings may have implications for the common clustering of these metabolic disorders.”

Lifton, R. P. et al. A Cluster of Metabolic Defects Caused by Mutation in a Mitochondrial tRNA. Science Express. Published online October 21, 2004.

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