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NIH Research Matters

February 14, 2011

Rare Artery Disease Linked to Gene Variant

Scientists have discovered a genetic cause for a rare disorder that leads to calcium deposits in arteries in the lower half of the body and in the joints of patients' hands and feet. The culprit is a mutation in the gene encoding CD73, a protein that normally helps to prevent calcium buildup. The researchers hope that understanding the basis for this disease, which they call arterial calcification due to deficiency of CD73 (ACDC), will help them find a cure.

X-ray photo of a knee.

An X-ray of a knee from a patient with ACDC, showing calcium buildup in the artery. Courtesy of NHGRI.

Currently, 9 patients are known to have ACDC, and all come from 3 families. The patients experienced pain in their buttocks, legs and joints, but doctors could find no signs of rheumatoid arthritis or other recognized problems that might cause the symptoms. A research team that included scientists from NIH’s National Heart, Lung and Blood Institute (NHLBI) and National Human Genome Research Institute (NHGRI) examined members of 2 affected families to search for a common thread.

MRI and X-rays showed that members of the 2 families all had calcium buildup in arteries in the lower half of their bodies, but not around their hearts. In one family, 5 siblings but neither parent was affected by the disorder. The researchers suspected that symptoms might be due to a recessive gene variant. Recessive variants only show their effects when found in both copies of the gene.

To test this theory, the team, led by Dr. William Gahl of NHGRI, compared DNA from the parents of the family to their children's. They found a region of DNA that was present only once in the parents, but twice in the children. The team then compared this region to the same region in 200 unaffected people. The results were published on February 3, 2011, in the New England Journal of Medicine.

The researchers found a variant in a gene called NT5E that unaffected people didn’t have. NT5E makes a protein called CD73, which produces a small molecule called adenosine that helps regulate many processes in the body.

The NHLBI team, led by Dr. Manfred Boehm and Dr. Cynthia St. Hilaire, cultured the patients’ cells to examine the effects of the mutation on an enzyme called TNAP (tissue-nonspecific alkaline phosphatase). TNAP is known to degrade a calcium buildup inhibitor and thus contribute to calcium deposits. The researchers found that the mutant cells produced higher levels of TNAP. Adding adenosine to the cell cultures restored normal levels of TNAP. In addition, while mutant cells made more calcium phosphate crystals in culture, restoring CD73 expression in the cells prevented crystal formation.

"Vascular calcification often results from poor diet and lack of exercise," says Gahl, who is NHGRI clinical director and director of the NIH Undiagnosed Diseases Program. "The calcium buildup in arteries of our patients, however, arises because the systems to inhibit it are not working in their cells. We hope that an understanding of this faulty mechanism will guide us in providing helpful treatments for these patients."

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Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

This page last reviewed on December 3, 2012

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