Oct. 5, 2000 Molecular geneticists at Jefferson Medical College have for the first time characterized gene mutations in families affected by a rare, inherited, connective tissue disorder that can lead to blindness and early heart attacks. The work provides the basis for DNA-based carrier detection, prenatal testing and a better understanding of the mechanisms behind the disease, known as pseudoxanthoma elasticum (PXE).
PXE is difficult to diagnose because the symptoms don't often show up until the teens or early 20s. Typically, the affected person appears to have severely sun-damaged skin. But the symptoms belie a much more dangerous condition, which, if unchecked, can lead to progressive loss of vision, gastrointestinal bleeding and cardiovascular disease, including poor circulation and early heart attacks.
Jouni Uitto, M.D, Ph.D., professor and chair of dermatology and cutaneous biology and Franziska Ringpfeil, M.D., assistant professor of dermatology and cutaneous biology, both of Jefferson Medical College of Thomas Jefferson University in Philadelphia, and their co-workers at Jefferson and at the Mt. Sinai School of Medicine in New York studied eight families in which 13 members with the disorder had a damaged gene, MRP6, on chromosome 16. They characterized each person's mutation type and compared the affected individuals' physical condition and genetics with that of 20 unaffected family members. The researchers also identified several carriers of the PXE trait in unaffected individuals.
Dr. Ringpfeil and her colleagues report their findings October 5 at the American Society of Human Genetics meeting in Philadelphia. Some of this research was previously published in the Proceedings of the National Academy of Sciences.
"These findings allow us now to provide accurate diagnosis and carrier detection within the family using a simple blood test," says Dr. Uitto, who is also director of the Jefferson Institute of Molecular Medicine. "We can look at children of affected individuals and do presymptomatic testing. If the families want, we can also perform prenatal testing." Jefferson's Molecular Diagnostics Laboratory, he notes, is an international center for diagnosing another devastating inherited disorder, epidermolysis bullosa, a painful skin blistering disease.
"This is the first gene to be identified as having mutations causing or at least contributing to the disease," he says. The mutation has several variations. In some cases, the gene's protein is altered and doesn't work; in others, an entire gene copy is missing.
According to Dr. Uitto, the MRP6 gene belongs to a family of genes that may make a protein that serves as a molecular pump as part of an internal detoxification mechanism. "No one knows exactly what MRP6 does, but it is primarily expressed by the kidney and liver," he says. If the gene is damaged and not working properly, he speculates, "some compounds may accumulate in the blood that have an affinity for elastic structure in various organs. This binds to elastin and calcium, resulting in progressive calcification. It would also explain the delayed onset of the disease, since the accumulation would take time."
PXE is relatively rare, with estimates ranging from one in 25,000 to 50,000 affected in the general population. Most cases are autosomal recessive, meaning if two faulty gene carriers have children, there is a one in four chance of the child having the disease.
PXE is diagnosed by skin lesions as well as the presence of angioid streaks, which are abnormalities in the back of the eye, and which can lead to blindness. Circulation problems from the disorder can lead to early heart attacks.
Dr. Uitto suggests that reducing calcium intake and avoiding cigarette smoking may help slow disease progression. Those with a family history of the disease should have regular eye examinations to head off possible problems. Plastic surgery is an option to remove excess sagging skin.
His group would next like to study additional PXE families to try to better understand how the damaged gene is inherited. "We would also like to understand the function of the gene and its protein and be able to find out if other genes are involved as well," he says. A key to really understanding the gene's function, he says, is to create a "knockout" mouse lacking the gene, enabling the scientists to see what the specific effects are of a missing gene and protein.
"Such animals would also provide a means to test novel treatment modalities, including gene therapy, for this progressive and often devastating disease," Dr. Uitto says.
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