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in Gene Causing Blindness, Early Heart Attacks in Rare Inherited Disorder
Mutations Identified in Gene Causing Blindness,
Early Heart Attacks in Rare Inherited Disorder
Jefferson in the News
The work of a research team led by Jouni Uitto, MD, PhD, Professor and Chair of Dermatology and Cutaneous Biology at Jefferson Medical College, has received some attention in the news media.
Articles in both the New York Times (May 23, 2000) and Science (June
2, 2000) describe the success story behind pseudoxanthoma elasticum (PXE), a
rare, inherited, connective tissue disorder that can lead to blindness and early
heart attacks. The stories describe both the science and the tireless efforts
of a patient advocacy group, PXE International, which helped three research groups,
including Dr. Uitto’s laboratory, pinpoint the identity of the gene for PXE. |
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.
“These findings allow us to provide accurate diagnosis and carrier detection within a family at risk for PXE using a simple blood test,” says Jouni Uitto, MD, PhD, Professor and Chair of Dermatology and Cutaneous Biology at Jefferson Medical College of Thomas Jefferson University, and senior author of the study. “We also can look at children of affected individuals and do presymptomatic testing, or even prenatal testing.”
PXE is difficult to diagnose because the symptoms often don’t 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.
Dr. Uitto, Franziska Ringpfeil, MD, a resident in the Department of Dermatology at Jefferson Medical College, and their colleagues reported their findings May 23, 2000 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, epidermylosis bullosa, a painful skin blistering disease.
“This is the first gene to be identified as having mutations causing or at least contributing to PXE,” 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.
Dr. Uitto and his 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.
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 that have an affinity for elastic structure in various organs may accumulate in the blood. 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 1 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 1 in 4 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.
What Patients Can Do
Patients can help themselves. Cutting down on calcium and avoiding cigarette smoking may slow down the disease’s effects, says
Dr. Uitto. If there’s a family history of the disease, get regular eye examinations to head off possible problems. Plastic surgery may take care of excess sagging skin.
His group would like to study additional families with PXE to
try to better understand how the damaged gene is inherited and
its effects.
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