An international research team headed by the University of Hawaii's Laboratory of Matrix Pathobiology has identified the first mutations responsible for a genetic disease that causes skin lesions, blindness and premature hardening of the arteries. The paper announcing the discovery appears in the June 1 issue of the journal Nature Genetics.

While relatively rare -- occurring in about one in 25,000 live births -- pseudoxanthoma elasticum, or PXE, can have devastating consequences, says Charles Boyd, a researcher in the UH Pacific Biomedical Research Center and director of the matrix pathobiology lab. "Discovery of responsible mutations makes it possible to screen for the disorder while its victims are still young enough for dietary interventions to lessen the impact of the disease," says Boyd.

In PXE, elastin fibers in the matrix, or space between cells, of the skin, retina and arteries become calcified and lose their resilience. Onset of the disease is usually signaled first by a rash of yellow papules on the skin, especially around the neck, groin and thighs. In more advanced forms, the skin sags and wrinkles, giving the appearance of premature aging. The disease is also characterized by pain and cramps related to poor circulation in the legs, hypertension and stroke. Rupture of a membrane at the back of the retina causes bleeding that leads to blindness, and premature arteriosclerosis can necessitate heart bypass surgery in patients still in their 20s. Gastro-intenstinal bleeding from ruptured blood vessels is a frequent cause of PXE-related death.

"PXE affects a small percentage of the population overall, but it may represent a larger proportion of people with cardiovascular disease," says Boyd. "If we can screen for the mutation and use intervention that moderates development of the disease, we can reduce the overall incidence of death from heart disease." Locally, Boyd hopes that such efforts could help reduce the high rate of heart disease among Native Hawaiians in particular.

Discovery of the PXE gene mutation builds on work by a Harvard team that identified a locus on Chromosome 16. Gene sequencing decoded as part of the Human Genome Project identified six likely genes out of the hundreds of thousands of base pairs in the targeted section of the DNA strand. Comparison of the gene's building-block base pairs turned up several mutations in PXE-affected individuals that were not present in DNA samples from a control group.

PXE is typically a recessive trait, but PXE can also appear in a dominant manner. In recessive traits, both parents carry the mutation on one of their pair of chromosomes but do not develop the disease; their offspring have a one-in-four chance of receiving two recessive genes, one from each parent, and developing the disease. In dominant cases, only one copy of the mutated gene is required to express the trait. With PXE, some carriers with one copy of the mutation do not get the full-blown disease, but are at risk of developing the associated cardiovascular disease. Scientists aren't yet sure why, but overall, there is a great deal of variation in the age of onset and the severity of the disease, even within the same family.

Scientists are also intrigued that the PXE-causing mutations occur on a gene that codes for production of an ABC transporter, which shuttles proteins across cell membranes. The gene is also of interest because it has been associated with drug resistance that occurs when drug compounds are not carried across the cell membrane into the cell. ABC transporters do not typically carry calcium, but miscoding in the gene may cause misdirection of the transporters. The findings by the UH group were reported in conjunction with a second Nature Genetics paper by a second research group, from Holland, and findings reported by a third group, from Jefferson Medical College, in the Proceedings of the National Academy of Sciences last week.

Boyd's group includes a UH postdoctoral researcher Olivier Le Saux, who is first author on the Nature Genetics paper. Additional collaborators included Matrix Pathobiology Lab faculty members Katalin Csiszar and Zsolt Urban and visiting German undergraduates Cordula Tschuch and Karina Treiber. The UH group worked closely with an international consortium of investigators from England, Belgium and Italy to find the PXE gene.

The research team's efforts were coordinated by Boyd and his collaborators on the hunt for the PXE gene, Sharon Terry, founder and president of PXE International. Terry and her husband Patrick have two children who both have PXE. In an attempt to help accelerate research that will lead to a cure for this crippling disease, the couple founded the organization to be a proactive force, and PXE International has worked closely with several research groups, particularly Boyd's Matrix Pathobiology Laboratory, in the hunt for the PXE gene. Their involvement has established an unprecedented model for citizen involvement in scientific research, including serving as co-principal investigator on a major federal grant and co-authoring four papers published in peer-reviewed publications. PXE International has not only raised money for research, it has hired researchers, organized National Institutes of Health�supported conferences, designed protocols and participated in research. The 1,500 samples in the blood and tissue bank established and maintained by PXE International are an integral resource for researchers.

"Lay advocacy organizations can do much, much more than provide scientists access to patients," says Terry. "We are part of a sea change in genetic research, one that is forging a new kind of partnership between patients and scientists. Our activity is clearly a new paradigm for lay/researcher collaboration."

The Laboratory of Matrix Pathobiology at UH was established with funding from the Pacific Biomedical Research Center's federal Research Centers in Minority Institutions grant. The PXE research was conducted under a grant from the National Institutes of Health.

Contact:
Charles Boyd, Pacific Biomedical Research Center
808-956-6341, cbkc@aol.com

Sharon Terry, PXE International
781-784-3817, sterry@pxe.org