The discovery could lead to development of drugs that target the defective gene, said the researchers at Duke University Medical Center who discovered the mutation.
The gene defect accounts for 6 percent to 7 percent of all cases of hereditary spastic paraplegia, they said. The discovery of the gene defect will provide important insights into the causes of other major neurodegenerative diseases, including amyotrophic lateral sclerosis or Lou Gehrig's disease, said Stephan Züchner, M.D., assistant professor at the Duke Center for Human Genetics and the Department of Psychiatry.
"Patients with these genetic diseases now have no real treatment options," said Züchner, co-leader of the study team. "Our discovery will open up a new opportunity to study these diseases from a different angle so we can better understand what is causing them and which genes to target in developing treatments to manage them."
The researchers report their findings in the August 2006 issue of the American Journal of Human Genetics, which is now available online. The research was funded by the National Institutes of Health and by donations to the Duke Center for Human Genetics from individuals and families affected by hereditary spastic paraplegia.
Hereditary spastic paraplegia, one of a number of related inherited disorders, causes progressive limb weakness and stiffness, often resulting in paralysis. As with many neurodegenerative diseases, patients typically begin to show symptoms during their mid-20s to mid-50s, and the symptoms grow progressively more debilitating with time. With no cure available, physicians can only treat symptoms with physical therapy to improve muscle strength and preserve range of motion.
In their study, the Duke researchers found that one form of hereditary spastic paraplegia is linked to a gene called REEP1. The gene normally produces proteins that support the cell's energy source, the mitochondria. But a defect in the gene may disable its proteins from performing their normal functions in mitochondria – most notably the mitochondria within the nervous system's cellular pathways. Precisely how this protein malfunction occurs is still unknown, said Margaret Pericak-Vance, Ph.D., director of Duke's Center for Human Genetics and co-leader of the study.
The Duke scientists began their search for genes associated with the disease by studying two families whose members had hereditary spastic paraplegia.
Using gene-mapping techniques, the researchers identified a small stretch of DNA on chromosome 2, where the disease-causing gene was thought to reside. The researchers screened nine candidate genes that play a potential role in governing the cellular pathways of neurodegenerative disease. By meticulously examining the DNA sequence of those genes, the researchers located mutations -- changes in the DNA sequence -- in the REEP1 gene among people who have hereditary spastic paraplegia but not in their unaffected relatives.
Pericak-Vance and team member Allison Ashley-Koch, Ph.D., said that the discovery of REEP1's role in hereditary spastic paraplegia strengthens the evidence that defects in mitochondria are responsible for many types of neurodegenerative diseases. For example, scientists have discovered that Lou Gehrig's disease is caused by mutations in SOD1, a gene whose protein is also expressed in mitochondria.
With REEP1's role now identified, scientists are developing a genetic test to identify patients who have the defect, Züchner said. The Duke team has licensed its gene discovery to Athena Diagnostics Inc. to develop a genetic test for patients at risk for the disease.
Other members of the research team were Gaofeng Wang, Khan Nhat Trans Viet, Martha Nance, Perry Gaskell and Jeffrey Vance.
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