Published: May 5, 2005
Updated: May 6, 2005
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By Duke Medicine News and Communications
Durham, N.C. -- Duke University Medical Center researchers have discovered a gene responsible for one form of chronic kidney disease. The disease, called familial focal segmental glomerulosclerosis (FSGS), can lead to complete kidney failure and affects 20 percent of patients on dialysis. The finding could lead to more effective treatments, according to the researchers.
By examining the genetic makeup of one large, multi-generational family with a dominant form of FSGS, the researchers linked a mutant form of the gene called Transient Receptor Potential Cation Channel 6 (TRPC6) to the disease. What's more, because the gene differs in function from those earlier implicated in FSGS, the finding represents a novel mechanism of kidney damage, said Michelle Winn, M.D., a kidney specialist and geneticist at the Duke Center for Human Genetics and lead author of the study.
Drugs that target the ion channel might offer an effective treatment to slow or prevent scarring of the kidney, the primary manifestation of the disease seen in patients, the researchers said. Such channels are pore-like proteins in the membranes of cells thought to control the flow of calcium.
"This gene represents the first ion channel to be associated with FSGS," Winn said. "It's a new mechanism for kidney disease, which may allow us to advance on new treatments as ion channels are known to be amenable to drug therapy."
In the United States, the prevalence of FSGS is increasing yearly, with a particularly high incidence among African-Americans, Winn said. The disease attacks tiny filtering units within the kidney called glomeruli -- leading to scarring, or hardening, of this filter. Symptoms of the disease include high blood pressure, an excess of protein in the urine, and insufficient elimination of wastes by the kidneys.
Drug therapies for FSGS are limited and non-specific, Winn added. Therefore, the kidney damage forces many patients to rely on hemodialysis, a procedure in which a patient's blood is fed through a machine. A filter in the dialysis machine removes wastes and extra fluids and returns purified blood to the body. Most dialysis patients undergo the procedure at a clinic three times a week for several hours.
While the causes of FSGS remain unclear, earlier evidence had linked three other genes to FSGS or FSGS-like diseases. The previously identified genes serve in the formation of structural proteins that support the cell membrane. In 1999, the Duke team identified a region of the genome linked to FSGS in a large New Zealand family.
In the current study, the researchers narrowed that span to the single gene, TRPC6, by screening 106 members of the seven-generation, 600-member family, including individuals with and without the disease.
In this family, all members with FSGS carry a mutation in the TRPC6 gene, the team reported. Further study of the gene variant in kidney cell cultures found that the mutation enhances the activity of the channels in response to angiotensin II, a protein known to promote high blood pressure and kidney injury, Winn said.
While TRPC6 mutations have yet to be reported in other families with hereditary FSGS, the findings raise a number of questions about the role of the channels in kidney function.
The channels may also offer a new target for kidney disease treatment, according to the researchers.
"Because channels tend to be amenable to pharmacological manipulation, our study raises the possibility that TRPC6 may be a useful therapeutic target in chronic kidney disease," Winn said.
The researchers have begun a broader genomic screen of additional families from around the world to further examine genetic mechanisms in FSGS.
Collaborators on the study include Merry Kay Farrington, April Hawkins, Nikki Daskalakis, Shu Ying Kwan, Seth Ebersviller, Margaret Pericak-Vance, Tony Creazzo and James Burchette, of Duke; Peter Conlon, of Beaumont Hospital in Dublin, Ireland; and Kelvin Lynn, of Christchurch Hospital in Christchurch, New Zealand. The National Institutes of Health supported the research.