Focal glomerulosclerosis is a common form of kidney disease. Actually, from the point of view of what causes it, it's several forms of kidney disease with the same name; patients can develop FSGS due to a genetic defect, as a secondary illness due to other diseases such as HIV infection or develop it spontaneously.

"The pathology of FSGS is the same" in all three cases, said Michelle Winn, assistant professor of nephrology at Duke University's center for human genetics. "It's just a question of what the etiology is."

That pathology is scarring of the glomeruli, structures in the kidney that filter blood. "When the glomeruli scar down, you can't filter the blood anymore, and so you get a buildup of toxins," Winn told BioWorld Today. The disease typically is progressive, with many patients ultimately needing dialysis and/or a kidney transplant.

In the May 5, 2005, issue of ScienceExpress, researchers from Duke University Medical Center; Beaumont Hospital in Dublin, Ireland; and Christchurch Hospital in Christchurch, New Zealand, report having identified the genetic defect that underlies some inherited cases of the disease. The culprit in those cases is a point mutation in a gene that codes for a defective ion channel.

"What is so exciting about this is that it's a completely novel mechanism," said Winn, the study's lead author. "This is the first time an ion channel has been linked to FSGS. It was totally unexpected."

The gene that Winn and her colleagues found is not the first gene that can cause FSGS to be identified, but all of the genes identified to date code for structural proteins. The scientists hope that the ion channel they have identified might be more amenable to pharmacological intervention, given that targeting receptor-dependent ion channels is one of the major drug development strategies - calcium channel blockers had sales in excess of $4 billion in 2004.

The disease certainly could use better treatment options. Currently, the first-line treatment for FSGS is steroids, which have a success rate of 30 percent to 50 percent; Winn also said that using steroids to treat the inherited forms of the disorder is controversial.

Winn and her colleagues studied a family with an aggressive form of autosomal dominant FSGS. Genomic screening and haplotype analysis pinpointed a region of chromosome 11 as the home of the defect. Among other genes, that region is home to the gene for an angiotensin-receptor dependent calcium channel; previous research had reported that that gene is expressed in the kidney. Sequencing of the gene's exons led to the identification of a point mutation of a highly conserved amino acid, proline 112, in the channel. All of the affected individuals in the family showed that mutation, while neither unaffected family members nor unrelated controls did.

The scientists then transfected cells with the mutant receptor to study its physiological role in vitro. Cells transfected with the mutant channel showed a much greater calcium influx in response to activation than cells transfected with the wild-type channel. When cells were co-transfected with the channel and the angiotensin receptor, the receptor that normally activates that channel, the same increases in calcium occurred in response to stimulation with angiotensin.

Winn noted that the mechanism by which the calcium influx damages the cells and leads to the pathology seen in FSGS is still unknown, but said that "excess calcium is known to cause apoptosis. So that would be a plausible mechanism."

Winn and her colleagues are constructing a mouse model of the defect to further investigate the exact mechanism, as well as possible therapeutic strategies, for the disease. Asked whether the findings might be the underlying cause of at least some cases of spontaneous, as well as inherited, FSGS, Winn said, "It's possible. We'll have to test a lot of people to find out how prevalent this is."