BioWorld International Correspondent
LONDON - A team of European researchers identified a fourth gene involved in the rare kidney disorder nephronophthisis. The discovery should, the researchers predict, eventually allow new insights into the mechanism underlying the much commoner condition of renal fibrosis, which is present in many people with chronic renal failure.
Corinne Antignac, professor of genetics at the H pital Necker in Paris, told BioWorld International, "This new gene encodes a previously unknown protein. The disease it causes when mutated is so rare that the impact of the finding on clinical medicine is likely to be small, but given that renal replacement therapy is so expensive, then every small stone in the wall that will help our understanding of how to delay the occurrence of end-stage renal failure is of scientific interest."
Antignac, who led the research with collaborators in France, Italy, the UK and Turkey, published the account of the gene's discovery in a paper in the Sept. 9, 2002, issue of Nature Genetics titled "The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin."
Nephronophthisis is present in between 6 percent and 10 percent of children with end-stage renal disease. Inherited in an autosomal recessive fashion, it causes deterioration in renal function in childhood or adolescence. One of its characteristic features is the presence of fibrosis in the kidney, which also occurs in renal failure resulting from other causes.
"We believe that the pathway affected by the mutation of this gene might be of interest when looking for therapies to treat renal fibrosis in general," Antignac said. "In the long term we hope to find a treatment that will delay the onset or progression of fibrosis in children with nephronophthisis, and of fibrosis formation in general."
Researchers already had mapped three genes known to play a role in nephronophthisis before Antignac and her collaborators embarked on their latest study. Those genes are called NPHP1, NPHP2 and NPHP3, with NPHP1 being the only one so far identified. Another team had mapped the locus for a fourth nephronophthisis gene to chromosome 1p36, so Antignac's team set out to map the inheritance of markers covering that region in a set of seven families with members affected by nephronophthisis who were known not to be linked to the loci already identified.
In Nature Genetics, the researchers report that three families failed to show linkage to chromosome 1p36, indicating that further mutated genes remain to be discovered. Haplotype analysis of the remaining four families made it possible to narrow the region containing the mutant gene down to one containing six genes.
Further investigations led the team to identify the gene responsible for the disease in those families as one encoding a protein of hitherto unknown function. It has been called NPHP4, with its protein named nephrocystin-4. All affected individuals in the families studied had mutations in this gene that would have led, in most of them, to a truncated protein.
Biochemical studies of nephrocystin-4 suggested that the protein could interact with a related molecule, nephrocystin, the protein encoded by NPHP1. Writing in Nature Genetics, Antignac and her colleagues conclude: "In light of these findings, our results suggest that nephrocystin-4 is an additional partner of a nephrocystin multimolecular signaling complex, and might regulate cell-cell and cell-matrix adhesion. Accordingly, mutant nephrocystin-4 might modify cell adhesion, leading to the renal tubular basement abnormalities observed in individuals with nephronophthisis. Defining the function of these proteins should shed more light on the mechanisms of renal fibrosis development and cyst formation."
Antignac told BioWorld International that she also hopes to investigate the protein's role in the eye and the brain, as nephronophthisis can also be associated with conditions affecting these organs - namely, retinitis pigmentosa and ocular motor apraxia. "It is very interesting that the genes encoding both nephrocystin and nephrocystin-4 are expressed in a very large number of tissues. Yet when they are mutated, they give rise to abnormalities only in the kidney and in some cases in the eye and brain," she said. "We want to investigate how and why this occurs."