- To maintain and update a world-wide computer network for registration of rare genetic diseases
- To identify the gene defect in Gitelman syndrome
- To identify the gene defect in Bartter syndrome
The International Study of Genetic Renal Diseases has implemented an electronic database , called "Kidbase" which provides an inventory of rare genetic diseases of the kidney and is linked to the Genome Database. Kidbase is accessible throughout the world by the World Wide Web. Every researcher may enter information on clinical aspects and availability of biological materials of families with genetic renal diseases. Kidbase is an important measure to overcome the rate limiting step in the elucidation of the disease genes, which is the availability of family material. Gitelman syndrome is mostly an autosomal recessive disorder affecting renal tubular function associated with hypokalemia and hypomagnesemia. Symptoms consist of fatigue, muscle weakness and recurrent episodes of carpopedal spasm due to hypomagnesemia. Functional studies point to a defect in the recently cloned thiazide-sensitive, electroneutral sodium-chloride transporter (TSC) in the distal renal tubule. Our first approach will be concentrated on this candidate gene. Based on the sequence of the rat cDNA clone and the availability of the cDNA probes from the rat, the human TSC gene will be cloned. The obtained clones will be used to determine the chromosomal localization on hybrid panels and via FISH analysis. After the localization, polymorphic markers will be selected for linkage analysis in the patients. If significant linkage is found, mutation detection will be performed by SSCP analysis and sequencing. In case a mutation in TSC is found, the mutated transcript will be subject to expression studies in Xenopus oocytes. Bartter syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemia, metabolic alkalosis and hyperaldosteronism with normal blood pressure. Symptoms such as polyuria, polydipsia, vomiting, a tendency to dehydration and failure to thrive develop after infancy. Functional studies point to a defect in the bumetanide-sensitive sodium-chloride cotransporter (BSC) in the thick ascending limb of Henle's loop in the mammalian kidney. Human and rat cDNA clones of this transporter are available to the groups within this Concerted Action. The role of BSC as a candidate gene for Bartter syndrome will be examined by a similar strategy as described above for Gitelman syndrome. If the candidate hypothesis for either or both Gitelman and Bartter syndrome is not verified, the positional candidate approach will be implemented to map the diasease locus and finally characterize the genetic defect.