ISOLATION AND PARTIAL CHARACTERIZATION OF A CHLORIDE CHANNEL GENE WHICH IS EXPRESSED IN KIDNEY AND IS A CANDIDATE FOR DENTS DISEASE (AN X-LINKED HEREDITARY NEPHROLITHIASIS)

Dent's disease, an X-linked renal tubular disorder, is a form of Fanco ni syndrome which is characterized by proteinuria, hypercalciuria, nep hrocalcinosis, kidney stones and renal failure. Previous studies local ised the gene responsible to Xp11.22, within a microdeletion involving the hypervariable locus DXS255. Further analysis using new probes whi ch flank this locus indicate that the deletion is less than 515 kb. A 185 kb YAC containing DXS255 was used to screen a cDNA library from ad ult kidney in order to isolate coding sequences falling within the del eted region which may be implicated in the disease aetiology. We ident ified two clones which are evolutionarily conserved, and detect a 9.5 kb transcript which is expressed predominantly in the kidney. Sequence analysis of 780 bp of ORF from the clones suggests that the identifie d gene, termed hCIC-K2, encodes a new member of the CIC family of volt age-gated chloride channels. Genomic fragments detected by the cDNA cl ones are completely absent in patients who have an associated microdel etion. On the basis of the expression pattern, proposed function and d eletion mapping, hCIC-K2 is a strong candidate for Dent's disease.