A COMMON MOLECULAR-BASIS FOR 3 INHERITED KIDNEY-STONE DISEASES

KIDNEY stones (nephrolithiasis), which affect 12% of males and 5% of f emales in the western world, are familial in 45% of patients(1,2) and are most commonly associated with hypercalciuria(1). Three disorders o f hypercalciuric nephrolithiasis (Dent's disease(3), X-linked recessiv e nephrolithiasis (XRN)(4), and X-linked recessive hypophosphataemic r ickets (XLRH)(5)) have been mapped to Xp11.22 (refs 5-7). A microdelet ion(6) in one Dent's disease kindred allowed the identification of a c andidate gene, CLCN5 (refs 8,9) which encodes a putative renal chlorid e channel. Here we report the investigation of 11 kindreds with these renal tubular disorders for CLCN5 abnormalities; this identified three nonsense, four missense and two donor splice site mutations, together with one intragenic deletion and one microdeletion encompassing the e ntire gene. Heterologous expression of wild-type CLCN5 in Xenopus oocy tes yielded outwardly rectifying chloride currents, which were either abolished or markedly reduced by the mutations. The common aetiology f or Dent's disease, XRN and XLRH indicates that CLCN5 may be involved i n other renal tubular disorders associated with kidney stones.