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.