Nature 379, 445 - 449 (01 February 1996); doi:10.1038/379445a0

A common molecular basis for three inherited kidney stone diseases

Sarah E. Lloyd^*, Simon H. S. Pearce^*, Simon E. Fisher^†, Klaus Steinmeyer^‡, Blanche Schwappach^‡, Steven J. Scheinman^*§, Brian Harding^*, Alessandra Bolino, Marcella Devoto, Paul Goodyer^¶, Susan P. A. Rigden^£, Oliver Wrong, Thomas J. Jentsch^‡, Ian W. Craig^† & Rajesh V. Thakker^*††

^* MRC Molecular Endocrinology Group, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 DNN, UK
^† Genetics Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
^‡ Centre for Molecular Neurobiology Hamburg (ZMNH), Hamburg University, Martinistrasse 52, D-20246 Hamburg, Germany
^§ Department of Medicine, State University of New York Health Science Center, Syracuse, New York 13210, USA
Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Largo Gaslini 5, 16148 Geneva, Italy
^¶ L'Hôpital de Montreal pour Enfants, 2300 rue Tupper, A717 Montreal, Quebec H3HIP3, Canada
^£ Department of Paediatric Nephrology, Guy's Hospital, St Thomas's Street, London SE1 9RT, UK
Department of Nephrology, The Middlesex Hospital, Mortimer Street, London WIN 8AA, UK
^†† To whom correspondence should be addressed.

KIDNEY stones (nephrolithiasis), which affect 12% of males and 5% of females in the western world, are familial in 45% of patients^1,2 and are most commonly associated with hypercalciuria¹. Three disorders of hypercalciuric nephrolithiasis (Dent's disease³, X-linked recessive nephrolithiasis (XRN)⁴, and X-linked recessive hypophosphataemic rickets (XLRH)⁵) have been mapped to Xpll.22 (refs 5–7). A microdeletion⁶ in one Dent's disease kindred allowed the identification of a candidate gene,CLCN5 (refs 8,9) which encodes a putative renal chloride 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 micro-deletion encompassing the entire gene. Heterologous expression of wild-type CLCN5 in Xenopus oocytes yielded outwardly rectifying chloride currents, which were either abolished or markedly reduced by the mutations. The common aetiology for Dent's disease, XRN and XLRH indicates that CLCN5 may be involved in other renal tubular disorders associated with kidney stones.

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