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A common molecular basis for three inherited kidney stone diseases

Nature volume 379, pages 445–449 (1996)Cite this article

Abstract

KIDNEY stones (nephrolithiasis), which affect 12% of males and 5% of females in the western world, are familial in 45% of patients1,2 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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Author notes

  1. Rajesh V. Thakker: To whom correspondence should be addressed.

Authors and Affiliations

  1. MRC Molecular Endocrinology Group, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London, W12 DNN, UK

    Sarah E. Lloyd, Simon H. S. Pearce, Steven J. Scheinman, Brian Harding & Rajesh V. Thakker

  2. Genetics Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

    Simon E. Fisher & Ian W. Craig

  3. Centre for Molecular Neurobiology Hamburg (ZMNH), Hamburg University, Martinistrasse 52, D-20246, Hamburg, Germany

    Klaus Steinmeyer, Blanche Schwappach & Thomas J. Jentsch

  4. Department of Medicine, State University of New York Health Science Center, Syracuse, New York, 13210, USA

    Steven J. Scheinman

  5. Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Largo Gaslini 5, 16148, Geneva, Italy

    Alessandra Bolino & Marcella Devoto

  6. L'Hôpital de Montreal pour Enfants, 2300 rue Tupper, A717, Montreal, Quebec, H3HIP3, Canada

    Paul Goodyer

  7. Department of Paediatric Nephrology, Guy's Hospital, St Thomas's Street, London, SE1 9RT, UK

    Susan P. A. Rigden

  8. Department of Nephrology, The Middlesex Hospital, Mortimer Street, London, WIN 8AA, UK

    Oliver Wrong

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  1. Sarah E. Lloyd
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  9. Marcella Devoto
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Lloyd, S., Pearce, S., Fisher, S. et al. A common molecular basis for three inherited kidney stone diseases. Nature 379, 445–449 (1996). https://doi.org/10.1038/379445a0

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