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Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis

Nature Genetics volume 33, pages 125–127 (2003)Cite this article

Abstract

Autosomal dominant distal renal tubular acidosis (ddRTA) is caused by mutations in SLC4A1, which encodes the polytopic chloride–bicarbonate exchanger AE1 that is normally expressed at the basolateral surface of α-intercalated cells in the distal nephron. Here we report that, in contrast with many disorders in which mutant membrane proteins are retained intracellularly and degraded, ddRTA can result from aberrant targeting of AE1 to the apical surface.

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Figure 1: Steady-state localization of full-length and truncated AE1 in polarized epithelial cells by confocal microscopy.
Figure 2: Steady-state localization of CD8–AE1 chimeras and AE1(Y904A) in filter-grown polarized MDCK (a–c) or LLC-PK1 cells (d–e).

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Acknowledgements

We thank N. Rungroj and Y. Su for technical assistance, P. Luzio, M. Robinson and R. Sandford for invaluable discussion and J. Schwartz for IMCD cells. This work was supported by the Wellcome Trust, the UK National Kidney Research Fund, Addenbrooke's Charities and Children's Kidney Care Fund and the Renal Care and Research Association. M.A.J.D. received a Sackler Fellowship.

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Author notes

  1. Gudrun Ihrke and Fiona E. Karet: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital Box 139, Cambridge, CB2 2XY, UK

    Mark A.J. Devonald, Annabel N. Smith, Jenny P. Poon & Fiona E. Karet

  2. Division of Nephrology, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital Box 139, Cambridge, CB2 2XY, UK

    Mark A.J. Devonald & Fiona E. Karet

  3. Department of Clinical Biochemistry, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital Box 139, Cambridge, CB2 2XY, UK

    Gudrun Ihrke

Authors
  1. Mark A.J. Devonald
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  2. Annabel N. Smith
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  3. Jenny P. Poon
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  4. Gudrun Ihrke
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  5. Fiona E. Karet
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Correspondence to Fiona E. Karet.

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The authors declare no competing financial interests.

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Devonald, M., Smith, A., Poon, J. et al. Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis. Nat Genet 33, 125–127 (2003). https://doi.org/10.1038/ng1082

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