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Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease

Nature Genetics volume 21, pages 271–277 (1999)Cite this article

Abstract

Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2+-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca2+-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.

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Figure 1: Clinical and histological features of Darier disease.
Figure 2: Tissue expression of the ATP2A2 transcripts.
Figure 3: Identification of ATP2A2 mutations in familial and sporadic patients with DD.
Figure 4: Model of the human SERCA2 polypeptide and mutations identified in patients with DD.

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Acknowledgements

We thank the clinicians and the families who participated; R. Cox and E. Levy for their contribution in the physical mapping and cytogenetic parts of the project; R. Gibbs for the freely available sequence from the NIH-funded Human Genome Sequencing effort at the Baylor College of Medicine Human Genome Sequencing Center (BCM-HGSC); and J. Bell for support and encouragement. A.S. has a fellowship from the Royal Thai Government and the faculty of Medicine, Ramathibodi Hospital, Mahidol University; S.M. had a Wellcome Trust prize studentship; A.P.M. is a Wellcome Principal Research Fellow; A.H. held a Wellcome Trust and an EC research fellowship. S.C. was supported by a Wellcome Trust Project Grant awarded to T.S., C.S.M. and J.R.; V.R.-P. holds an EC fellowship. The work in Cardiff was supported by grants from the Wellcome Trust. N.C. is a Wellcome Senior Research Fellow.

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Authors and Affiliations

  1. The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK

    Anavaj Sakuntabhai, Sarah Monk, G. Mark Lathrop, Anthony P. Monaco & Alain Hovnanian

  2. Department of Human Genetics, University of Newcastle upon Tyne, NE1 7RU, UK

    Victor Ruiz-Perez, Simon Carter, Melanie Smith & Tom Strachan

  3. Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, CF4 4XN, UK

    Nick Jacobsen, Michael O'Donovan & Mike Owen

  4. Department of Dermatology, Churchill Hospital, Oxford, OX3 7LJ, UK

    Susan Burge

  5. Department of Dermatology, Southern General Hospital, Glasgow, G51 4TF, UK

    Colin S. Munro

  6. Department of Psychiatry, University of Birmingham, Birmingham, B15 2QZ, UK

    Nick Craddock

  7. Department of Molecular Genetics, Albert Einstein College of Medicine, New York, 10461, New York, USA

    Raju Kucherlapati

  8. Department of Dermatology, University of Newcastle upon Tyne, NE1 7RU, UK

    Jonathan L. Rees

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Correspondence to Tom Strachan or Alain Hovnanian.

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Sakuntabhai, A., Ruiz-Perez, V., Carter, S. et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet 21, 271–277 (1999). https://doi.org/10.1038/6784

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