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Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease

Nature Genetics volume 24, pages 61–65 (2000)Cite this article

Abstract

Hailey-Hailey disease (HHD, MIM 16960) is inherited in an autosomal dominant manner and characterized by persistent blisters and erosions of the skin1. Impaired intercellular adhesion and epidermal blistering also occur in individuals with pemphigus (which is due to autoantibodies directed against desmosomal proteins) and in patients with Darier disease (DD, MIM 124200), which is caused by mutations in a gene encoding a sarco/endoplasmic reticulum (ER)-Golgi calcium pump2. We report here the identification of mutations in ATP2C1, encoding the human homologue of an ATP-powered pump that sequesters calcium into the Golgi in yeast, in 21 HHD kindreds. Regulation of cytoplasmic calcium is impaired in cultured keratinocytes from HHD patients, and the normal epidermal calcium gradient is attenuated in vivo in HHD patients. Our findings not only provide an understanding of the molecular basis of HHD, but also underscore the importance of calcium control to the functioning of stratified squamous epithelia.

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Figure 1: Clinical and histological features of HHD.
Figure 2: Physical map of HHD gene region.
Figure 3: Expression of the ATP2C1transcript.
Figure 4: Mutation analysis in HHD families.
Figure 5: Response of normal and HHD keratinocytes to raised extracellular Ca2+.

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References

  1. Burge, S.M. Hailey-Hailey disease: the clinical features, response to treatment and prognosis . Br. J. Dermatol. 126, 275– 282 (1992).

    Article  CAS  Google Scholar 

  2. Sakuntabhai, A. et al. Mutations in ATP2A2, encoding a Ca2+pump, cause Darier disease. Nature Genet. 21, 271–277 (1999).

    Article  CAS  Google Scholar 

  3. Ikeda, S. et al. Localization of the gene whose mutations underlie Hailey-Hailey disease to chromosome 3q. Hum. Mol. Genet. 3, 1147–1150 (1994).

    Article  CAS  Google Scholar 

  4. Peluso, A.M. et al. Narrowing of the Hailey-Hailey disease gene region on chromosome 3q and identification of one kindred with a deletion in this region. Genomics 30, 77–80 ( 1995).

    Article  CAS  Google Scholar 

  5. Richard, G. et al. Hailey-Hailey disease maps to a 5 cM interval on chromosome 3q21–q24. J. Invest. Dermatol. 105, 357–360 (1995).

    Article  CAS  Google Scholar 

  6. Gunteski-Hamblin, A.M., Greeb, J. & Shull, G.E. A novel Ca2+ pump expressed in brain, kidney, and stomach is encoded by an alternative transcript of the slow-twitch muscle sarcoplasmic reticulum Ca-ATPase gene. Identification of cDNAs encoding Ca2+ and other cation-transporting ATPases using an oligonucleotide probe derived from the ATP-binding site. J. Biol. Chem. 263, 15032–15040 (1988).

    CAS  PubMed  Google Scholar 

  7. Gunteski-Hamblin, A.M., Clarke, D.M. & Shull, G.E. Molecular cloning and tissue distribution of alternatively spliced mRNAs encoding possible mammalian homologues of the yeast secretory pathway calcium pump. Biochemistry 31, 7600 –7608 (1992).

    Article  CAS  Google Scholar 

  8. Rudolph, H.K. et al. The yeast secretory pathway is perturbed by mutations in PMR1, a member of a Ca2+ ATPase family. Cell 58, 133–145 (1989).

    Article  CAS  Google Scholar 

  9. Antebi, A. & Fink, G. The yeast Ca(2+)-ATPase homologue, PMR1, is required for normal Golgi function and localizes in a novel Golgi-like distribution. Mol. Biol. Cell 3, 633–654 (1992).

    Article  CAS  Google Scholar 

  10. Sorin, A., Rosas, G. & Rao, R. PMR1, a Ca2+-ATPase in yeast Golgi, has properties distinct from sarco/endoplasmic reticulum and plasma membrane calcium pumps. J. Biol. Chem. 272, 9895–9901 (1997).

    Article  CAS  Google Scholar 

  11. Ikeda, S. & Ogawa, H. Effects of steroid, retinoid, and protease inhibitors on the formation of acantholysis induced in organ culture of skins from patients with benign familial chronic pemphigus. J. Invest. Dermatol. 97, 644–648 (1991).

    Article  CAS  Google Scholar 

  12. Krizaj, D. & Copenhagen, D.R. Compartmentalization of calcium extrusion mechanisms in the outer and inner segments of photoreceptors. Neuron 21, 249–256 ( 1998).

    Article  CAS  Google Scholar 

  13. Mauro, T., Dixon, D.B., Komuves, L., Hanley, K. & Pappone, P.A. Keratinocyte K+channels mediate Ca2+-induced differentiation. J. Invest. Dermatol. 108, 864–870 (1997).

    Article  CAS  Google Scholar 

  14. Mauro, T. et al. Acute barrier perturbation abolishes the Ca2+ and K+ gradients in urine epidermis: quantitative measurement using PIXE. J. Invest. Dermatol. 111, 1198 –1201 (1998).

    Article  CAS  Google Scholar 

  15. Elias, P.M. et al. Formation of the epidermal calcium gradient coincides with key milestones of barrier ontogenesis in the rodent. J. Invest. Dermatol. 110, 399–404 ( 1998).

    Article  CAS  Google Scholar 

  16. Resing, K.A., al-Alawi, N., Blomquist, C., Fleckman, P. & Dale, B.A. Independent regulation of two cytoplasmic processing stages of the intermediate filament-associated protein filaggrin and role of Ca2+ in the second stage. J. Biol. Chem. 268, 25139–25145 ( 1993).

    CAS  PubMed  Google Scholar 

  17. Chakravarthy, B., Isaacs, R., Morley, P., Durkin, J. & Whitfield, J. Stimulation of protein kinase C during Ca2+ induced keratinocyte differentiation. J. Biol. Chem. 270, 1362–1368 (1995).

    Article  CAS  Google Scholar 

  18. Amar, L.S., Shabana, A.H., Oboeuf, M., Martin, N. & Forest, N. Involvement of desmoplakin phosphorylation in the regulation of desmosomes by protein kinase C, in HeLa cells. Cell Adhes. Commun. 7, 125–138 (1999).

    Article  CAS  Google Scholar 

  19. Berth-Jones, J., Smith, S. & Graham-Brown, R. Benign familial chronic pemphigus (Hailey-Hailey disease) responds to cyclosporin. Clin. Exp. Dermatol. 20, 70–72 (1994).

    Article  Google Scholar 

  20. Oda, K. Calcium depletion blocks proteolytic cleavages of plasma protein precursors which occur at the Golgi and/or trans-Golgi network. Possible involvement of Ca(2+)-dependent Golgi endoproteases. J. Biol. Chem. 267, 17465–17471 (1992).

    CAS  PubMed  Google Scholar 

  21. Kaufman, R., Swaroop, M. & Murtha-Riel, P. Depletion of manganese within the secretory pathway inhibits O-linked glycosylation in mammalian cells. Biochemistry 33, 9813–9819 ( 1994).

    Article  CAS  Google Scholar 

  22. Amagai, M., Ishii, K., Takayanagi, A., Nishikawa, T. & Shimizu, N. Transport to endoplasmic reticulum by signal peptide, but not proteolytic processing, is required for formation of conformational epitopes of pemphigus vulgaris antigen (Dsg3). J. Invest. Dermatol. 107, 539–542 (1996).

    Article  CAS  Google Scholar 

  23. Vulpe, C. & Packman, S. Cellular copper transport. Annu. Rev. Nutr. 15, 293–322 (1995).

    Article  CAS  Google Scholar 

  24. Riley, J. et al. A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. Nucleic Acids Res. 18, 2887–2890 ( 1990).

    Article  CAS  Google Scholar 

  25. Aszterbaum, M. et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with basal cell nevus syndrome. J. Invest. Dermatol. 110, 885–888 (1998).

    Article  CAS  Google Scholar 

  26. Christiano, A. et al. Strategy for identification of seqence variants in COL7a1, and a novel 2-bp deletion mutation in recessive dystrophic epidermolysis bullosa . Hum. Mutat. 10, 408–414 (1997).

    Article  CAS  Google Scholar 

  27. Bunse, T., Steigleder, G.K., Hofert, M. & Gonsior, B. PIXE analysis in uninvolved skin of atopic patients and aged skin. Acta Derm. Venereol. 71, 287–290 (1991).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank patients and family members for participation; H. Baden and other referring clinicians; C. Collins, P. O'Donnell, K. Gardiner, J. Korenberg and G. Magrane for physical mapping advice and assistance; C. Carlson and D. Cox for assistance in establishing the somatic cell hybrids; D. Crumrine and S. Pennypacker for cell culture and technical assistance; B. Grant and J. Kropp for advice and equipment for TaqMan assays; M. Amagai, L. Diaz, G. Guidice, A. Haake, C. Loomis, S. Rosen, T. Sun and J. Xie for advice and assistance and for the provision of reagents; C. Botka at SACs at UCSF for computer assistance; and M. Aszterbaum, D. Copenhagen and D. Geyer Hagen for helpful discussion and assistance. Z.H. was partly supported by a SmithKline-Beecham Fellowship of the Dermatology Foundation. This work was supported by NIH AR43119 (E.H.E.) and AR44341 (T.M.), the Medical Research Service, San Francisco Veteran's Affairs and the US Department of Energy by Lawrence Livermore National Laboratory under contract W-7405-ENG-48 (G.B.).

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Authors and Affiliations

  1. Department of Dermatology, San Francisco General Hospital, University of California at San Francisco, San Francisco, California, USA

    Zhilan Hu, Jeannette M. Bonifas, Jenna Beech & Ervin H. Epstein Jr

  2. Department of Dermatology, VA Medical Center, University of California at San Francisco, San Francisco, California , USA

    Theodora Mauro

  3. Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, California , USA

    Graham Bench

  4. Department of Dermatology, Juntendo University, School of Medicine, Tokyo, Japan

    Takako Shigihara, Hideoki Ogawa & Shigaku Ikeda

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Correspondence to Zhilan Hu or Ervin H. Epstein Jr.

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Hu, Z., Bonifas, J., Beech, J. et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet 24, 61–65 (2000). https://doi.org/10.1038/71701

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