Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease
Abstract
Hailey-Hailey disease (HHD, MIM 16960) is inherited in an autosomal dominant manner and characterized by persistent blisters and erosions of the skin. 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 pump. 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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The calcium concentration of the Golgi compartment is highly regulated in keratinocytes.
“Recent work has shown that the calcium concentration of the Golgi compartment is highly regulated in keratinocytes (32,33), and the calcium gradients across the Golgi play a fundamental part in intracellular calcium signaling and homeostasis (for review, see Ref. 34).”
From SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis (2008) · cites this paper as [32]
Cites
Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease
Sakuntabhai, A., Ruiz-Perez, V., Carter, S., Jacobsen, N., Burge, S., Monk, S., Smith, M., Munro, C. S., O'Donovan, M., Craddock, N., et al. (1999) · Nature Genetics · doi:10.1038/6784 · Cited by 740 · see citing works
Riley, J. W., Butler, R., Ogilvie, D., Finniear, R. S., Jenner, D. C., Powell, S., Anand, R., Smith, J. C., & MARKHAM, A. F. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.10.2887 · Cited by 644 · see citing works
The yeast secretory pathway is perturbed by mutations in PMR1, a member of a Ca2+ ATPase family
Rudolph, H. K., Antebi, A., Fink, G. R., Buckley, C. M. F., Dorman, T. E., LeVitre, J., Davidow, L. S., Mao, J.-I., & Moir, D. T. (1989) · Cell · doi:10.1016/0092-8674(89)90410-8 · Cited by 536 · see citing works
Antebi, A., & Fink, G. R. (1992) · Molecular Biology of the Cell · doi:10.1091/mbc.3.6.633 · Cited by 443 · see citing works
Aszterbaum, M., Rothman, A., Fisher, M. P., Xie, J., Bonifas, J. M., Zhang, X., Epstein, E. H., Johnson, R. L., & Scott, M. P. (1998) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.1998.00222.x · Cited by 306 · see citing works
Self-citationHailey–Hailey disease: the clinical features, response to treatment and prognosis
BURGE, S. M. (1992) · British Journal of Dermatology · doi:10.1111/j.1365-2133.1992.tb00658.x · Cited by 306 · see citing works
Vulpe, C. D., & Packman, S. (1995) · Annual Review of Nutrition · doi:10.1146/annurev.nu.15.070195.001453 · Cited by 289 · see citing works
Gunteski-Hamblin, A. M., Greeb, J., & Shull, G. E. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68142-6 · Cited by 271 · see citing works
Sorin, A., Rosas, G. O., & Rao, R. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.15.9895 · Cited by 240 · see citing works
Mauro, T. M., Elias, P. M., Cullander, C., Bench, G., Haddad, E. S., & Feingold, K. R. (1998) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.1998.00421.x · Cited by 172 · see citing works
Self-citationKrižaj, D., & Copenhagen, D. R. (1998) · Neuron · doi:10.1016/s0896-6273(00)80531-0 · Cited by 138 · see citing works
Gunteski-Hamblin, A. M., Clarke, D. M., & Shull, G. E. (1992) · Biochemistry · doi:10.1021/bi00148a023 · Cited by 112 · see citing works
Kaufman, R. J., Swaroop, M., & Murtha-Riel, P. (1994) · Biochemistry · doi:10.1021/bi00199a001 · Cited by 88 · see citing works
Resing, K. A., Al-Alawi, N., Blomquist, C. L., et al. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74580-3 · Cited by 86 · see citing works
Elias, P. M., Nau, P., Hanley, K. P., et al. (1998) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.1998.00151.x · Cited by 86 · see citing works
Benign familial chronic pemphigus (Hailey-Hailey disease) responds to cyclosporin
Berth‐Jones, J., Smith, S., & GRAHAM-BROWN, R. A. C. (1995) · Clinical and Experimental Dermatology · doi:10.1111/j.1365-2230.1995.tb01290.x · Cited by 57 · see citing works
Keratinocyte K+ Channels Mediate Ca2+-Induced Differentiation
Mauro, T. M., Dixon, D. B., Kömüves, L. G., et al. (1997) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12292585 · Cited by 55 · see citing works
Self-citationStimulation of Protein Kinase C during Ca2+-induced Keratinocyte Differentiation
Chakravarthy, B. R., Isaacs, R. J., Morley, P., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.3.1362 · Cited by 52 · see citing works
Oda, K. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41949-7 · Cited by 51 · see citing works
Localization of the gene whose mutations underlie Hailey—Hailey disease to chromosome 3q
Ikeda, S., Welsh, E. A., Peluso, A. M., et al. (1994) · Human Molecular Genetics · doi:10.1093/hmg/3.7.1147 · Cited by 45 · see citing works
Self-citationHailey-Hailey Disease Maps to a 5 cM Interval on Chromosome 3q21-q24
Richard, G., Korge, B. P., Wright, A., et al. (1995) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12320741 · Cited by 36 · see citing works
Amar, L. S., Shabana, A.-H. M., Oboeuf, M., et al. (1999) · Cell Communication & Adhesion · doi:10.3109/15419069909034396 · Cited by 25 · see citing works
MARIAPELUSO, A., Bonifas, J. M., Ikeda, S., et al. (1995) · Genomics · doi:10.1006/geno.1995.0011 · Cited by 22 · see citing works
Self-citationCasals, T., Pacheco, P. R., Barreto, C., Giménez, J., Ramos, M., Pereira, S., Pinheiro, J. A., Cobos, N., Curvelo, A., Vázquez, C., et al. (1997) · Human Mutation · doi:10.1002/(sici)1098-1004(1997)10:5 · Cited by 15 · see citing works
Amagai, M., Ishii, K., Takayanagi, A., et al. (1996) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12582796 · Cited by 14 · see citing works
Ikeda, S., & Ogawa, H. (1991) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12483596 · Cited by 12 · see citing works
Self-citationPIXE analysis in uninvolved skin of atopic patients and aged skin.
Bunse, T., Steigleder, G. K., Hofert, M. D., et al. (1991) · Acta Dermato Venereologica · doi:10.2340/0001555571287290 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The cornified envelope: a model of cell death in the skin
Candi, E., Schmidt, R., & Melino, G. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1619 · Cited by 1,776 · see citing works
Ginger, R. S., Askew, S. E., Ogborne, R. M., Wilson, S., Ferdinando, D., Dadd, T., Smith, A. M., Kazi, S., Szerencsei, R. T., Winkfein, R. J., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707521200 · Cited by 158 · see citing works
- Authors
- Hu, Z., Bonifas, J. M., Beech, J., Bench, G., Shigihara, T., Ogawa, H., Ikeda, S., Mauro, T., & Epstein, E. H.
- Affiliations
- San Francisco General Hospital (US)
- Lawrence Livermore National Laboratory (US)
- Juntendo University (JP)
- San Francisco VA Medical Center (US)
- Corresponding author
- Hu, Zhilan
- Epstein, Ervin H.
- Venue
- Nature Genetics
- Published
- 2000-01
- Volume
- 24
- Issue
- 1
- Pages
- 61-65
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1543013349
- Cited by
- 567
- References
- 27
- Citations by year
- 2026: 18 · 2025: 12 · 2024: 22 · 2023: 13 · 2022: 15 · 2021: 17 · 2020: 17 · 2019: 21 · 2018: 14 · 2017: 22 · 2016: 31 · 2015: 18 · 2014: 22 · 2013: 25 · 2012: 29
- FWCI
- 16.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r01ar043119-01a1, 5r29ar044341-05)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR44341, AR43119)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- Hailey-Hailey disease, ATP2C1, calcium pump, sarco/endoplasmic reticulum calcium ATPase, autosomal dominant inheritance, keratinocytes, skin blistering, desmosomal proteins, pemphigus, Darier disease, genetic mutations
- MeSH terms
- Calcium-Transporting ATPases, Adult, Base Sequence, Cell Differentiation, Cells, Cultured, DNA, Female, Humans, Hybrid Cells, Male, Molecular Sequence Data, Mutation, Pedigree, Keratinocytes, Pemphigus, Benign Familial, Chromosomes, Artificial, Yeast
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
