Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump
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Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Previous genetic linkage studies localized the gene to a 5 cM interval on human chromosome 3q21. After reducing the disease critical region to <1 cM, we used a positional cloning strategy to identify the gene ATP2C1, which is mutated in HHD. ATP2C1 encodes a new class of P-type Ca(2+)-transport ATPase, which is the homologue for the rat SPLA and the yeast PMR1 medial Golgi Ca(2+)pumps and is related to the sarco(endo)plasmic calcium ATPase (SERCA) and plasma membrane calcium ATPase (PCMA) families of Ca(2+)pumps. The predicted protein has the same apparent transmembrane organization and contains all of the conserved domains present in other P-type ATPases. ATP2C1 produces two alternative splice variants of approximately 4.5 kb encoding predicted proteins of 903 and 923 amino acids. We identified 13 different mutations, including nonsense, frameshift insertion and deletions, splice-site mutations, and non-conservative missense mutations. This study demonstrates that defects in ATP2C1 cause HHD and together with the recent identification of ATP2A2 as the defective gene in Darier's disease, provide further evidence of the critical role of Ca(2+)signaling in maintaining epidermal integrity.
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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 [33]
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- Authors
- Sudbrak, R.
- Affiliations
- Centre for Human Genetics (GB)
- Corresponding author
- Sudbrak, R.
- ORCID
- Sudbrak, R.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-04-12
- Volume
- 9
- Issue
- 7
- Pages
- 1131-1140
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2151642090
- Cited by
- 321
- References
- 45
- Citations by year
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- FWCI
- 8.78
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Dystrophic Epidermolysis Bullosa Research Association
- Wellcome Trust
- Bundesministerium für Bildung und Forschung (01KW9608/2)
- 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, acantholysis, epidermal integrity, positional cloning, splice variants, nonsense mutation, missense mutations, Darier disease, SERCA2, calcium signaling, autosomal dominant skin disorder
- MeSH terms
- Calcium-Transporting ATPases, Amino Acid Sequence, Cell Adhesion, Chromosomes, Human, Pair 3, Exons, Genetic Markers, Genotype, Humans, Introns, Molecular Sequence Data, Mutation, Pedigree, Recombination, Genetic, Keratinocytes, Pemphigus, Benign Familial, In Situ Hybridization, Fluorescence, DNA, Complementary, Physical Chromosome Mapping
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