Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump

Sudbrak, Ralf; Brown, Joanna H.; Dobson‐Stone, Carol; Carter, Simon; Ramser, Juliane; White, Jacqueline K.; Healy, Eugene; Dissanayake, Manel; Larrègue, M; Perrussel, M.; Lehrach, Hans; Munro, Colin S.; Strachan, Tom; Burge, Susan; Hovnanian, Alain; Monaco, Anthony P.

doi:10.1093/hmg/9.7.1131

Cited by 275 publications

(274 citation statements)

References 40 publications

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“…In humans, the ATP2C1 gene-encoding SPCA1 was mapped to chromosome 3 and gained interest when it proved to be the gene that causes Hailey-Hailey disease (OMIM 169600), an acantholytic skin disease (Hu et al 2000;Sudbrak et al 2000).…”

Section: Short Historymentioning

confidence: 99%

The Ca2+ Pumps of the Endoplasmic Reticulum and Golgi Apparatus

Vandecaetsbeek

Vangheluwe²,

Raeymaekers³

et al. 2011

Cold Spring Harbor Perspectives in Biology

182

170

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The various splice variants of the three SERCA-and the two SPCA-pump genes in higher vertebrates encode P-type ATPases of the P 2A group found respectively in the membranes of the endoplasmic reticulum and the secretory pathway. Of these, SERCA2b and SPCA1a represent the housekeeping isoforms. The SERCA2b form is characterized by a luminal carboxy terminus imposing a higher affinity for cytosolic Ca 2þ compared to the other SERCAs. This is mediated by intramembrane and luminal interactions of this extension with the pump. Other known affinity modulators like phospholamban and sarcolipin decrease the affinity for Ca 2þ . The number of proteins reported to interact with SERCA is rapidly growing. Here, we limit the discussion to those for which the interaction site with the ATPase is specified: HAX-1, calumenin, histidine-rich Ca 2þ -binding protein, and indirectly calreticulin, calnexin, and ERp57. The role of the phylogenetically older and structurally simpler SPCAs as transporters of Ca 2þ , but also of Mn 2þ , is also addressed.

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Section: Short Historymentioning

confidence: 99%

The Ca2+ Pumps of the Endoplasmic Reticulum and Golgi Apparatus

Vandecaetsbeek

Vangheluwe²,

Raeymaekers³

et al. 2011

Cold Spring Harbor Perspectives in Biology

182

170

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“…It is caused by germline mutations in the ATP2C1 gene (OMIM 604384) on chromosome 3q21-q24, encoding an adenosine triphosphatepowered (ATP-powered) calcium channel pump (2,3).…”

Section: Introductionmentioning

confidence: 99%

Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept

Poblete‐Gutiérrez¹,

Wiederholt²,

König³

et al. 2004

J. Clin. Invest.

125

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Hailey-Hailey disease (HHD) is an autosomal dominant trait characterized by erythematous and oozing skin lesions preponderantly involving the body folds. In the present unusual case, however, unilateral segmental areas along the lines of Blaschko showing a rather severe involvement were superimposed on the ordinary symmetrical phenotype. Based on this observation and similar forms of mosaicism as reported in other autosomal dominant skin disorders, we postulated that in such cases, 2 different types of segmental involvement can be distinguished. Accordingly, the linear lesions as noted in the present case would exemplify type 2 segmental HHD. In the heterozygous embryo, loss of heterozygosity occurring at an early developmental stage would have given rise to pronounced linear lesions reflecting homozygosity or hemizygosity for the mutation. By analyzing DNA and RNA derived from blood and skin samples as well as keratinocytes of the index patient with various molecular techniques including RT-PCR, real-time PCR, and microsatellite analysis, we found a consistent loss of the paternal wild-type allele in more severely affected segmental skin regions, confirming this hypothesis for the first time, to our knowledge, at the molecular and cellular level.

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“…Moreover, defective ion transport has been shown to play a role in the pathogenesis of a wide range of extracutaneous and skin diseases 15 . Prominent recent examples in the field of Dermatology are the pathogenesis of Hailey-Hailey and Darier's diseases, wherein intracellular calcium-ATP'ases are defective 14,35,37 . Epidermis displays two unique and characteristic electrolytic gradients: First, a calcium (Ca 2+ ) gradient, which regulates numerous epidermal functions via cell-physiologic processes and effects on differentiation.…”

Section: Introductionmentioning

confidence: 99%

Fluorescence lifetime to image epidermal ionic concentrations

Behne

Barry

Moll³

et al. 2004

SPIE Proceedings

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Measurements of ionic concentrations in skin have traditionally been performed with an array of methods which either did not reveal detailed localization information, or only provided qualitative, not quantitative information. FLIM combines a number of advantages into a method ideally suited to visualize concentrations of ions such as H + in intact, unperturbed epidermis and stratum corneum (SC). Fluorescence lifetime is dye concentration-independent, the method requires only low light intensities and is therefore not prone to photobleaching or phototoxic artifacts, and because multiphoton lasers of IR wavelength are used, light penetrates deep into intact tissue. The standard method to measure SC pH is the flat pH electrode, which provides reliable information only about surface pH changes, without further vertical or subcellular spatial resolution; i.e., specific microdomains such as the corneocyte interstices are not resolved, and the deeper SC is inaccessible without resorting to inherently disruptive stripping methods. Furthermore, the concept of a gradient of pH through the SC stems from such stripping experiments, but other confirmation for this concept is lacking. Our investigations into the SC pH distribution so far have revealed the crucial role of the Sodium/Hydrogen Antiporter NHE1 in generation of SC acidity, the colocalization of enzymatic lipid processing activity in the SC with acidic domains of the SC, and the timing and localization of emerging acidity in the SC of newborns. Together, these results have led to an improved understanding of the SC pH, its distribution, origin, and regulation. Future uses for this method include measurements of other ions important for epidermal processes, such as Ca 2+ , and a quantitative approach to topical drug penetration.

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Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump

Cited by 275 publications

References 40 publications

The Ca2+ Pumps of the Endoplasmic Reticulum and Golgi Apparatus

The Ca2+ Pumps of the Endoplasmic Reticulum and Golgi Apparatus

Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept

Fluorescence lifetime to image epidermal ionic concentrations

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