Involvement of the adherens junction – actin filament system in acantholytic dyskeratosis of Hailey‐Hailey disease

Metze, Dieter; Hamm, Henning; Schorat, Annette; Luger, Thomas A.

doi:10.1111/j.1600-0560.1996.tb01469.x

Cited by 51 publications

(48 citation statements)

References 48 publications

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“…A similar study of DD patients indicated that the morphological changes in the suprabasal layer were similar to those of HHD and suggested that the loss of connection between tonofilaments and desmosomes preceded the loss of desmosomes [70,71]. This view has been supported by other investigators [72-74], although there are counterviews [75,76], and non-lesional skin of HHD patients is more fragile [76], indicating that the process of acantholysis is not identical in the two diseases.…”

Section: Haploinsufficiency Of Either Spca1 or Serca2 Causes Acantmentioning

confidence: 69%

Secretory pathway stress responses as possible mechanisms of disease involving Golgi Ca2+ pump dysfunction

2011

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In mammalian tissues, uptake of Ca2+ and Mn2+ by Golgi membranes is mediated by the secretory pathway Ca2+- ATPases, SPCA1 and SPCA2, encoded by the ATP2C1 and ATP2C2 genes. Loss of one copy of the ATP2C1 gene, which causes SPCA1 haploinsufficiency, leads to squamous cell tumors of keratinized epithelia in mice and to Hailey-Hailey Disease, an acantholytic skin disease, in humans. Although the disease phenotypes resulting from SPCA1 haploinsufficiency in mice and humans are quite different, each species-specific phenotype is remarkably similar to those arising as a result of null mutations in one copy of the ATP2A2 gene, encoding SERCA2, the endoplasmic reticulum (ER) Ca2+ pump. SERCA2 haploinsufficiency, like SPCA1 haploinsufficiency, causes squamous cell tumors in mice and Darier’s Disease, also an acantholytic skin disease, in humans. The phenotypic similarities between SPCA1 and SERCA2 haploinsufficiency in the two species, and the general functions of the two pumps in consecutive compartments of the secretory pathway, suggest that the underlying disease mechanisms are similar. In this review we discuss evidence supporting the view that chronic Golgi stress and/or ER stress resulting from Ca2+ pump haploinsufficiencies leads to activation of cellular stress responses in keratinocytes, with the predominance of pro-apoptotic pathways (though not necessarily apoptosis itself) leading to acantholytic skin disease in humans and the predominance of pro-survival pathways leading to tumors in mice.

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Section: Haploinsufficiency Of Either Spca1 or Serca2 Causes Acantmentioning

confidence: 69%

Secretory pathway stress responses as possible mechanisms of disease involving Golgi Ca2+ pump dysfunction

2011

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“…9). Aggregates of keratin filaments in the perinuclear region of keratinocytes are a distinctive feature (120,122,201). Following the first description of the defect in the SPCA gene, ϳ100 additional mutations were identified, randomly scattered in the gene (300).…”

Section: The Hailey-hailey's Diseasementioning

confidence: 99%

Calcium Pumps in Health and Disease

Brini¹,

Carafoli²

2009

Physiological Reviews

579

469

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Ca2+-ATPases (pumps) are key actors in the regulation of Ca2+ in eukaryotic cells and are thus essential to the correct functioning of the cell machinery. They have high affinity for Ca2+ and can efficiently regulate it down to very low concentration levels. Two of the pumps have been known for decades (the SERCA and PMCA pumps); one (the SPCA pump) has only become known recently. Each pump is the product of a multigene family, the number of isoforms being further increased by alternative splicing of the primary transcripts. The three pumps share the basic features of the catalytic mechanism but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca2+. The molecular understanding of the function of the pumps has received great impetus from the solution of the three-dimensional structure of one of them, the SERCA pump. These spectacular advances in the structure and molecular mechanism of the pumps have been accompanied by the emergence and rapid expansion of the topic of pump malfunction, which has paralleled the rapid expansion of knowledge in the topic of Ca2+-signaling dysfunction. Most of the pump defects described so far are genetic: when they are very severe, they produce gross and global disturbances of Ca2+ homeostasis that are incompatible with cell life. However, pump defects may also be of a type that produce subtler, often tissue-specific disturbances that affect individual components of the Ca2+-controlling and/or processing machinery. They do not bring cells to immediate death but seriously compromise their normal functioning.

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“…Additional phenotypes include reduced brood size and some larval lethality (Table 1). The terminal phenotypes due to pmr-1 disruption, such as ventral enclosure defects and head enclosure failures, are at least superficially similar to the neural tube closure failures in mice lacking the PMR-1 homolog SPCA, as well as the cell adhesion defects observed in Hailey-Hailey disease patients [19], [23], [24].…”

Section: Resultsmentioning

confidence: 86%

“…Mice embryos homozygous for null mutations in SPCA1 die with defects in neural tube closure, while heterozygotes show susceptibility to squamous cell tumors, a phenotype observed occasionally in humans with Hailey-Hailey [19]–[22]. The primary cellular defect in Hailey-Hailey disease patients is keratinocyte acantholysis or loss of cell adhesion, marked by aggregation of keratin intermediate filaments that have retracted from desmosomes [23], [24]. In mice, cell adhesion appears normal, but cells show signs of Golgi dysfunction, which likely induces the high levels of apoptosis observed in the neural tube and mesenchyme [19].…”

Section: Introductionmentioning

confidence: 99%

The Secretory Pathway Calcium ATPase PMR-1/SPCA1 Has Essential Roles in Cell Migration during Caenorhabditis elegans Embryonic Development

et al. 2013

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Maintaining levels of calcium in the cytosol is important for many cellular events, including cell migration, where localized regions of high calcium are required to regulate cytoskeletal dynamics, contractility, and adhesion. Studies show inositol-trisphosphate receptors (IP3R) and ryanodine receptors (RyR), which release calcium into the cytosol, are important regulators of cell migration. Similarly, proteins that return calcium to secretory stores are likely to be important for cell migration. The secretory protein calcium ATPase (SPCA) is a Golgi-localized protein that transports calcium from the cytosol into secretory stores. SPCA has established roles in protein processing, metal homeostasis, and inositol-trisphosphate signaling. Defects in the human SPCA1/ATP2C1 gene cause Hailey-Hailey disease (MIM# 169600), a genodermatosis characterized by cutaneous blisters and fissures as well as keratinocyte cell adhesion defects. We have determined that PMR-1, the Caenorhabditis elegans ortholog of SPCA1, plays an essential role in embryogenesis. Pmr-1 strains isolated from genetic screens show terminal phenotypes, such as ventral and anterior enclosure failures, body morphogenesis defects, and an unattached pharynx, which are caused by earlier defects during gastrulation. In Pmr-1 embryos, migration rates are significantly reduced for cells moving along the embryo surface, such as ventral neuroblasts, C-derived, and anterior-most blastomeres. Gene interaction experiments show changing the activity of itr-1/IP3R and unc-68/RyR modulates levels of embryonic lethality in Pmr-1 strains, indicating pmr-1 acts with these calcium channels to regulate cell migration. This analysis reveals novel genes involved in C. elegans cell migration, as well as a new role in cell migration for the highly conserved SPCA gene family.

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Involvement of the adherens junction – actin filament system in acantholytic dyskeratosis of Hailey‐Hailey disease

Cited by 51 publications

References 48 publications

Secretory pathway stress responses as possible mechanisms of disease involving Golgi Ca2+ pump dysfunction

Secretory pathway stress responses as possible mechanisms of disease involving Golgi Ca2+ pump dysfunction

Calcium Pumps in Health and Disease

The Secretory Pathway Calcium ATPase PMR-1/SPCA1 Has Essential Roles in Cell Migration during Caenorhabditis elegans Embryonic Development

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