Disease relevance of ATP2C1

• Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease [1].
• 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 [2].
• This finding suggests that mutation of the ATP2C1 gene may give rise to an extracutaneous phenotype, such as the liver dysfunction observed in severe cases, including our own [3].
• Consequently, infected HHD, H-2Db-/- beta2m-/- mice generate only HLA-A2.1-restricted CD8(+) CTL responses against influenza A and vaccinia viruses [4].
• We demonstrate that expression of hSPCA1 in yeast fully complements pmr1 phenotypes of hypersensitivity to Ca(2+) chelators and Mn(2+) toxicity [5].

Psychiatry related information on ATP2C1

• Hailey-Hailey disease with affective disorder: report of a case with novel ATP2C1 gene mutation [6].
• The second of these theories implies three personality patterns: IRA (Impulsiveness, Repression, Aggressiveness), HHD (Hypochondriasis, Hysteria, Depression) and SAD (Stress, Anxiety, Depression) [7].

High impact information on ATP2C1

• 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 [1].
• The current study examined whether endonuclease-mediated mRNA decay involved the selective binding of PMR1 to substrate mRNA on polysomes [8].
• Endonuclease-mediated mRNA decay involves the selective targeting of PMR1 to polyribosome-bound substrate mRNA [8].
• Deletion mutagenesis identified polysome-targeting domains in the N and C termini of PMR1, either of which could target GFP to polysomes [8].
• The availability of purified PMR-1 and recombinant vigilin made it possible to test the hypothesis that RNA-binding proteins interact with cis-acting elements to stabilize target mRNAs by blocking cleavage by site-specific mRNA endonucleases [9].

Chemical compound and disease context of ATP2C1

• Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump [2].
• Knock down of pmr-1 as well as overexpression of truncated Caenorhabditis elegans PMR1, which mimics dominant mutations observed in human Hailey-Hailey disease, renders the worm highly sensitive to EGTA and Mn2+ [10].
• The present case suggests that oral etretinate is effective against the generalized eruptions even in cases in which bacterial infection has triggered the generalization of HHD [11].
• Furthermore, treatment of these mice with 5-FU delayed or prevented the occurrence of tumors formed by inoculation with autologous (TS+)EL-4/HHD lymphoma cells [12].

Biological context of ATP2C1

• ATP2C1 inactivation also diminishes Darier disease keratinocyte viability, suggesting that compensatory ATP2C1 upregulation maintains viability and partially compensates for defective endoplasmic reticulum Ca2+-ATPase in Darier disease keratinocytes [13].
• The novel mutations comprise three nonsense, six insertion/deletion, three splice-site, and six missense mutations and are distributed throughout the ATP2C1 gene [14].
• In this study, we used conformation-sensitive gel electrophoresis to screen all 28 translated exons of ATP2C1 in 24 Hailey-Hailey disease families and three sporadic cases with the disorder [14].
• In this study, key regulatory regions necessary for the expression of the gene encoding human ATP2C1 were investigated [15].
• In accordance with this result, when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter [15].

Anatomical context of ATP2C1

• Deficiency of ATP2C1 results in a human disease (Hailey-Hailey), which primarily affects keratinocytes [16].
• Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress [16].
• ATP2C1-encoded protein is detected in the Golgi complex in a calcium-dependent manner [16].
• Role for plasma membrane-related Ca2+-ATPase-1 (ATP2C1) in pancreatic beta-cell Ca2+ homeostasis revealed by RNA silencing [17].
• Here, we explore the importance of the secretory pathway Ca(2+)-ATPase, plasma membrane-related Ca(2+)-ATPase-1 (PMR1; human orthologue ATP2C1) in intracellular Ca(2+) homeostasis in pancreatic islet beta-cells [17].

Associations of ATP2C1 with chemical compounds

• Recently, functional analysis of a series of site-specific mutants, designed to mimic missense mutations found in ATP2C1, uncovered specific defects in Ca(2+) and/or Mn(2+) transport and protein expression in mutant hSPCA1 polypeptides [18].
• The addition of retinoids or corticosteroids to the cell culture inhibited the UVB-induced suppression of both ATP2A2 and ATP2C1 mRNA levels, and UVB-induced suppression of ATP2C1 mRNA was also inhibited by the addition of ciclosporin, tacrolimus and vitamin D(3) [19].
• CONCLUSION: Our results suggest that ATP2C1 plays an essential role for basal keratinocytes to keep in the undifferentiated state and that its reduction evokes differentiation and up-localization to suprabasal layers most likely via the manganese starvation in the Golgi apparatus of keratinocytes [20].
• Neither detachment of keratinocyte from culture dish nor treatment with high concentrations of calcium suppressed ATP2C1 expression, while both procedures induced differentiation markers, K10 keratin and involucrin [20].
• Recent studies have revealed that HHD is caused by mutations in the ATP2C1 gene encoding a novel Ca(2+) pump [21].

Regulatory relationships of ATP2C1

• The catalytic turnover rate of SPCA2 was found enhanced relative to SPCA1 pumps [22].

Other interactions of ATP2C1

• Human secretory pathway Ca2+/Mn2+-ATPase (SPCA) 2 encoded by ATP2C2 is only expressed in a limited number of tissues, unlike the ubiquitously expressed SPCA1 pump (encoded by ATP2C1, the gene defective in Hailey-Hailey disease) [22].
• Transcriptional regulation of ATP2C1 gene by Sp1 and YY1 and reduced function of its promoter in Hailey-Hailey disease keratinocytes [15].
• The ATP2C1 is localized to the Golgi apparatus in human keratinocytes, similar to its localization in yeast and Caenorhabditis elegans [23].
• In conclusion, A7r5 and 16HBE14o- cells express a Pmr1-containing Ca(2+) store with properties that differ substantially from the SERCA-containing Ca(2+) store [24].
• Plasma membrane, sarco-endoplasmic reticulum and secretory pathway Ca2+-ATPases (designated PMCA, SERCA and SPCA) regulate intracellular Ca2+ in animal cells [25].

Analytical, diagnostic and therapeutic context of ATP2C1

• In order to investigate the molecular and physiological basis of HHD in the patient carrying missense mutation A528P, located in the putative nucleotide binding domain of the molecule, site-directed mutagenesis was employed to introduce this mutation into the wild-type ATP2C1 (hSPCA1) sequence [18].
• In this study, we used denaturing high-performance liquid chromatography to screen all 28 exons and flanking intron boundaries of ATP2C1 for mutations in 9 HHD patients [18].
• The transient reporter assay demonstrated that region +21/+57 was necessary for activation of the ATP2C1 promoter, and the electrophoretic mobility shift assay demonstrated that the region was recognized by the transcription factors, Sp1 and YY1 [15].
• The addition of anti-interleukin (IL)-6 antibody to the cell culture prevented the UVB-induced suppression of ATP2A2 and ATP2C1 mRNA; in contrast, the addition of anti-IL-8 antibody slightly accelerated the suppression [19].
• Mutation of ATP2C1 gene was detected by polymerase chain reaction (PCR) and DNA sequencing [26].

References