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The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey–Hailey Disease
BACKGROUND: Hailey–Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca(2+)/Mn(2+)-ATPase 1 (SPCA1),...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Dove
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569160/ https://www.ncbi.nlm.nih.gov/pubmed/36254249 http://dx.doi.org/10.2147/CCID.S384443 |
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author | Li, Peiyao Qi, Jialin Zhou, Baishun Ding, Ting Long, Juan Xiao, Heng |
author_facet | Li, Peiyao Qi, Jialin Zhou, Baishun Ding, Ting Long, Juan Xiao, Heng |
author_sort | Li, Peiyao |
collection | PubMed |
description | BACKGROUND: Hailey–Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca(2+)/Mn(2+)-ATPase 1 (SPCA1), whose deficiency is responsible for HHD. An ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was previously identified in a Han Chinese family with HHD. METHODS: In this study, the identified ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was investigated in transfected human embryonic kidney 293 cells to analyze its pathogenic mechanism in HHD patients by using cycloheximide chase assay, CCK8 assay and in silico modeling of SPCA1 mutant. RESULTS: Cycloheximide chase assay showed that the degradation rate of the SPCA1 mutant was not obviously faster than that of the normal SPCA1. CCK8 assay showed that cell proliferation rates in the wild-type, A109_Q120del, and empty vector control groups all decreased in the gradient Mn(2+) solutions in a dose-dependent manner. The cell proliferation rate in the wild-type was lower than that in the A109_Q120del and empty vector control (both P < 0.01), indicating overexpression of normal SPCA1 may rather induce Golgi stress, and even cell death. The cell proliferation rate in the A109_Q120del was lower than that in the empty vector control (P < 0.01), indicating that overexpression of the mutated SPCA1 may decrease its detoxification capability. Three-dimensional (3D) structure model of SPCA1 built by SWISS-MODEL and PyMOL showed that absence of the 12 amino acids from p.Ala109 to p.Gln120 in the SPCA1 mutant can cause obviously shortened transmembrane 2, which may affect correct localization of SPCA1 on the Golgi. CONCLUSION: These results demonstrate that the ATP2C1 mutation (c.325-2A>G, p.Ala109_Gln120del) may cause impaired SPCA1 capability to detoxify Mn(2+) and abnormal SPCA1 structure, which reveals a new side for the pathogenesis of HHD. |
format | Online Article Text |
id | pubmed-9569160 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-95691602022-10-16 The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey–Hailey Disease Li, Peiyao Qi, Jialin Zhou, Baishun Ding, Ting Long, Juan Xiao, Heng Clin Cosmet Investig Dermatol Original Research BACKGROUND: Hailey–Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca(2+)/Mn(2+)-ATPase 1 (SPCA1), whose deficiency is responsible for HHD. An ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was previously identified in a Han Chinese family with HHD. METHODS: In this study, the identified ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was investigated in transfected human embryonic kidney 293 cells to analyze its pathogenic mechanism in HHD patients by using cycloheximide chase assay, CCK8 assay and in silico modeling of SPCA1 mutant. RESULTS: Cycloheximide chase assay showed that the degradation rate of the SPCA1 mutant was not obviously faster than that of the normal SPCA1. CCK8 assay showed that cell proliferation rates in the wild-type, A109_Q120del, and empty vector control groups all decreased in the gradient Mn(2+) solutions in a dose-dependent manner. The cell proliferation rate in the wild-type was lower than that in the A109_Q120del and empty vector control (both P < 0.01), indicating overexpression of normal SPCA1 may rather induce Golgi stress, and even cell death. The cell proliferation rate in the A109_Q120del was lower than that in the empty vector control (P < 0.01), indicating that overexpression of the mutated SPCA1 may decrease its detoxification capability. Three-dimensional (3D) structure model of SPCA1 built by SWISS-MODEL and PyMOL showed that absence of the 12 amino acids from p.Ala109 to p.Gln120 in the SPCA1 mutant can cause obviously shortened transmembrane 2, which may affect correct localization of SPCA1 on the Golgi. CONCLUSION: These results demonstrate that the ATP2C1 mutation (c.325-2A>G, p.Ala109_Gln120del) may cause impaired SPCA1 capability to detoxify Mn(2+) and abnormal SPCA1 structure, which reveals a new side for the pathogenesis of HHD. Dove 2022-10-11 /pmc/articles/PMC9569160/ /pubmed/36254249 http://dx.doi.org/10.2147/CCID.S384443 Text en © 2022 Li et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Li, Peiyao Qi, Jialin Zhou, Baishun Ding, Ting Long, Juan Xiao, Heng The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey–Hailey Disease |
title | The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey–Hailey Disease |
title_full | The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey–Hailey Disease |
title_fullStr | The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey–Hailey Disease |
title_full_unstemmed | The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey–Hailey Disease |
title_short | The Pathogenic Mechanism of the ATP2C1 p.Ala109_Gln120del Mutation in Hailey–Hailey Disease |
title_sort | pathogenic mechanism of the atp2c1 p.ala109_gln120del mutation in hailey–hailey disease |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569160/ https://www.ncbi.nlm.nih.gov/pubmed/36254249 http://dx.doi.org/10.2147/CCID.S384443 |
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