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The disease almost exclusively affects epidermis, where it mainly results in acantholysis of the suprabasal layers. The etiology of the disease is complex and not well understood. We applied a yeast based complementation system to characterize fourteen disease-causing <jats:italic>ATP2C1<\/jats:italic> missense mutations in presence or absence of wild type <jats:italic>ATP2C1<\/jats:italic> or <jats:italic>ATP2A2<\/jats:italic>, encoding SERCA2. In our yeast model system, mutations in <jats:italic>ATP2C1<\/jats:italic> affected Mn<jats:sup>2+<\/jats:sup> transport more than Ca<jats:sup>2+<\/jats:sup> transport as twelve out of fourteen mutations were unable to complement Mn<jats:sup>2+<\/jats:sup> sensitivity while thirteen out of fourteen to some extent complemented the high Ca<jats:sup>2+<\/jats:sup>requirement. Nine out of fourteen mutations conferred a cold sensitive complementation capacity. In absence of a wild type <jats:italic>ATP2C1<\/jats:italic> allele, twelve out of fourteen mutations induced an unfolded protein response indicating that <jats:italic>in vivo<\/jats:italic> folding of hSPCA1 is sensitive to disease causing amino acid substitutions and four of the fourteen mutations caused the hSPCA1 protein to accumulate in the vacuolar membrane. Co-expression of either wild type <jats:italic>ATP2C1<\/jats:italic> or <jats:italic>ATP2A2<\/jats:italic> prevented induction of the unfolded protein response and hSPCA1 mis-localization.<\/jats:p>","DOI":"10.1038\/s41598-019-48866-y","type":"journal-article","created":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T10:03:18Z","timestamp":1566900198000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Characterization of Hailey-Hailey Disease-mutants in presence and absence of wild type SPCA1 using Saccharomyces cerevisiae as model organism"],"prefix":"10.1038","volume":"9","author":[{"given":"Daniel","family":"Muncanovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette Heberg","family":"Justesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Spruce","family":"Preisler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8648-9748","authenticated-orcid":false,"given":"Per Amstrup","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,27]]},"reference":[{"key":"48866_CR1","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1093\/hmg\/9.7.1131","volume":"9","author":"R Sudbrak","year":"2000","unstructured":"Sudbrak, R. et al. 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