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Hailey-Hailey disease is an autosomal genetic disease caused by mutations in one of the two  ATP2C  1  alleles encoding the secretory pathway Ca 2+ /Mn 2+ -ATPase, hSPCA1. 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  ATP2C1  missense mutations in presence or absence of wild type  ATP2C1  or  ATP2A2 , encoding SERCA2. In our yeast model system, mutations in  ATP2C1  affected Mn 2+  transport more than Ca 2+  transport as twelve out of fourteen mutations were unable to complement Mn 2+  sensitivity while thirteen out of fourteen to some extent complemented the high Ca 2+ requirement. Nine out of fourteen mutations conferred a cold sensitive complementation capacity. In absence of a wild type  ATP2C1  allele, twelve out of fourteen mutations induced an unfolded protein response indicating that  in vivo  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  ATP2C1  or  ATP2A2  prevented induction of the unfolded protein response and hSPCA1 mis-localization.

Characterization of Hailey-Hailey Disease-mutants in presence and absence of wild type SPCA1 using Saccharomyces cerevisiae as model organism