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

Hailey-Hailey disease is an autosomal genetic disease caused by mutations in one of the two ATP2C1 alleles encoding the secretory pathway Ca/Mn-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 transport more than Ca transport as twelve out of fourteen mutations were unable to complement Mn sensitivity while thirteen out of fourteen to some extent complemented the high Carequirement. 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.