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.
As a result of an error during figure assembly, in Figure 6 an image for Galactose+0.9mM BAPTA at 35°C is a duplicate of image for Galactose+1.0mM BAPTA at 35°C, and Galactose+1.2mM BAPTA at 35°C is a duplicate of image for Galactose+1.1mM BAPTA at 35°C. The correct Figure 6 is shown below as Figure 1.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.