Department of Biology, August Krogh Building, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, OE, Denmark.
Sci Rep. 2019 Aug 27;9(1):12442. doi: 10.1038/s41598-019-48866-y.
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.
Hailey-Hailey 病是一种常染色体遗传性疾病，由编码分泌途径 Ca/Mn-ATP 酶 hSPCA1 的两个 ATP2C1 等位基因中的一个突变引起。该疾病几乎仅影响表皮，主要导致基底层的棘层松解。该疾病的病因复杂，尚未完全了解。我们应用酵母互补系统，在存在或不存在野生型 ATP2C1 或 ATP2A2（编码 SERCA2）的情况下，对 14 种致病 ATP2C1 错义突变进行了表征。在我们的酵母模型系统中，ATP2C1 中的突变对 Mn 转运的影响大于 Ca 转运，因为 14 个突变中有 12 个不能互补 Mn 敏感性，而 13 个突变在某种程度上互补了高 Ca 需求。9 个突变赋予了冷敏感的互补能力。在缺乏野生型 ATP2C1 等位基因的情况下，14 个突变中有 12 个诱导未折叠蛋白反应，表明 hSPCA1 的体内折叠对致病氨基酸取代敏感，14 个突变中有 4 个导致 hSPCA1 蛋白在液泡膜中积累。野生型 ATP2C1 或 ATP2A2 的共表达可防止未折叠蛋白反应的诱导和 hSPCA1 的定位错误。
