Atp2c1-flox Mouse

ATP2C1, encoding the secretory pathway Ca(2+)/Mn(2+)-ATPase pump type 1 (SPCA1), is located on chromosome 3q21-q24. Its key function is to maintain normal intracellular concentrations of Ca2+/Mn2+ by transporting them into the Golgi apparatus, which is crucial for normal cellular function [1,2].

Mutations in ATP2C1 have been identified as the cause of Hailey-Hailey disease (HHD), a rare autosomal dominant acantholytic dermatosis [1,2]. Loss of ATP2C1 function leads to impaired Notch1 signalling, promoting upregulation of the active NOTCH1 protein (NICD-Val1744), but without transcriptional enhancement of its targets and with cytoplasmic localization of NICD-Val1744. Also, ATP2C1-loss is associated with the degradation of NICD-Val1744 through the lysosomal/proteasome pathway, suggesting a mechanism by which NOTCH1 is endocytosed and degraded, disrupting skin homeostasis and causing HHD manifestation [3]. In addition, ATP2C1 knockdown in keratinocytes leads to decreased levels of cytoskeletal and tight junction proteins, mimicking the acantholysis seen in HHD, without affecting keratinocyte proliferation, apoptosis, or intracellular calcium concentrations [4].

In conclusion, ATP2C1 is essential for maintaining normal intracellular Ca2+/Mn2+ concentrations. Studies on ATP2C1-related loss-of-function models, such as those mimicking HHD, have revealed its role in skin-related biological processes. Understanding the role of ATP2C1 in HHD pathogenesis through these models contributes to better clinical diagnosis and may provide new treatment and prevention strategies for HHD [1,3,4].