1. ^*Department of Dermatology, University of California, San Francisco, California, USA
2. ^†Dermatology Service, Endocrine Unit, VA Medical Center, San Francisco, California, USA
3. ^‡Department of Medicine, Endocrine Unit, VA Medical Center, San Francisco, California, USA
4. ^§Department of Dermatology, San Francisco General Hospital, San Francisco, California, USA
5. Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, California, USA
6. ^¶Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche (CNR) Center for the Study of Biomembranes, University of Padova, 35121 Padova, Italy

Correspondence: Martin J. Behne, Dermatology Service (190), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. Email: behnemj@itsa.ucsf.edu

Received 5 November 2002; Revised 17 February 2003; Accepted 12 May 2003; Published online 25 September 2003.

Abstract

Hailey–Hailey disease (MIM16960) is a blistering skin disease caused by mutations in the Ca²⁺ ATPase ATP2C1. We found that the abnormal Ca²⁺ signaling seen in Hailey–Hailey disease keratinocytes correlates with decreased protein levels of ATP2C1. Human ATP2C1 protein approximated 115 kDa in size. The ATP2C1 is localized to the Golgi apparatus in human keratinocytes, similar to its localization in yeast and Caenorhabditis elegans. To test whether the ATP2C1 controls Golgi Ca²⁺ stores, we measured intraorganelle Ca²⁺ concentrations using specifically targeted aequorins. Whereas normal keratinocytes display Golgi Ca²⁺ levels comparable to other epithelial cells, Hailey–Hailey disease keratinocyte Golgi Ca²⁺ refill is slower, and the maximum Ca²⁺ concentration reached is significantly lower. These findings were replicated in vivo, because clinically normal Hailey–Hailey disease epidermis contained lower Ca²⁺ stores and displayed an abnormal Ca²⁺ gradient. In this report we localize the ATP2C1, demonstrate its physiologic relevance in mammalian cells, and measure intraorganelle Golgi Ca²⁺ in keratinocytes.