ATP2C1 Gene

ATP2C1 (ATP2C1 is the acronym for "ATPase Secretory Pathway Ca2+ Transporting 1") is a protein-coding gene located on chromosome 3q22.1. The enzyme encoded by this gene belongs to the family of P-type cation transport ATPases. This magnesium-dependent ATPase catalyzes the hydrolysis of ATP in conjunction with the transport of calcium ions. Mutations in this gene cause pemphigus chronicus benignus familiaris (Hailey-Hailey disease) (Deng H et al. 2017), a localized, autosomal dominant acantholytic disorder of the skin and forms of epidermolysis bullosa hereditaria. Alternatively spliced transcript variants encoding different isoforms have been identified. An important paralog of this gene is ATP2C2.

In a catalytic cycle, Ca(2+) or Mn(2+) ions are taken up on the cytoplasmic side of the membrane and transported to the luminal side. Ion transfer across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from an inward to an outward state (Dode L et al. 2005).

ATPase Plays an important role in maintaining Ca(2+) homeostasis in the trans-Golgi compartment with functional effects on Golgi and post-Golgi protein sorting as well as structural effects on cisternal morphology (Behne MJ et al. 2003).

Responsible for loading Golgi stores with Ca(2+) ions in keratinocytes, contributing to keratinocyte differentiation and epidermal integrity (Behne MJ et al. 2003).

May also play a role in maintaining Ca(2+) and Mn(2+) homeostasis and signaling in the cytosol while preventing cytotoxicity (Mukhopadhyay S et al. 2011)

Furthermore, the enzyme is involved in the uptake of Ca(2+) and Mn(2+) ions into the Golgi store of hippocampal neurons and regulates protein trafficking required for neuronal polarity. It may also play a role in maintaining Ca(2+) and Mn(2+) homeostasis and signaling in the cytosol while preventing cytotoxicity.

1. Behne MJ et alk. (2003) Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores. J Invest Dermatol121:688-694.
   
2. Chen J et al. (2019) An N-terminal Ca2+-binding motif regulates the secretory pathway Ca2+/Mn2+-transport ATPase SPCA1. J Biol Chem 294:7878-7891
3. Deng H et al. (2017) The role of the ATP2C1 gene in Hailey-Hailey disease. Cell Mol Life Sci 74: 3687-3696.
4. Dode L et al. (2005) Functional comparison between secretory pathway Ca2+/Mn2+-ATPase (SPCA) 1 and sarcoplasmic reticulum Ca2+-ATPase (SERCA) 1 isoforms by steady-state and transient kinetic analyses. J Biol Chem 280:39124-39134
5. Fairclough RJ et al. (2003) Effect of Hailey-Hailey disease mutations on the function of a new variant of human secretory pathway Ca2+/Mn2+-ATPase (hSPCA1). J Biol Chem 278:24721-24730.
6. Mukhopadhyay S et al. (2011) Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn2+ efflux and protects against toxicity. Proc Natl Acad Sci U S A. 108:858-863.
7. Yang L et al. (2021) Generalized Hailey-Hailey disease: Novel splice-site mutations of ATP2C1 gene in Chinese population and a literature review. Mol Genet Genomic Med 9: e1580.