ATP2A2 Gene

The ATP2A2 gene encodes the calcium-pumping ATPase (also known as SERCA2 = sarco(endo) plasmic reticulum Ca2+-ATPase 2), which is localized in the sarco- and endoplasmic reticulum of skeletal muscle. Calcium-pumping ATPases have the task of maintaining a low cytoplasmic concentration of Ca2+ ions. They are transporters with high affinity and low capacity and complement the action of the Na+/Ca2+ exchanger with low affinity and high capacity. Ca2+-ATPases are P-type ATPases.

The SERCA2 enzyme is a magnesium-dependent enzyme, an ATPase. The enzyme catalyzes the hydrolysis of ATP in conjunction with the translocation of calcium from the cytosol into the lumen of the sarcoplasmic reticulum and is involved in the regulation of the contraction/relaxation cycle. An important paralog of this gene is ATP2A1. The enzyme is also involved in the following biological processes:

• Autophagy in response to starvation
• controls ER isolation membrane contacts for autophagosome formation after interaction with VMP1 and activation
• also modulates ER contacts with lipid droplets, mitochondria and endosomes
• involved in the regulation of the contraction/relaxation cycle
• acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with TMEM64, which is responsible for TNFSF11-induced CREB1 activation and mitochondrial ROS formation required for proper osteoclast formation

Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca(2+) spikes for NFATC1 activation and mitochondrial ROS production, triggering Ca(2+) signaling cascades that promote osteoclast differentiation and activation.

Mutations of the gene lead to defective enzyme formation and secondarily to inadequate replenishment of the calcium stores of the endoplasmic reticulum. This results in the expression of altered, calcium-dependent adhesion molecules (desmosomal cadherins). These proteins are necessary for adhesion processes of epithelial cells. Their impaired biological function leads to loss of adhesion, acantholysis and apoptosis of the keratinocytes.

The corresponding clinical picture is Darier's disease (White)(dyskeratosis follicularis), an autosomal dominant skin disease characterized by a loss of adhesion between the epidermal cells and abnormal keratinization.

Furthermore, the clinical picture of acrokeratosis verruciformis is associated with mutations in ATPA2.

Other types of mutations in this gene have been associated with various forms of muscular dystrophies.

Alternative splicing leads to several transcript variants encoding different isoforms.

Polymorphisms in the ATP2A2 gene are detected significantly more frequently in patients with colon cancer (P < 0.0001, odds ratio OR = 25.3) or lung cancer (P = 0.046, OR = 8.05) (Korosec B et al. 2006): These were mismutations, intronic deletions, intronic insertions, and single nucleotide changes in both the coding region, intronic region, and promoter region. This results in loss or decreased expression of the gene product (Korosec B et al. 2006):

1. Korosec B et al (2006) Alterations in the ATP2A2 gene in correlation with colon and lung cancer. Cancer Genet Cytogenet 171:105-111
2. Ren YQ et al (2006) Five mutations of ATP2A2 gene in Chinese patients with Darier's disease and a literature review of 86 cases reported in China. Arch Dermatol Res 298:58-63.
3. Zhao YG et al (2018) The ER-localized autophagy protein EPG-3/VMP1 regulates ER contacts with other organelles by modulating ATP2A/SERCA activity. Autophagy 14:362-363.