Table 1.

Overview of the expression profile and disease links of Ca²⁺-ATPases

Gene	Isoform	Tissue distribution	Human disease and associated alterations on genetic/protein level	OMIM
ATP2A1	SERCA1a	Fast twitch skeletal muscle (adult)	Brody disease (autosomal recessive inheritance): splice site mutations, premature stop codons, missense mutations	108730
	SERCA1b	Fast twitch skeletal muscle (fetal)	Myotonic dystrophy type 1: SERCA1b alternative mRNA splicing and dysregulated expression
ATP2A2	SERCA2a	Highly expressed in cardiac and slow twitch skeletal muscle, smooth muscle, neuronal cells	Darier–White disease (autosomal dominant): acrokeratosis verruciformis	108740
	SERCA2b	Ubiquitous	Heart failure: impaired SERCA2a protein expression and ATPase activity, mutations in PLB and reduced DWORF expression
	SERCA2c	Cardiac muscle (slow and fast twitch) skeletal muscle, myeloid and nonmyeloid cells, primary blood monocytes	Cancer: dysregulated protein expression, targeted SERCA inhibition as cancer therapy
ATP2A3	SERCA3a–f	3a, d, f: cardiac muscle; nonisoform specific: smooth muscle and other nonmuscle cells (endothelial, epithelial cells, lung, and pancreas)	Gastric carcinomas, colon and lung cancer: dysregulated protein expression Diabetes: dysregulated protein expression	601929
ATP2C1	SPCA1a–d	Ubiquitous	Hailey–Hailey disease (autosomal inheritance): nonsense, splice-site, and nonconservative missense mutations; frameshift insertion and deletions Breast cancer: up-regulated protein expression	604384
ATP2C2	SPCA2	Gastrointestinal tract, trachea, thyroid gland, salivary gland, mammary gland, prostate, brain (hippocampal neurons), keratinocytes (mRNA level)	Breast cancer: up-regulated protein expression	613082
ATP2B1	PMCA1a–e	Ubiquitous (1b: fetal; 1a: adult) 1a, 1c, 1e: brain; 1c in skeletal muscle	Cardiovascular disease risk, preeclampsia, salt sensitivity: associated SNPs	108741
ATP2B2	PMCA2a–f	Brain (fetal and adult), cerebellar Purkinje cells, hair cells in the inner ear, mammary gland	Autosomal-recessive deafness: heterozygous point mutation (one case report) Autism: associated SNPs	108733
ATP2B3	PMCA3a–c	Widely expressed in the embryo Brain: cerebellum	Early-onset spinocerebellar ataxia-1 (X-linked): point mutation	300014
			Aldosterone-producing adenomas: somatic point mutation
ATP2B4	PMCA4a–g	Ubiquitous	Familial spastic paraplegia: point mutation Malaria resistance: associated SNPs	108732

Overview of the specific characteristics of expression profile and disease links of Ca²⁺-ATPases. SERCA, SPCA, and PMCA are closely related based on phylogeny and their function as active Ca²⁺-transporters. However, differences in physiological function between these proteins arise through the expression of multiple isoforms, their structural differences, and specific tissue distribution. Additionally, many of these genes/proteins are linked to several human diseases and therefore may serve as interesting therapeutic targets. OMIM, Online Mendelian Inheritance in Man; mRNA, messenger RNA; PLB, phospholamban; DWORF, DWARF open reading frame; GWAS, genome-wide association studies; SNPs, single-nucleotide polymorphisms.