Alternative titles; symbols
HGNC Approved Gene Symbol: ATP2A2
SNOMEDCT: 400085009, 48611009; ICD10CM: E50.8;
Cytogenetic location: 12q24.11 Genomic coordinates (GRCh38): 12:110,280,616-110,351,093 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.11 | Acrokeratosis verruciformis | 101900 | Autosomal dominant | 3 |
| Darier disease | 124200 | Autosomal dominant | 3 |
Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases (SERCAs), such as ATP2A2, are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. They are closely related to the plasma membrane Ca(2+)-ATPases, or PMCAs (see ATP2B1; 108731).
Lytton and MacLennan (1988) cloned human kidney cDNAs coding for 2 alternatively spliced products of the cardiac Ca(2+)-ATPase gene. The difference between these proteins is the replacement of the C-terminal 4 amino acids in SERCA2a by an extended sequence of 49 amino acids in SERCA2b. SERCA2a and SERCA2b also have distinct tissue-expression patterns (Lytton and MacLennan, 1988). SERCA2a is located primarily in heart and slow-twitch skeletal muscle, whereas SERCA2b is present in smooth muscle and nonmuscle tissues (Missiaen et al., 1991).
By RT-PCR, Santiago-Garcia et al. (1996) found variable expression of the PMCA and SERCA genes during human fetal heart development. SERCA2a and SERCA2b were expressed at all stages of fetal heart development examined and in adult heart and placenta. Expression of SERCA2b was relatively constant, whereas the level of SERCA2a mRNA increased during fetal development.
By PCR and EST database analysis, Gelebart et al. (2003) identified a third splice variant of SERCA2, which they designated SERCA2c, that included a 61-bp intronic sequence between exons 20 and 21 of SERCA2a. The deduced 999-amino acid protein is predicted to contain 10 transmembrane segments. An alignment of the SERCA2c, SERCA2a, SERCA2b sequences revealed that the first 993 amino acids are identical, but the proteins differ at their C termini. SERCA2c was detected at various levels in all myeloid and nonmyeloid cell lines examined and in primary blood monocytes. SERCA2b was the most abundant message in hematopoietic cells.
Together with the highly related SERCA1 and SERCA3 isoforms encoded by ATP2A1 and ATP2A3 (601929), respectively, SERCA2 belongs to the large family of P-type cation pumps that couple ATP hydrolysis with cation transport across membranes. SERCA pumps specifically maintain low cytosolic Ca(2+) concentrations by actively transporting Ca(2+) from the cytosol into the sarco/endoplasmic reticulum lumen (MacLennan et al., 1985).
Using a mouse monoclonal antibody specific for human SERCA2 in a standard ABC immunoperoxidase technique, Sheridan et al. (2002) investigated SERCA2 expression in normal human skin (40 samples), oral and vaginal mucosa (13 samples), and Darier disease lesional skin (6 samples). SERCA2 was expressed in all specimens, with pronounced expression in the subnuclear aspect of basal epidermal keratinocytes. There was variable suprabasal expression. SERCA2 expression was also observed in the infundibulum and outer root sheath of hair follicles; germinative and mature cells of sebaceous glands; secretory coil and duct of eccrine glands; apocrine gland cells; and arrector pili muscle. Fibroblasts and blood vessels (endothelium and muscle) expressed SERCA2, whereas nerves did not. SERCA2 expression was observed throughout oral and vaginal mucosa. In Darier disease skin, strong SERCA2 positivity was detected in the basal, suprabasal, and acantholytic lesional cells. Perilesional Darier disease skin was comparable to normal skin.
Gelebart et al. (2003) found that the expression of SERCA2a, SERCA2b, and SERCA2c was induced during the differentiation of a monocytic cell line toward a more mature phenotype.
Upon activation, quiescent hepatic stellate cells proliferate, change morphologically into myofibroblasts, and increase their synthesis of extracellular matrix proteins. Stefanovic et al. (2004) demonstrated that both SERCA2b and TRAM2 (608485) were involved in upregulating collagen type I (see 120150) synthesis during hepatic stellate cell activation. Deletion of the C terminus of TRAM2, and pharmacologic inhibitors of SERCA2b, inhibited type I collagen synthesis. In addition, depletion of ER Ca(2+) resulted in inhibition of triple helical collagen folding and increased intracellular degradation. Stefanovic et al. (2004) proposed that during activation of hepatic stellate cells, TRAM2 recruits SERCA2b to the translocon, a multiprotein complex involved in the posttranslational processing of nascent secretory and membrane proteins at the ER. SERCA2b at the translocon then couples procollagen synthesis and Ca(2+)-dependent molecular chaperones involved in collagen folding.
Kim et al. (2003) developed transgenic mice with cardiac-specific overexpression of active Akt (164730). These mice not only exhibited hypertrophy but also showed enhanced left ventricular function. Isolated ventricular myocytes showed increased contractility, which was associated with increased Ca(2+) transients and Ca(2+) channel currents. The rate of relaxation was also enhanced. Kim et al. (2003) determined that Serca2a protein levels were increased by 6.6-fold in transgenic animals, and inhibitor studies suggested that Serca2a overexpression mediated the enhanced left ventricular function of Akt-overexpressing mice.
Greene et al. (2000) developed transgenic mice that overexpressed rat Serca2b cDNA in the heart. Confocal microscopy showed that Serca2b localized preferentially around the T-tubules of the sarcoplasmic reticulum (SR), whereas Serca2a distributed both transversely and longitudinally in the SR membrane. Serca2b transgenic hearts had higher rates of contraction and relaxation, shorter time to peak pressure, and shorter half-time for relaxation than wildtype hearts. Greene et al. (2000) concluded that SERCA2b plays a specialized role in regulating the beat-to-beat contraction of the heart.
Asahi et al. (2004) generated mice with cardiac-specific overexpression of epitope-tagged rabbit sarcolipin (SLN; 602203). Overexpression of Sln decreased the apparent affinity of Serca2a for calcium in transgenic hearts. The mice had altered calcium currents, impaired cardiac contractility with altered tension and relaxation times, and ventricular hypertrophy. Coimmunoprecipitation indicated that overexpressed Sln bound both Serca2a and phospholamban (PLN; 172405), forming a ternary complex. The results suggested that Sln overexpression inhibits Serca2a through stabilization of Serca2a-Pln interaction and through inhibition of Pln phosphorylation. Asahi et al. (2004) concluded that inhibition of Serca2a impairs contractility and calcium cycling, but responsiveness to beta-adrenergic agonists may prevent progression to heart failure.
Kho et al. (2011) showed that SERCA2a is SUMOylated at lys480 and lys585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. The level of SUMO1 (601912) and SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated-virus-mediated gene delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated calcium decay. Transgene-mediated SUMO1 overexpression rescued cardiac dysfunction induced by pressure overload concomitantly with increased SERCA2a function. By contrast, downregulation of SUMO1 using small hairpin RNA accelerated pressure overload-induced deterioration of cardiac function and was accompanied by decreased SERCA2a function. However, knockdown of SERCA2a resulted in severe contractile dysfunction both in vitro and in vivo, which was not rescued by overexpression of SUMO1. Kho et al. (2011) concluded that, taken together, their data showed that SUMOylation is a critical posttranslational modification that regulates SERCA2a function, and provided a platform for the design of novel therapeutic strategies for heart failure.
Using high-throughput functional screening of the human microRNAome, Wahlquist et al. (2014) identified microRNAs (miRNAs) that suppress intracellular calcium handling in heart muscle by interacting with mRNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a. Of 875 miRNAs tested, MIR25 (612150) potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of MIR25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomir) against MIR25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomir. Wahlquist et al. (2014) concluded that their data revealed that increased expression of endogenous MIR25 contributes to declining cardiac function during heart failure and suggested that it might targeted therapeutically to restore function.
Crystal Structure
Toyoshima and Mizutani (2004) described the crystal structure of the calcium pump of skeletal muscle sarcoplasmic reticulum with an ATP analog, a magnesium ion, and 2 calcium ions in the respective binding sites. In this state, the ATP analog reorganizes the 3 cytoplasmic domains (A, N, and P), which are widely separated without nucleotide, by directly bridging the N and P domains. The structure of the P domain itself is altered by the binding of the ATP analog and magnesium. As a result, the A-domain is tilted so that one of the transmembrane helices moves to lock the cytoplasmic gate of the transmembrane calcium-binding sites. This appears to be the mechanism for occluding the bound calcium ions, before releasing them into the lumen of the sarcoplasmic reticulum.
MacLennan et al. (1987) mapped the slow-twitch ATPase gene (ATP2A2) to chromosome 12. By fluorescence in situ hybridization, Otsu et al. (1993) demonstrated that the ATP2A2 gene, which encodes the SERCA2 isoform of the Ca(2+) pump, maps to 12q23-q24.1. Using rat-mouse backcross analysis, Ohno et al. (1996) mapped the rat ATP2A2 gene to chromosome 12.
Darier-White Disease
Darier-White disease (DAR; 124200), also known as keratosis follicularis, is an autosomal dominant skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk, flexures, scalp, and forehead), palmoplantar pits, and distinctive nail abnormalities. By positional cloning, Sakuntabhai et al. (1999) identified heterozygous mutations in the ATP2A2 gene (see, e.g., 108740.0001-108740.0003) in patients with Darier disease.
Ruiz-Perez et al. (1999) showed that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only SERCA2b is expressed abundantly in epidermal structures. Using extended mutation analysis with SSCP and/or direct sequencing in European patients with Darier-White disease, Ruiz-Perez et al. (1999) identified 40 different patient-specific mutations in 47 families. The majority (23 of 40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial hemorrhagic variant, where all 4 families tested had a missense mutation. Three of the families (1 Scottish and 2 unrelated Italian families) exhibited the same asn767-to-ser substitution in the M5 transmembrane domain (108740.0004), and a fourth family, from Sweden, had a cys268-to-phe substitution in the M3 transmembrane domain (108740.0005). Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic but inconsistent effect of defective ATP2A2 expression.
Jacobsen et al. (1999) performed mutation analysis on the ATP2A2 gene in 19 unrelated Darier disease patients, of whom 10 had neuropsychiatric manifestations. They identified and verified 17 novel mutations predicting conservative and nonconservative amino acid changes, potential premature translation terminations, and potential altered splicing. In the neuropsychiatric cases, there was a nonrandom clustering of mutations at the 3-prime end of the gene (p = 0.01) and a predominance of missense mutations. Jacobsen et al. (1999) concluded from these data that the Darier disease gene has pleiotropic effects in brain and that mutations in ATP2A2 may be involved in the pathogenesis of neuropsychiatric disorders.
Chao et al. (2002) reviewed 103 distinct mutations identified to that time in ATP2A2, concluding that missense mutations are the most common molecular changes (47 of 103 mutations; 46%). The others comprised 12 nonsense mutations, 33 deletion/insertion mutations, and 11 splice-site mutations. Most pathogenic mutations were private. Of these, 15 mutations had been reported more than once, mostly only twice. The mutations were scattered throughout the ATP2A2 gene, with some clustering in the amino terminal and S1, and the C-terminal transmembrane region. No hotspot mutation had been identified, although both asn767 to ser (108740.0004) and arg131 to gln (108740.0012) had each occurred 4 times.
Ahn et al. (2003) examined the effect of 12 Darier disease-associated mutations on the stability and physiology of SERCA2b following transfection in human embryonic kidney cells. Most mutations markedly affected protein expression, partially due to enhanced proteasome-mediated degradation. All of the mutants showed lower channel activity than the wildtype pump, and several mutations inhibited the activity of the endogenous or coexpressed wildtype SERCA2b. Inhibition was not due to changes in passive Ca(2+) leak, inositol 1,4,5-triphosphate receptor (see 147265) activity, or sensitivity to inositol 1,4,5-triphosphate. Since SERCA2b formed dimers, Ahn et al. (2003) proposed that mutant SERCA2b proteins may inhibit channel activity by dimerizing with wildtype proteins.
In Drosophila, Kaneko et al. (2014) identified a dominant missense mutation (A617T) in the calcium ATPase Serca gene that conferred temperature-sensitive motor uncoordination in a gain-of-function manner. The homologous residue is conserved by different type II P-type ATPases, including ATP1A2 (182340). Introduction of an R751Q mutation in the Drosophila Serca gene also caused a temperature-sensitive uncoordination phenotype. The corresponding residue in human SERCA2, ATP1A2, and ATP1A3 (182350) is mutated in the human diseases Darier disease, FHM2, and dystonia-12 (DYT12; 128235), respectively. Cellular expression of Drosophila A617T resulted in temperature-induced decreased levels of stored calcium compared to wildtype, whereas cellular expression of R751Q elicited depletion of stored calcium even without heating. These calcium changes were due to leakage through the mutant channel pores that overwhelmed the pumping capacity of the cell. Similar results occurred after transfection of these mutations, as well as other disease-causing mutations that affected different parts of the protein, into mouse cells. Kaneko et al. (2014) concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases. Kaneko et al. (2014) concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases.
Acrokeratosis Verruciformis
In affected members of a family with acrokeratosis verruciformis (AKV; 101900) in 6 generations, Dhitavat et al. (2003) identified a heterozygous pro602-to-leu mutation (P602L; 108740.0011) in the ATP2A2 gene.
In an 11-year-old Afghan boy with AKV, Berk et al. (2010) identified a heterozygous ala698-to-val mutation (A698V; 108740.0013) in the ATP2A2 gene.
Using a mouse model with a null mutation in 1 copy of the Serca2 gene, in which Serca2 protein levels were reduced by about a third, Ji et al. (2000) observed decreased sarcoplasmic reticulum calcium stores and release in isolated cardiomyocytes. In addition, these mice had reduced myocyte contractility. However, the rate of calcium transient decline was not altered significantly. Immunoblot analysis showed a concomitant decrease in the SERCA2 inhibitor, phospholamban, and an increase in Pln phosphorylation at ser16 and thr17, which reduced Pln activity. RNase protection analysis revealed no significant difference in Ncx (see SLC8A1; 182305) levels, but quantitative immunoblot analysis detected an additional partial compensatory mechanism, an increase in Ncx protein expression and current density. Ji et al. (2000) concluded that the net effect of decreased SERCA2 pump level is a deficit in cardiac function.
Liu et al. (2001) found that aged heterozygous mutant (Atp2a2 +/-) mice developed squamous cell tumors of the forestomach, esophagus, oral mucosa, tongue, and skin. Hyperkeratinized squamous cell papillomas and carcinomas of the upper digestive tract were the most frequent finding, and many animals had multiple tumors. Liu et al. (2001) concluded that haploinsufficiency predisposes murine keratinocytes to neoplasia, and that perturbation of Ca(2+) homeostasis or signaling can be a primary initiating event in cancer.
Homozygous disruption of the mouse Serca2 gene is embryonic lethal. Zhao et al. (2001) found that heterozygous mutants showed mild impairment of cardiac function under resting conditions, but were otherwise indistinguishable from wildtype controls. The nearly normal phenotype of Serca2 +/- mice was likely due to adaptation of the Ca(2+) signaling machinery and Ca(2+)-dependent cell function. There was adaptive upregulation of Pmca (108731), which, in turn, caused a 2-fold reduction in intracellular Ca(2+) concentration oscillation frequency evoked by agonists. Agonist-stimulated exocytosis was identical in wildtype and Serca2 +/- mice due to an adaptive increase in the apparent affinity for Ca(2+) in stimulating exocytosis in mutant cells.
Ohno et al. (1996) examined the ATP2A2 gene as a possible cause of hypertension in spontaneous hypertensive rats (SHR). When SHR were crossed with wildtype rats, ATP2A2 RFLPs did not cosegregate with blood pressure. Ohno et al. (1996) ruled out ATP2A2 as the cause of the SHR phenotype. However, the ATP2A2 locus contributes to the abnormal intracellular Ca(2+) homeostasis of the SHR.
In a patient with Darier disease (DAR; 124200), Sakuntabhai et al. (1999) demonstrated a heterozygous 68G-A transition in exon 1 of the ATP2A2 gene, resulting in a gly23-to-glu mutation in the gene product. This was a nonconservative amino acid substitution at a position highly homologous between species. The mutation was observed in an affected individual who had a genetically identical twin (as confirmed by typing at a series of highly polymorphic marker loci used routinely in zygosity testing) who, like the 2 parents, was unaffected.
Sakuntabhai et al. (1999) demonstrated that a patient with Darier disease (DAR; 124200) had a heterozygous nonsense mutation (gln108 to ter) involving the last codon of exon 4 and causing an in-frame skipping of exon 4.
In a patient with Darier disease (DAR; 124200), Sakuntabhai et al. (1999) described a heterozygous splicing mutation, 544+1G-A, in the ATP2A2 gene. The mutation occurred at the guanine of the conserved GT dinucleotide in the donor splice site of intron 6. The mutation was predicted to alter splicing of exon 6 and to have deleterious effects on expression of ATP2A2.
In 1 Scottish and 2 unrelated Italian families with Darier disease (DAR; 124200), Ruiz-Perez et al. (1999) identified the same A-to-G transition at nucleotide 2300 of the ATP2A2 gene, resulting in an asn767-to-ser substitution in the M5 transmembrane domain. Affected members in these families showed the acral hemorrhagic type of Darier disease, in which hemorrhage into acantholytic vesicles on the palms and dorsal aspects of the fingers gives rise to black macules.
In a Swedish family, Ruiz-Perez et al. (1999) found that affected members with the acral hemorrhagic type of Darier disease (DAR; 124200) had a G-to-T transversion at nucleotide 803 of the ATP2A2 gene, resulting in a cys268-to-phe substitution in the M3 transmembrane domain. These findings and those of the asn767-to-ser mutation (108740.0004) suggested that certain mutations may be specifically disruptive to ATP2A2 function not only in keratinocytes but also in vascular endothelium cells, or that the mutant protein has a secondary effect in the blood vessels.
In 2 apparently unrelated cases of Darier disease (DAR; 124200) associated with mood disorder, Jacobsen et al. (1999) identified a T-to-C transition at nucleotide 1678 of the ATP2A2 gene, resulting in a cys560-to-arg substitution.
Among a series of 24 novel ATP2A2 mutations in familial and sporadic cases of Darier disease (DAR; 124200), Sakuntabhai et al. (1999) described an 18-bp insertion in intron 2, 12 bp upstream of exon 3. Use of a cryptic splice acceptor site resulted in the addition of amino acid sequence MFLTGK N-terminal to sequence encoded by exon 3.
Among a series of 24 novel ATP2A2 mutations in familial and sporadic cases of Darier disease (DAR; 124200), Sakuntabhai et al. (1999) described loss of an ACA triplet from an (ACA)3 repeat in exon 15, leading to loss of the codon for asn754 in the stalk 5 region of the protein.
In genomic DNA extracted from affected skin from a 48-year-old female with acantholytic dyskeratotic nevi (DAR; 124200), Sakuntabhai et al. (2000) detected a C-to-A transversion at nucleotide 2682 of the ATP2A2 gene, resulting in a tyrosine-to-stop substitution at codon 894 (Y894X). Analysis of genomic DNA from unaffected skin and peripheral blood leukocytes did not show this change. This mutation is expected to result in nonsense-mediated mRNA instability, leading to a null allele.
In genomic DNA from affected skin of a 35-year-old male with acantholytic dyskeratotic nevi (DAR; 124200), Sakuntabhai et al. (2000) detected a G-to-A transition at nucleotide 2305 of the ATP2A2 gene, changing glycine-769 to arginine (G769R). Analysis of genomic DNA from unaffected skin and peripheral blood leukocytes did not show this change. The authors considered it likely that this mutation interferes with SERCA2 function and impairs Ca(2+) transport across the sarco/endoplasmic reticulum membrane.
Dhitavat et al. (2003) studied a 6-generation family with acrokeratosis verruciformis (AKV; 101900) and identified a heterozygous pro602-to-leu (P602L) mutation in ATP2A2 resulting from a C-to-T transition at nucleotide position 1805. Functional analysis of the P602L mutant showed that it had lost its ability to transport Ca(2+).
In 1 Taiwanese family with Darier disease (DAR; 124200) and in 1 sporadic case, Chao et al. (2002) found a G-to-A transition at nucleotide 392 in exon 5 of the ATP2A2 gene, resulting in an arg-to-gln mutation at codon 131 (R131Q). This mutation had been reported by Sakuntabhai et al. (1999) and Ringpfeil et al. (2001).
In an 11-year-old Afghan boy with acrokeratosis verruciformis (AKV; 101900), who presented with a 6-year history of asymptomatic bumps on the hands and feet, Berk et al. (2010) identified a heterozygous C-to-T transition in exon 14 of the ATP2A2 gene, resulting in an ala698-to-val (A698V) substitution. Alanine-698 is highly conserved throughout evolution. Neither parent had the mutation, suggesting that it had occurred de novo in the patient.
Ahn, W., Lee, M. G., Kim, K. H., Muallem, S. Multiple effects of SERCA2b mutations associated with Darier's disease. J. Biol. Chem. 278: 20795-20801, 2003. [PubMed: 12670936] [Full Text: https://doi.org/10.1074/jbc.M301638200]
Asahi, M., Otsu, K., Nakayama, H., Hikoso, S., Takeda, T., Gramolini, A. O., Trivieri, M. G., Oudit, G. Y., Morita, T., Kusakari, Y., Hirano, S., Hongo, K., Hirotani, S., Yamaguchi, O., Peterson, A., Backx, P. H., Kurihara, S., Hori, M., MacLennan, D. H. Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) activity and impairs cardiac function in mice. Proc. Nat. Acad. Sci. 101: 9199-9204, 2004. [PubMed: 15201433] [Full Text: https://doi.org/10.1073/pnas.0402596101]
Berk, D. R., Taube, J. M., Bruckner, A. L., Lane, A. T. A sporadic patient with acrokeratosis verruciformis of Hopf and a novel ATP2A2 mutation. (Letter) Brit. J. Derm. 163: 653-654, 2010. [PubMed: 20518781] [Full Text: https://doi.org/10.1111/j.1365-2133.2010.09876.x]
Chao, S.-C., Yang, M.-H., Lee, J. Y.-Y. Mutation analysis of the ATP2A2 gene in Taiwanese patients with Darier's disease. Brit. J. Derm. 146: 958-963, 2002. [PubMed: 12072062] [Full Text: https://doi.org/10.1046/j.1365-2133.2002.04786.x]
Dhitavat, J., Macfarlane, S., Dode, L., Leslie, N., Sakuntabhai, A., MacSween, R., Saihan, E., Hovnanian, A. Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease. J. Invest. Derm. 120: 229-232, 2003. [PubMed: 12542527] [Full Text: https://doi.org/10.1046/j.1523-1747.2003.t01-1-12045.x]
Gelebart, P., Martin, V., Enouf, J., Papp, B. Identification of a new SERCA2 splice variant regulated during monocytic differentiation. Biochem. Biophys. Res. Commun. 303: 676-684, 2003. [PubMed: 12659872] [Full Text: https://doi.org/10.1016/s0006-291x(03)00405-4]
Greene, A. L., Lalli, M. J., Ji, Y., Babu, G. J., Grupp, I., Sussman, M., Periasamy, M. Overexpression of SERCA2b in the heart leads to an increase in sarcoplasmic reticulum calcium transport function and increased cardiac contractility. J. Biol. Chem. 275: 24722-24727, 2000. [PubMed: 10816568] [Full Text: https://doi.org/10.1074/jbc.M001783200]
Jacobsen, N. J. O., Lyons, I., Hoogendoorn, B., Burge, S., Kwok, P.-Y., O'Donovan, M. C., Craddock, N., Owen, M. J. ATP2A2 mutations in Darier's disease and their relationship to neuropsychiatric phenotypes. Hum. Molec. Genet. 8: 1631-1636, 1999. [PubMed: 10441325] [Full Text: https://doi.org/10.1093/hmg/8.9.1631]
Ji, Y., Lalli, M. J., Babu, G. J., Xu, Y., Kirkpatrick, D. L., Liu, L. H., Chiamvimonvat, N., Walsh, R. A., Shull, G. E., Periasamy, M. Disruption of a single copy of the SERCA2 gene results in altered Ca(2+) homeostasis and cardiomyocyte function. J. Biol. Chem. 275: 38073-38080, 2000. [PubMed: 10970890] [Full Text: https://doi.org/10.1074/jbc.M004804200]
Kaneko, M., Desai, B. S., Cook, B. Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases. Nature Genet. 46: 144-151, 2014. [PubMed: 24336169] [Full Text: https://doi.org/10.1038/ng.2850]
Kho, C., Lee, A., Jeong, D., Oh, J. G., Chaanine, A. H., Kizana, E., Park, W. J., Hajjar, R. J. SUMO1-dependent modulation of SERCA2a in heart failure. Nature 477: 601-605, 2011. [PubMed: 21900893] [Full Text: https://doi.org/10.1038/nature10407]
Kim, Y.-K., Kim, S.-J., Yatani, A., Huang, Y., Castelli, G., Vatner, D. E., Liu, J., Zhang, Q., Diaz, G., Zieba, R., Thaisz, J., Drusco, A., Croce, C., Sadoshima, J., Cordorelli, G., Vatner, S. F. Mechanism of enhanced cardiac function in mice with hypertrophy induced by overexpressed Akt. J. Biol. Chem. 278: 47622-47628, 2003. [PubMed: 13129932] [Full Text: https://doi.org/10.1074/jbc.M305909200]
Liu, L. H., Boivin, G. P., Prasad, V., Periasamy, M., Shull, G. E. Squamous cell tumors in mice heterozygous for a null allele of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform 2 Ca(2+) pump. J. Biol. Chem. 276: 26737-26740, 2001. [PubMed: 11389134] [Full Text: https://doi.org/10.1074/jbc.C100275200]
Lytton, J., MacLennan, D. H. Molecular cloning of cDNAs from human kidney coding for two alternatively spliced products of the cardiac Ca(2+)-ATPase gene. J. Biol. Chem. 263: 15024-15031, 1988. [PubMed: 2844796]
MacLennan, D. H., Brandl, C. J., Champaneria, S., Holland, P. C., Powers, V. E., Willard, H. F. Fast-twitch and slow-twitch/cardiac Ca(2+) ATPase genes map to human chromosomes 16 and 12. Somat. Cell Molec. Genet. 13: 341-346, 1987. Note: Erratum: Somat. Cell Molec. Genet. 14: 645 only, 1988. [PubMed: 2842876] [Full Text: https://doi.org/10.1007/BF01534928]
MacLennan, D. H., Brandl, C. J., Korczak, B., Green, N. M. Amino-acid sequence of a Ca(2++) Mg(2+)-dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence. Nature 316: 696-700, 1985. [PubMed: 2993904] [Full Text: https://doi.org/10.1038/316696a0]
Missiaen, L., Wuytack, F., Raeymaekers, L., De Smedt, H., Droogmans, G., Declerck, I., Casteels, R. Ca(2+) extrusion across plasma membrane and Ca(2+) uptake by intracellular stores. Pharm. Ther. 50: 191-232, 1991. [PubMed: 1662401] [Full Text: https://doi.org/10.1016/0163-7258(91)90014-d]
Ohno, Y., Matsuo, K., Suzuki, H., Tanase, H., Serikawa, T., Takano, T., Saruta, T. Genetic linkage of the sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase II gene to intracellular Ca(2+) concentration in the spontaneously hypertensive rat. Biochem. Biophys. Res. Commun. 227: 789-793, 1996. [PubMed: 8886011] [Full Text: https://doi.org/10.1006/bbrc.1996.1586]
Otsu, K., Fujii, J., Periasamy, M., Difilippantonio, M., Uppender, M., Ward, D. C., MacLennan, D. H. Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes. Genomics 17: 507-509, 1993. [PubMed: 8406504] [Full Text: https://doi.org/10.1006/geno.1993.1357]
Ringpfeil, F., Raus, A., DiGiovanna, J. J., Korge, B., Harth, W., Mazzanti, C., Uitto, J., Bale, S. J., Richard, G. Darier disease--novel mutations in ATP2A2 and genotype-phenotype correlation. Exp. Derm. 10: 19-27, 2001. [PubMed: 11168576] [Full Text: https://doi.org/10.1034/j.1600-0625.2001.100103.x]
Ruiz-Perez, V. L., Carter, S. A., Healy, E., Todd, C., Rees, J. L., Steijlen, P. M., Carmichael, A. J., Lewis, H. M., Hohl, D., Itin, P., Vahlquist, A., Gobello, T., Mazzanti, C., Reggazini, R., Nagy, G., Munro, C. S., Strachan, T. ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class. Hum. Molec. Genet. 8: 1621-1630, 1999. [PubMed: 10441324] [Full Text: https://doi.org/10.1093/hmg/8.9.1621]
Sakuntabhai, A., Burge, S., Monk, S., Hovnanian, H. Spectrum of novel ATP2A2 mutations in patients with Darier's disease. Hum. Molec. Genet. 8: 1611-1619, 1999. [PubMed: 10441323] [Full Text: https://doi.org/10.1093/hmg/8.9.1611]
Sakuntabhai, A., Dhitavat, J., Burge, S., Hovnanian, A. Mosaicism for ATP2A2 mutations causes segmental Darier's disease. J. Invest. Derm. 115: 1144-1147, 2000. [PubMed: 11121153] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.00182.x]
Sakuntabhai, A., Ruiz-Perez, V., Carter, S., Jacobsen, N., Burge, S., Monk, S., Smith, M., Munro, C. S., O'Donovan, M., Craddock, N., Kucherlapati, R., Rees, J. L., Owen, M., Lathrop, G. M., Monaco, A. P., Strachan, T., Hovnanian, A. Mutations in ATP2A2, encoding a Ca(2+) pump, cause Darier disease. Nature Genet. 21: 271-277, 1999. [PubMed: 10080178] [Full Text: https://doi.org/10.1038/6784]
Santiago-Garcia, J., Mas-Oliva, J., Saavedra, D., Zarain-Herzberg, A. Analysis of mRNA expression and cloning of a novel plasma membrane Ca(2+)-ATPase splice variant in human heart. Molec. Cell. Biochem. 155: 173-182, 1996. [PubMed: 8700162] [Full Text: https://doi.org/10.1007/BF00229314]
Sheridan, A. T., Hollowood, K., Sakuntabhai, A., Dean, D., Hovnanian, A., Burge, S. Expression of sarco/endo-plasmic reticulum Ca(2+)-ATPase type 2 isoforms (SERCA2) in normal human skin and mucosa, and Darier's disease skin. Brit. J. Derm. 147: 670-674, 2002. [PubMed: 12366411] [Full Text: https://doi.org/10.1046/j.1365-2133.2002.04916.x]
Stefanovic, B., Stefanovic, L., Schnabl, B., Bataller, R., Brenner, D. A. TRAM2 protein interacts with endoplasmic reticulum Ca2+ pump Serca2b and is necessary for collagen type I synthesis. Molec. Cell. Biol. 24: 1758-1768, 2004. [PubMed: 14749390] [Full Text: https://doi.org/10.1128/MCB.24.4.1758-1768.2004]
Toyoshima, C., Mizutani, T. Crystal structure of the calcium pump with a bound ATP analogue. Nature 430: 529-535, 2004. [PubMed: 15229613] [Full Text: https://doi.org/10.1038/nature02680]
Wahlquist, C., Jeong, D., Rojas-Munoz, A., Kho, C., Lee, A., Mitsuyama, S., van Mil, A., Park, W. J., Sluijter, J. P. G., Doevendans, P. A. F., Hajjar, R. J., Mercola, M. Inhibition of miR-25 improves cardiac contractility in the failing heart. Nature 508: 531-535, 2014. [PubMed: 24670661] [Full Text: https://doi.org/10.1038/nature13073]
Zhao, X.-S., Shin, D. M., Liu, L. H., Shull, G. E., Muallem, S. Plasticity and adaptation of Ca(2+) signaling and Ca(2+)-dependent exocytosis in SERCA2+/- mice. EMBO J. 20: 2680-2689, 2001. [PubMed: 11387203] [Full Text: https://doi.org/10.1093/emboj/20.11.2680]