Alternative titles; symbols
HGNC Approved Gene Symbol: PPP3CA
Cytogenetic location: 4q24 Genomic coordinates (GRCh38): 4:101,023,418-101,347,526 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q24 | Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development | 618265 | Autosomal dominant | 3 |
| Developmental and epileptic encephalopathy 91 | 617711 | Autosomal dominant | 3 |
The PPP3CA gene encodes the alpha isoform of a subunit of calcineurin, which encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biologic processes, including synaptic vesicle recycling (summary by Myers et al., 2017).
Calcineurin, the Ca(2+)/calmodulin-regulated protein phosphatase, first detected in skeletal muscle and brain, has been found in all cells from yeast to mammals. It is a heterodimer of a 19-kD Ca(2+)-binding protein, calcineurin B, and a 61-kD calmodulin-binding catalytic subunit, calcineurin A. Guerini and Klee (1989) presented evidence that the different forms of calcineurin A result from alternative splicing. Multiple catalytic subunits of calcineurin are derived from at least 2 structural genes, type 1 (calcineurin A-alpha) and type 2 (calcineurin A-beta; CALNA2, 114106), each of which can produce alternatively spliced transcripts (Giri et al., 1991).
Semsarian et al. (1999) and Musaro et al. (1999) independently showed that IGF1 (147440) stimulates skeletal muscle hypertrophy and a switch to glycolytic metabolism by activating calcineurin A and inducing the nuclear translocation of transcription factor NFATC1 (600489). Semsarian et al. (1999) found that hypertrophy was suppressed by the calcineurin inhibitors cyclosporin A or FK506, but not by inhibitors of the MAP kinase or phosphatidylinositol-3-OH kinase pathways. Musaro et al. (1999) showed that expression of a dominant-negative calcineurin mutant also repressed myocyte differentiation and hypertrophy. Musaro et al. (1999) demonstrated that either IGF1 or activated calcineurin induces expression of transcription factor GATA2 (137295), which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of NFATC1.
DCSR1 (RCAN1; 602917) is a locus on chromosome 21 that is implicated in the pathophysiology of Down syndrome (190685). Fuentes et al. (2000) demonstrated that DSCR1 is overexpressed in the brain of Down syndrome fetuses, and interacts physically and functionally with calcineurin A. The DSCR1-binding region in calcineurin A is located in the linker region between the calcineurin A catalytic domain and the calcineurin B-binding domain, outside of other functional domains previously defined in calcineurin A. DSCR1 belongs to a family of evolutionarily conserved proteins with 3 members in humans: DSCR1, ZAKI4 (RCAN2; 604876) and DSCR1L2 (RCAN3; 605860). Overexpression of DSCR1 and ZAKI4 inhibited calcineurin-dependent gene transcription through the inhibition of NFAT translocation to the nucleus. The authors hypothesized that members of this family of human proteins are endogenous regulators of calcineurin-mediated signaling pathways and may be involved in many physiologic processes.
Leinwand (2001) discussed calcineurin inhibition and cardiac hypertrophy.
Seitz et al. (2002) found calcineurin in all bovine ocular tissues and postulated that it is involved in the immunologic privilege of the cornea, in retinal signal transduction, and in the toxic effects of immunosuppressants on the eye.
Baksh et al. (2002) found that ectopic expression of NFATC2 (600490) inhibited the basal activity of the human CDK4 (123829) promoter. Additionally, both Calna -/- and Nfatc2 -/- mice had elevated protein levels of Cdk4, confirming a negative regulatory role for the calcineurin/NFAT pathway. This pathway may thus regulate the expression of CDK4 at the transcriptional level and control how cells reenter a resting, nonproliferative state.
Elevations in circulating glucose and gut hormones during feeding promote pancreatic islet cell viability in part via the calcium- and cAMP-dependent activation of the transcription factor CREB (123810). Screaton et al. (2004) identified a signaling module that mediated the synergistic effects of these pathways on cellular gene expression by stimulating the dephosphorylation and nuclear entry of TORC2 (608972), a CREB coactivator. This module consisted of the calcium-regulated phosphatase calcineurin and the ser/thr kinase SIK2 (608973), both of which associated with TORC2. Under resting conditions, TORC2 was sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins (see 601288). Triggering of the calcium and cAMP second messenger pathways by glucose and gut hormones disrupted TORC2:14-3-3 complexes via complementary effects on TORC2 dephosphorylation; calcium influx increased calcineurin activity, whereas cAMP inhibited SIK2 kinase activity. The results illustrated how a phosphatase/kinase module connects 2 signaling pathways in response to nutrient and hormonal cues.
In frog eggs, calcium ion activates calcium/calmodulin-activated kinase (e.g., 114078), which inactivates cytostatic factor, allowing the anaphase-promoting factor to turn on and ubiquitinate cyclins and securin, which returns the cell cycle to interphase. Mochida and Hunt (2007) showed that the calcium-activated protein phosphatase calcineurin is also important in this process. Calcineurin was transiently activated after adding calcium ion to egg extracts, and inhibitors of calcineurin such as cyclosporin A delayed the destruction of cyclins, the global dephosphorylation of M-phase-specific phosphoproteins, and the reformation of a fully functional nuclear envelope. Mochida and Hunt (2007) found that a second wave of phosphatase activity directed at mitotic phosphoproteins appeared after the spike of calcineurin activity. This activity disappeared the next time the extract entered M phase and reappeared at the end of mitosis. Mochida and Hunt (2007) surmised that inhibition of this second phosphatase activity is important in allowing cells to enter mitosis and, conversely, that its activation is required for a timely return to interphase. Calcineurin is required to break the deep cell cycle arrest imposed by the Mos-MAP kinase pathway, and Mochida and Hunt (2007) showed that Fizzy/Cdc20 (603618), a key regulator of the anaphase-promoting factor, is an excellent substrate for this phosphatase.
Using cell-free extracts from unfertilized eggs of Xenopus laevis, Nishiyama et al. (2007) showed that calcineurin is transiently activated immediately after calcium ion addition to a concentration that induces meiosis II exit. When calcineurin activation was inhibited, cyclin-dependent kinase-1 (CDK1; 116940) inactivation by means of cyclin B (123836) degradation was prevented and sperm chromatin incubated in the extracts remained condensed. Similarly, if calcineurin was inhibited in intact eggs, meiosis II exit on egg activation was prevented. In addition, the activation contraction in the cortex was suppressed whereas cortical granule exocytosis occurs. Nishiyama et al. (2007) further demonstrated that, when a high level of calcineurin activity was maintained after activation, growth of sperm asters was prevented in egg extracts and, consistently, migration of male and female pronuclei towards each other was hindered in fertilized eggs. Thus, Nishiyama et al. (2007) concluded that both activation and the subsequent inactivation of calcineurin in fertilized eggs are crucial for the commencement of vertebrate embryonic development.
Kishi et al. (2007) stated that RCN proteins (see RCN1; 602735) are highly conserved and, depending on their phosphorylation status, either stimulate or inhibit calcineurin. In yeast, Kishi et al. (2007) found that Cdc4 (FBXW7; 606278) bound directly to phosphorylated Rcn1, resulting in Rcn1 ubiquitination and subsequent degradation and relief of calcineurin inhibition.
Wang et al. (2011) found that Cna-alpha and -beta were critical in executing a proapoptotic program following exposure of neonatal rat cardiomyocytes to anoxia. Cna-alpha and -beta dephosphorylated the mitochondrial fission protein Drp1 (DNM1L; 603850), permitting translocation of Drp1 from the cytosol to mitochondria, followed by mitochondrial fragmentation and apoptosis. Wang et al. (2011) characterized upstream events in this apoptotic pathway and found that p53 (191170) downregulated expression of microRNA-499 (MIR499; 613614), which relieved Mir499-dependent repression of Cna-alpha and -beta. Knockdown of either Cna-alpha or Cna-beta via small interfering RNA attenuated Drp1 accumulation in mitochondria, mitochondria fragmentation, and anoxia-induced cell death.
Wang et al. (2012) showed in mice that glucagon stimulates CRTC2 (608972) dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent PPP3CA. Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs) (ITPR1, 147265; ITPR2, 600144; ITPR3, 147267), which associated with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signaling reduced CRTC2 activity via the AKT (164730)-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrated how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.
Hisamitsu et al. (2012) found that human Na+/H+ exchanger-1 (NHE1, or SLC9A1; 107310) directly bound CANA in the CANA-CANB dimer and promoted serum-induced NFAT nuclear translocation and signaling in human fibroblasts. NHE1 and CANA colocalized in membrane lipid rafts, and calcineurin activity was strongly enhanced at increased pH. NHE1-induced NFAT signaling required Na+/H+ exchange, suggesting that NHE1 may promote calcineurin-NFAT signaling by increasing pH at localized membrane microdomains. Overexpression of NHE1 also induced nuclear translocation of NFAT in primary rat cardiomyocytes and induced hypertrophic signaling.
By the analysis of genomic DNA from human/hamster hybrid cell lines using probes designed to bind selectively to exon 3 of the open reading frame, Giri et al. (1991) found from hybridization to Southern blots that CALNA1 mapped to chromosome 4, whereas CALNA2 mapped to chromosome 10. By Southern analysis of somatic cell hybrids, Wang et al. (1996) confirmed assignment of the CALNA gene to chromosome 4 and used the symbol PPP3CA.
In 6 unrelated patients with developmental and epileptic encephalopathy-91 (DEE91; 617711), Myers et al. (2017) identified 5 different de novo heterozygous mutations in the PPP3CA gene (114105.0001-114105.0005). The patients were ascertained from several large independent cohorts of patients with neurodevelopmental or seizure disorders (see, e.g., the EuroEPINOMICS-RES Consortium et al., 2014 and Zhu et al., 2015); the mutations were found by exome sequencing and confirmed by Sanger sequencing. There was 1 nonsense mutation and 4 missense mutations, 3 of which occurred in the catalytic domain. Functional studies of the variants and studies of patient cells were not performed. However, Myers et al. (2017) noted that calcineurin is a key regulator of synaptic vesicle recycling at nerve terminals and interacts with DNM1 (602377), suggesting that disruption of this process could lead to early-onset epilepsy and neurodevelopmental abnormalities. Five of the individuals were found among 4,760 probands with neurodevelopmental disorders who were studied.
By whole-exome sequencing, Mizuguchi et al. (2018) identified 6 heterozygous mutations in the PPP3CA gene, including 3 missense mutations in the catalytic domain, 1 frameshift insertion (114105.0006), and 2 missense mutations in the autoinhibitory domain (114105.0007-114105.0008). The mutations were confirmed by Sanger sequencing; both parents were available for study in all but 1 patient with a mutation in the catalytic domain, and mutations were found to be de novo. Using a yeast model, 2 functionally distinct types of mutations were identified: loss-of-function mutations (as evidenced by decreased calcineurin signaling) at the catalytic domain, and constitutively activating mutations (as evidenced by increased calcineurin signaling) at the autoinhibitory domain. The loss-of-function mutations in the catalytic domain and the frameshift mutation were associated with DEE91, whereas the gain-of-function mutations in the autoinhibitory domain were associated with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ACCIID; 618265).
Winder et al. (1998) generated transgenic mice that overexpressed a truncated form of the murine calcineurin A-alpha catalytic subunit under the control of the CaMKII-alpha promoter. Mice expressing this transgene show increased calcium-dependent phosphatase activity in the hippocampus. Physiologic studies and pharmacologic experiments revealed a novel, intermediate phase of long-term potentiation (I-LTP) in the CA1 region of the hippocampus. This I-LTP differs from the E-LTP (early component of LTP) by requiring multiple trains for induction and in being dependent on PKA (cAMP-dependent protein kinase). It also differs from the L-LTP (late component of LTP) in not requiring new protein synthesis. These data suggested to Winder et al. (1998) that calcineurin acts as an inhibitory constraint on I-LTP that is relieved by PKA, and that this inhibitory constraint acts as a gate to regulate the synaptic induction of L-LTP.
Mansuy et al. (1998) studied the transgenic mice generated by Winder et al. (1998) that overexpressed a truncated form of calcineurin. These mice have normal short-term memory but defective long-term memory evident on both a spatial task and on a visual recognition task, providing genetic evidence for the role of the rodent hippocampus in spatial and nonspatial memory. The defect in long-term memory could be fully rescued by increasing the number of training trials, suggesting to these investigators that the mice had the capacity for long-term memory. Mansuy et al. (1998) also analyzed mice overexpressing calcineurin in a regulated manner (by repression of the transgene by doxycycline) and found that the memory defect was reversible and not due to a developmental abnormality. These results suggested that calcineurin has a role in the transition from short- to long-term memory.
The calcineurin inhibitory agents cyclosporin A and FK506 have been extensively used to evaluate the importance of the calmodulin pathway in rodent models of cardiac hypertrophy. To investigate more specific inhibitory strategies, De Windt et al. (2001) generated transgenic mice expressing the calcineurin inhibitory domains of either calcineurin-binding protein-1 (CAIN, or CABIN1; 604251) or A-kinase-anchoring protein-79 (AKAP79, or AKAP5; 604688). With each they found partial reduction in catecholamine- and pressure overload-induced cardiac hypertrophy. Adenoviral-mediated gene delivery of CAIN in adult rat hearts also attenuated overload-induced cardiac hypertrophy. These divergent approaches strongly implicated calcineurin as an important regulator of the mechanism whereby cardiomyocytes respond to pathophysiologic stimuli.
Because cyclosporine A and FK506 cause profound bone loss in humans and animal models, Sun et al. (2005) examined the role of calcineurin in skeletal remodeling. They found that mouse osteoblasts contained mRNA and protein for all isoforms of calcineurin A and B. Overexpression of calcineurin A-alpha resulted in enhanced expression of the osteoblast differentiation markers Runx2 (600211), alkaline phosphatase (ALPL; 171760), bone sialoprotein (SPP1; 166490), and osteocalcin (BGLAP; 112260), and this expression was associated with dramatic enhancement of bone formation in intact calvarial cultures. Calcineurin A-alpha -/- mice displayed severe osteoporosis, markedly reduced mineral apposition rates, and attenuated colony formation in 10-day ex vivo stromal cell cultures. The latter was associated with significant reductions in expression of osteoblast marker genes and decreased response to FK506. Sun et al. (2005) concluded that calcineurin regulates bone formation through an effect on osteoblast differentiation.
Rothermel et al. (2001) inhibited calcineurin in the hearts of intact animals by engineering transgenic mice overexpressing a human cDNA encoding myocyte-enriched calcineurin-interacting protein-1 (MCIP1; 602917) under control of the cardiac-specific alpha-myosin heavy chain promoter. In unstressed mice, forced expression of MCIP1 resulted in a 5 to 10% decline in cardiac mass relative to wildtype littermates, but otherwise produced no apparent structural or functional abnormalities. However, cardiac-specific expression of MCIP1 inhibited cardiac hypertrophy, reinduction of fetal gene expression, and progression to dilated cardiomyopathy that otherwise resulted from expression of a constitutively active form of calcineurin. Expression of the MCIP1 transgene also inhibited hypertrophic responses to beta-adrenergic receptor stimulation or exercise training. These results demonstrated that levels of MCIP1 producing no apparent deleterious effects in cells of the normal heart are sufficient to inhibit several forms of cardiac hypertrophy. The future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure.
The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, Malleret et al. (2001) examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent reverse tetracycline-controlled transactivator system to express a calcineurin inhibitor (the C-terminal autoinhibitory domain of CNA-alpha) reversibly in the mouse brain, they found that transient reduction of calcineurin activity facilitated long-term potentiation (LTP) in vitro and in vivo. This facilitation was PKA dependent and persisted over several days in vivo. It was accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements were reversed fully by suppression of transgene expression. These results demonstrated that endogenous calcineurin constrains LTP and memory.
In a 7-year-old boy of Korean and European descent (patient EGI0251B1) with developmental and epileptic encephalopathy-91 (DEE91; 617711), Myers et al. (2017) identified a de novo heterozygous c.1333C-T transition (c.1333C-T, NM_000944.4) in the PPP3CA gene, resulting in a gln445-to-ter (Q445X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server, 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed.
In a 12.5-year-old boy of European descent (patient lgsnd30299is1) with developmental and epileptic encephalopathy-91 (DEE91; 617711), Myers et al. (2017) identified a de novo heterozygous c.275A-G transition (c.275A-G, NM_000944.4) in the PPP3CA gene, resulting in a his92-to-arg (H92R) substitution in the catalytic domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server, 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed.
In a 21.5-year-old woman of Ashkenazi and Sephardic descent (patient isrl69xx3) with developmental and epileptic encephalopathy-91 (DEE91; 617711), Myers et al. (2017) identified a de novo heterozygous c.1339G-A transition (c.1339G-A, NM_000944.4) in the PPP3CA gene, resulting in an ala447-to-thr (A447T) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server, 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed.
In a 10-year-old girl of Maori and European New Zealander descent (patient T26323) with developmental and epileptic encephalopathy-91 (DEE91; 617711), Myers et al. (2017) identified a de novo heterozygous c.843C-G transversion (c.843C-G, NM_000944.4) in the PPP3CA gene, resulting in a his281-to-gln (H281Q) substitution in the catalytic domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server, 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed.
In 2 unrelated patients (individuals 5 and 6) with developmental and epileptic encephalopathy-91 (DEE91; 617711), Myers et al. (2017) identified a de novo heterozygous c.844G-A transition (c.844G-A, NM_000944.4) in the PPP3CA gene, resulting in a glu282-to-lys (E282K) substitution in the catalytic domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server, 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies of the variant and studies of patients cells were not performed. One patient was of Pakistani origin and the other was of mixed European and Ashkenazi descent.
In a 2-year-old girl (patient 4) with developmental and epileptic encephalopathy-91 (DEE91; 617711), who was initially diagnosed with West syndrome, Mizuguchi et al. (2018) identified a de novo heterozygous 1-bp duplication (c.1290dupC, NM_000944.4) in the PPP3CA gene, resulting in a frameshift (Met431HisfsTer20). The mutation was found by whole-exome sequencing and validated by Sanger sequencing.
In a 5-year-old girl (patient 5) with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ACCIID, 618265), Mizuguchi et al. (2018) identified a de novo heterozygous transition (c.1408T-C, NM_000944.4) in the PPP3CA gene, resulting in a phe470-to-leu (F470L) substitution at a conserved residue in the autoinhibitory domain. The patient's phenotype had some similarities to that of osteocraniostenosis (602361), which arises from mutations in the FAM111A gene (615292), but exome sequencing data showed no mutation in that gene.
In a 7-year-old boy (patient 6) with arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ACCIID; 618265), Mizuguchi et al. (2018) identified a de novo heterozygous transition (c.1417G-A, NM_000944.4) in the PPP3CA gene, resulting in an ala473-to-thr (A473T) substitution at a conserved residue in the autoinhibitory domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
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