Alternative titles; symbols
HGNC Approved Gene Symbol: PRKCD
Cytogenetic location: 3p21.1 Genomic coordinates (GRCh38) : 3:53,161,209-53,192,717 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.1 | Autoimmune lymphoproliferative syndrome, type III | 615559 | Autosomal recessive | 3 |
The PRKCD gene encodes a member of the protein kinase C family, members of which are critical for regulation of cell survival, proliferation, and apoptosis. In B lymphocytes, PRKCD is involved in B-cell receptor-mediated signaling (summary by Salzer et al., 2013).
Although the sequence homology among the PRKC family of genes is extensive, the pattern of expression varies among tissues. For example, the delta polypeptide appears to be the major isoform expressed in mouse hematopoietic cells. Mischak et al. (1991) isolated and characterized the mouse Prkcd gene.
Aris et al. (1993) obtained 2 PKC-delta clones from a HepG2 human liver cell cDNA library. The clones differed at 3 nucleotides, resulting in nonconservative changes at positions 375 (phe to ser) and 593 (val to met) in the deduced 676-amino acid protein. Human PKC-delta shares about 90% amino acid identity with mouse and rat Pkc-delta. Western blot analysis detected a 76-kD protein following expression of either PKC-delta clone in insect cells.
Aris et al. (1993) found that PKC-delta underwent calcium-independent autophosphorylation in the presence of phosphatidylserine and diacylglycerol. Diacylglycerol was an absolute requirement for PKC-delta activation. This and other cofactor and substrate requirements distinguished human PKC-delta from its mouse homolog.
Liu et al. (2006) showed that preexisting nuclear RELA (164014), which is an NFKB subunit (see 164011), positively regulates ultraviolet (UV) irradiation-induced activation of JNK (MAPK8; 601158). In UV-irradiated mouse fibroblasts, they found that Pkc-delta was required for Rela to activate Jnk, thereby contributing to UV-induced apoptosis.
Tu et al. (2007) showed that Wnt3a (606359) signaling induced osteoblastogenesis in a mouse stromal bone marrow cell line, ST2, through G-alpha-q (GNAQ; 600998) and G-alpha-11 (GNA11; 139313), leading to activated phosphatidylinositol signaling and Prkcd. Wnt7b (601967), expressed by osteogenic cells in vivo, induced osteoblast differentiation in ST2 and mouse mesenchymal cells via the Prkcd-mediated pathway. Tu et al. (2007) concluded that PRKCD is part of a noncanonical WNT signaling cascade.
In a cultured bovine retinal pericyte model, Geraldes et al. (2009) demonstrated that hyperglycemia persistently activates PRKCD and p38-alpha MAPK (MAPK14; 600289), thus increasing expression of SHP1 (PTPN6; 176883), and that this occurs independently of NFKB (see 164011) activation. This signaling cascade leads to PDGF receptor-beta (PDGFRB; 173410) dephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis, the most specific vascular histopathology associated with diabetic complications. The authors observed increased PRKCD activity and an increase in the number of acellular capillaries in diabetic mouse retinas, which were not reversible with insulin treatment that achieved normoglycemia. Unlike diabetic age-matched wildtype mice, diabetic Prkcd -/- mice did not show activation of MAPK14 or SHP1, inhibition of PDGFB (190040) signaling in vascular cells, or the presence of acellular capillaries. The authors also observed PRKCD, MAPK14, and SHP1 activation in brain pericytes and in the renal cortex of diabetic mice. Geraldes et al. (2009) concluded that this represents a new signaling pathway by which hyperglycemia can induce PDGFB resistance and increased vascular cell apoptosis to cause diabetic vascular complications.
Haubensak et al. (2010) used molecular genetic approaches to map the functional connectivity of a subpopulation of GABA-containing neurons located in the lateral subdivision of the central amygdala (CEl), which express PRKCD. Channelrhodopsin-2-assisted circuit mapping in amygdala slices and cell-specific viral tracing indicated that PRKCD-positive neurons inhibit output neurons in the medial central amygdala (CEm), and also make reciprocal inhibitory synapses with PRKCD-negative neurons in CEl. Electrical silencing of PRKCD-positive neurons in vivo suggested that they correspond to physiologically identified units that are inhibited by the conditioned stimulus, called CEl(off) units. Haubensak et al. (2010) concluded that this correspondence, together with behavioral data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.
Ciocchi et al. (2010) used in vivo electrophysiologic, optogenetic, and pharmacologic approaches in mice to demonstrate that neuronal activity in the CEl is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the CEm. Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization.
Burguillos et al. (2011) showed that the orderly activation of caspase-8 (601763) and caspase-3/7 (601761), known executioners of apoptotic cell death, regulate microglia activation through a PRKCD-dependent pathway. Burguillos et al. (2011) found that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently, reduced neurotoxicity. The authors observed that these caspases are activated in microglia in the ventral mesencephalon of Parkinson disease (168600) and the frontal cortex of individuals with Alzheimer disease (104300). Burguillos et al. (2011) concluded that caspase-8 and caspase-3/7 are involved in regulating microglia activation, and suggested that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
Qu et al. (2012) showed that PRKCD phosphorylates NLRC4 (606831) and that this phosphorylation is critical for inflammasome assembly. Using knockin mice expressing NLRC4 with a carboxy-terminal 3XFlag tag, Qu et al. (2012) identified phosphorylation of NLRC4 on a single, evolutionarily conserved residue, ser533, following infection of macrophages with Salmonella enterica serovar Typhimurium. Western blotting with an NLRC4 phospho-ser533 antibody confirmed that this posttranslational modification occurs only in the presence of stimuli known to engage NLRC4 and not the related protein NLRP3 (606416) or AIM2 (604578). Nlrc4-null macrophages reconstituted with NLRC4 mutant S533A, unlike those reconstituted with wildtype NLRC4, did not activate caspase-1 (147678) and pyroptosis in response to S. typhimurium, indicating that S533 phosphorylation is critical for NLRC4 inflammasome function. Conversely, phosphomimetic NLRC4 S533D caused rapid macrophage pyroptosis without infection. Biochemical purification of the NLRC4-phosphorylating activity and a screen of kinase inhibitors identified PRKCD as a candidate NLRC4 kinase. Recombinant PRKCD phosphorylated NLRC4 S533 in vitro, immunodepletion of PRKCD from macrophage lysates blocked NLRC4 S533 phosphorylation in vitro, and Prkcd-null macrophages exhibited greatly attenuated caspase-1 activation and IL1-beta (147720) secretion specifically in response to S. typhimurium. Phosphorylation-defective NLRC4 S533A failed to recruit procaspase-1 and did not assemble inflammasome specks during S. typhimurium infection, so phosphorylation of NLRC4 S533 probably drives conformational changes necessary for NLRC4 inflammasome activity and host innate immunity.
Du et al. (2018) found that the expression of PKC-delta and BACE1 (604252) is elevated in Alzheimer disease (AD; 104300). PKC-delta downregulation in a human neuroblastoma cell line and a PKC-delta knockout mouse cell line reduced BACE1 expression, BACE1-mediated amyloid precursor protein (APP; 104760) processing, and beta-amyloid protein production. PKC-delta overexpression in a mouse neuroblastoma cell line upregulated BACE1 expression and beta-amyloid protein production. Modulation of the expression levels of PKC-delta in human and mouse cells further revealed that downregulation of PKC-delta decreased IKB-alpha (NFKBIA; 164008) and p65 (RELA; 164014) phosphorylation, whereas overexpression increased phosphorylation. PKC-delta-dependent phosphorylation of IKB-alpha and p65 upregulated BACE1 expression to enhance beta-amyloid protein production. Treatment of double-transgenic APP/PS1 (104311) mice, which model AD, with the PKC-delta inhibitor rottlerin significantly improved spatial learning and memory, rescued cognitive deficits, and reduced beta-amyloid protein production and deposition in brain. Further, in cell lines and double-transgenic mice, reduction of PKC-delta expression reduced BACE1 expression through mediating IKB-alpha/p65 phosphorylation, thereby attenuating BACE1-mediated APP processing and beta-amyloid protein production.
By study of a panel of somatic cell human/hamster hybrid DNAs, Huppi et al. (1994) mapped the PRKCD gene to human chromosome 3. By analysis of recombination frequency in an interspecific panel of backcross mice, they mapped the murine homolog to chromosome 14 in a region syntenic with human 3p.
The genes encoding the protein kinase C enzymes are widely distributed, e.g., PRKCA (176960) is on chromosome 17, PRKCB1 (176970) on 16, and PRKCG (176980) on 19.
In a boy with autoimmune lymphoproliferative syndrome type III (ALPS3; 615559), Salzer et al. (2013) identified a homozygous splice site mutation in the PRKCD gene (176977.0001). The mutation was found by homozygosity mapping and exome sequencing and segregated with the disorder in the family. Western blot analysis showed absent expression of the PRKCD protein in patient cells, with decreased expression in cells from the heterozygous father. Patient cells showed defective phosphorylation of MARCKS (177061), a downstream target of PRKCD, as well as increased IL6 (147620) production after stimulation. The patient had recurrent infections since infancy and also showed autoimmune disorders, including membranous glomerulonephritis and antiphospholipid syndrome. The patient's father had Behcet disease and mild autoimmune thyroiditis. Genetic analysis also revealed a heterozygous variant (rs231775) in the CTLA4 gene (123890.0001) in the patient and his father, which may acted as a disease modifier given its association with autoimmune disorders.
In 3 sibs, born of consanguineous parents of northern European descent, with autoimmune lymphoproliferative syndrome type III (ALPS3; 615559), Belot et al. (2013) identified a homozygous missense mutation in the PRKCD gene (G510S; 176977.0002). The mutation was found by a combination of linkage analysis and whole-exome sequencing. The mutant protein was demonstrated to have decreased activity. The patients had increased numbers of immature B cells and decreased numbers of memory B cells. B cells from 1 patient showed a hyperproliferative response to stimulation, and mutant lymphocytes were resistant to calcium-dependent apoptosis. The findings indicated that PRKCD plays a crucial role in regulating B-cell tolerance and preventing self-reactivity in humans.
Kuehn et al. (2013) identified a homozygous missense mutation in the PRKCD gene (R614W; 176977.0003) in a Hispanic boy with ALPS3. Western blot analysis showed low levels of mutant protein expression in patient cells, and immunohistochemical studies showed absent protein expression in the patient's lymph node. Patient B cells were increased in number and showed hyperproliferation in response to stimulus; T cells did not show an increased rate of proliferation. Knockdown of PRKCD by siRNA in control B cells also caused an increase in B-cell proliferation without an increase in T-cell proliferation.
Neehus et al. (2021) characterized the cellular phenotype of 17 patients from 10 unrelated families with biallelic mutations in the PRKCD gene, 5 of whom from 3 families were newly reported (see, e.g., 176977.0004-176977.0006). EBV-transformed B cells were studied in 8 of the patients, and all of the cells demonstrated a defect in PMA-induced apoptosis, indicative of loss of PRKCD function. All of the patient EBV-transformed B cells also had decreased intracellular superoxide production after PMA stimulation, indicating impaired NADPH oxidase activity. Further studies in phagocytic cells from the patient cohort, including neutrophils and monocytes, also demonstrated impaired NADPH oxidase activity as well as impaired neutrophil extracellular trap (NET) formation following PMA stimulation.
PRKCD is involved in B cell signaling and in the regulation of growth, apoptosis, and differentiation of a variety of cell types. Prkcd is most abundant in B and T lymphocytes of lymphoid organs, cerebrum, and intestine of normal mice. By generating mice with a disruption in the Prkcd gene, Miyamoto et al. (2002) observed that the mice are viable up to 1 year but prone to autoimmune disease, with enlarged lymph nodes and spleens containing numerous germinal centers. Flow cytometric analysis showed increased numbers of bone marrow-derived B cells, but no change in CD5+ B cells or T cells. Transfer of B cells into Rag1 (179615) -/- mice resulted in greater numbers of splenic B cells and germinal centers in mice receiving Prkcd -/- cells. Prkcd-deficient B cells also mounted a stronger proliferative response than those from wildtype mice. RT-PCR analysis detected higher levels of IL6 (147620), but not other cytokines, in mutant than in wildtype B cells. EMSA analysis showed increased DNA-binding activity of NFIL6 (CEBPB; 189965) but not NFKB. Serum IgG1 and IgA, but not other isotype, concentrations were greater in Prkcd-deficient mice. Although Miyamoto et al. (2002) did not detect antinuclear antibodies, they did observe high levels of primarily IgG antibodies to chromatin in older mutant mice. Histologic analysis revealed evidence of glomerulonephritis with deposition of IgG and complement component C3. Miyamoto et al. (2002) noted that crosslinking of B cell receptors leads to activation of both Prkcb (176970) and Prkcd, but that proliferation in mice deficient in these enzymes is reduced and enhanced, respectively, possibly allowing for fine regulation of the immune response.
Mecklenbrauker et al. (2002) generated mice with a null mutation in Prkcd. They found that this deficiency prevents B cell tolerance and allows maturation and terminal differentiation of self-reactive B cells in the presence of a tolerizing antigen, soluble hen egg lysozyme. The authors detected high levels of serum anti-DNA antibodies as well as polyreactive antibodies to antigens without previous immunization. They concluded that although Prkcd deficiency does not affect B cell receptor-mediated activation in response to immunogens, induction of tolerance is compromised in the mutant mice.
Using a mouse model, Mecklenbrauker et al. (2004) reported a mechanism for the regulation of peripheral B-cell survival by serine/threonine protein kinase C-delta: spontaneous death of resting B cells is regulated by nuclear localization of Pkcd that contributes to phosphorylation of histone H2B (see 609904) at serine-14. Treatment of B cells with the potent B-cell survival factor Baff (603969) prevented nuclear accumulation of Pkcd. Mecklenbrauker et al. (2004) concluded that their data suggested the existence of a previously unknown BAFF-induced and PKCD-mediated nuclear signaling pathway which regulates B-cell survival.
Tu et al. (2007) found that Prkcd -/- mouse embryos showed much less ossification and delayed chondrocyte maturation in long bones compared to control embryos. The level of phospho-Marcks (177061) was lower in the cytosol of Prkcd -/- limb primordial cells than in control cells at embryonic day 14.5, suggesting MARCKS may be an endogenous PRKCD substrate.
Schwegmann et al. (2007) used microarray and quantitative RT-PCR analyses of Listeria monocytogenes (LM)-infected macrophages from Nfil6 -/- mice to identify candidate genes downstream of Nfil6 in pathways of LM killing independent of reactive nitrogen and oxygen intermediates. They found increased expression of Pkcd in LM-infected Nfil6 -/- macrophages compared with wildtype controls. Compared with LM-infected wildtype mice, LM-infected Pkcd -/- mice exhibited higher mortality accompanied by higher LM burden and increased inflammation with hepatic microabscesses, despite enhanced levels of Nfil6 and Il6. Pkcd -/- macrophages showed no impairment in activation, but they had high bacterial load and increased bacterial escape from phagosomes. Schwegmann et al. (2007) concluded that PKCD is a critical factor for confinement and killing of LM within macrophage phagosomes.
In a patient, born of consanguineous Turkish parents, with autoimmune lymphoproliferative syndrome type III (ALPS3; 615559), Salzer et al. (2013) identified a homozygous G-to-A transition (c.1352+1G-A) in the PRKCD gene, resulting in a splice site mutation. (The authors described the disorder as a common variable immunodeficiency-type disorder, which was formerly cataloged in OMIM as CVID9.) The mutation was found by homozygosity mapping combined with exome sequencing. The mutation was confirmed by Sanger sequencing, was not present in the dbSNP or 1000 Genomes databases, and segregated with the disorder in the family. Western blot analysis showed absent expression of the PRKCD protein in patient cells, with decreased expression in cells from the heterozygous father. Patient cells showed defective phosphorylation of MARCKS (177061), a downstream target of PRKCD, as well as increased IL6 (147620) production after stimulation. The patient had recurrent infections since infancy and also showed autoimmune disorders, including membranous glomerulonephritis and antiphospholipid syndrome. The patient's father had Behcet disease and mild autoimmune thyroiditis. Genetic analysis also revealed a heterozygous variant (rs231775) in the CTLA4 gene (123890.0001) in the patient and his father, which may have acted as a disease modifier given its association with autoimmune disorders.
In 3 sibs, born of consanguineous parents of northern European descent, with autoimmune lymphoproliferative syndrome type III (ALPS3; 615559), Belot et al. (2013) identified a homozygous c.1528G-A transition in the PRKCD gene, resulting in a gly510-to-ser (G510S) substitution at a highly conserved residue in the activation loop. The mutation, which was found using a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. It segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Cellular expression of the mutation showed that the mutant protein could not be phosphorylated at the activation loop (T507); it was also inactive under basal conditions and refractory to activation by conventional agonists. The mutant protein was degraded at a faster rate than wildtype, consistent with a loss of function.
In a Hispanic boy with autoimmune lymphoproliferative syndrome type III (ALPS3; 615559), Kuehn et al. (2013) identified a homozygous c.1840C-T transition in the PRKCD gene, resulting in an arg614-to-trp (R614W) substitution in the nuclear localization sequence. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis showed low levels of mutant protein expression in patient cells, and immunohistochemical studies showed absent protein expression in the patient's lymph node.
In a Turkish patient (patient 13, kindred H) with autoimmune lymphoproliferative syndrome type III (ALPS3; 615559), Neehus et al. (2021) identified homozygosity for a c.571+2dupC mutation in intron 7 of the PRKCD gene, resulting in a splicing defect and premature termination. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. PRKCD protein expression was absent in EBV-transformed B cells, neutrophils, monocytes, and monocyte-derived macrophages from the patient. Patient phagocytes and monocyte-derived cells demonstrated impaired reactive oxygen species production after stimulation.
In 2 Turkish sibs (patients 14 and 15, kindred I) with autoimmune lymphoproliferative syndrome type III (ALPS3; 615559), Neehus et al. (2021) identified homozygosity for a c.1384C-T transition in exon 15 of the PRKCD gene, resulting in a gln462-to-ter (Q462X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. PRKCD protein expression was absent in monocyte-derived macrophages from one of the sibs. Phagocytes and monocyte-derived cells from both sibs demonstrated impaired reactive oxygen species production after stimulation.
In 2 sibs (patients 16 and 17, kindred J), born of consanguineous Iranian parents, with autoimmune lymphoproliferative syndrome type III (ALPS3; 615559), Neehus et al. (2021) identified homozygosity for a 1-bp deletion (c.642del) in exon 8 the PRKCD gene, predicted to result in a frameshift. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. PRKCD protein expression was absent in monocyte-derived macrophages from both sibs. Phagocytes and monocyte-derived cells from both sibs demonstrated impaired reactive oxygen species production after stimulation.
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