Alternative titles; symbols
HGNC Approved Gene Symbol: PIK3CD
SNOMEDCT: 711480000;
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38): 1:9,627,258-9,729,114 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.22 | ?Roifman-Chitayat syndrome, digenic | 613328 | Digenic recessive | 3 |
| Immunodeficiency 14A, autosomal dominant | 615513 | Autosomal dominant | 3 | |
| Immunodeficiency 14B, autosomal recessive | 619281 | Autosomal recessive | 3 |
Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position of the inositol ring of inositol lipids. PIK3CD is a class I PI3K and displays a broad phosphoinositide lipid substrate specificity (Vanhaesebroeck et al., 1997).
By RT-PCR of mRNA from a T-cell line with degenerate primers derived from conserved regions of PI3K catalytic core domains, Vanhaesebroeck et al. (1997) isolated a cDNA encoding a protein that they designated p110-delta. Sequence analysis revealed that the predicted 1,044-amino acid p110-delta protein is a PI3K that is 58% identical to p110-beta (602925). By Northern blot analysis of human tissues and immunolocalization in rat tissues, Vanhaesebroeck et al. (1997) found that p110-delta is selectively expressed in leukocytes. The p110-delta transcript is approximately 6 kb.
Independently, Seki et al. (1997) also cloned and characterized PIK3CD.
Chantry et al. (1997) isolated mouse and human p110-delta cDNAs. Sequence analysis revealed that the predicted proteins are 94% identical.
Clayton et al. (2001) determined that the mouse Pik3cd gene contains 22 exons and spans over 13 kb. Its exon structure most closely resembles that of Pik3cb.
Using FISH and radiation hybrid analysis, Seki et al. (1997) mapped the PIK3CD gene to chromosome 1p36.2, a region frequently lost in malignancy.
Clayton et al. (2001) suggested that the mouse Pik3d gene may be located on chromosome 4 in a region of syntenic homology with human chromosome 1p36.2-p32.
Vanhaesebroeck et al. (1997) classified p110-delta as a class I PI3K because it displayed broad in vitro lipid substrate specificity. Like p110-alpha (PIK3CA; 171834) and p110-beta, p110-delta binds p85 adaptor proteins and GTP-bound Ras. These 3 class I PI3Ks were indistinguishable at the level of p85 adaptor protein selection or recruitment to activated receptor complexes. However, unlike p110-alpha, p110-delta does not phosphorylate p85, but instead has an autophosphorylation activity.
Zhang et al. (2002) noted that p110-delta had not detected in platelets. By examining human platelets, they found that p110-delta was highly susceptible to proteolytic degradation. Using Western blot, RT-PCR, activity, and immunoprecipitation analyses of lysed human platelets and detergent-insoluble cytoskeletal fractions from resting and thrombin receptor (F2R; 187930)-activated human platelets, Zhang et al. (2002) showed that p110-delta was present in association with p85-alpha (PIK3R1; 171833) and p85-beta (PIK3R2; 603157) in both cytosolic and cytoskeletal fractions of platelets. Zhang et al. (2002) proposed that cytoskeletal function in activated platelets and platelet spawning from megakaryocytes may be influenced by p110-delta.
Ali et al. (2004) reported that genetic or pharmacologic inactivation of the p110-delta isoform of PI(3)K in mast cells led to defective stem cell factor (SCF; 184745)-mediated in vitro proliferation, adhesion, and migration, and to impaired allergen-IgE (147180)-induced degranulation and cytokine release. Inactivation of p110-delta protected mice against anaphylactic allergic responses.
Ali et al. (2014) reported that p110-delta inactivation in mice protects against a broad range of cancers, including nonhematologic solid tumors, and demonstrated that p110-delta inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells and induces tumor regression. Ali et al. (2014) concluded that p110-delta inhibitors can break tumor-induced immune tolerance.
Autosomal Dominant Immunodeficiency 14A With Lymphoproliferation
In 17 patients from 7 unrelated families with autosomal dominant primary immunodeficiency-14A (IMD14A; 615513), Angulo et al. (2013) identified the same heterozygous missense mutation (602839.0001) in the PIK3CD gene that resulted in a dominant gain of function. The E1021K mutation enhanced membrane association and kinase activity of p110-delta. Selective p110-delta inhibitors reduced the activity of the mutant enzyme in vitro, suggesting a therapeutic approach for these patients.
In a Taiwanese boy of Chinese descent with IMD14A, Jou et al. (2006) identified a heterozygous missense mutation in the PIK3CD gene (E1021K; 602839.0001). Functional studies of the variant were not performed. The PIK3CD gene was chosen for study because Pik3cd-null mice show a B-cell immunodeficiency; the patient was the only one of 15 probands with immunodeficiency who was found to carry a pathogenic PIK3CD mutation.
In 14 patients from 7 unrelated families with IMD14A, Lucas et al. (2014) identified 3 different heterozygous gain-of-function mutations in the PIK3CD gene (602839.0001-602839.0003). The mutations were found by whole-exome sequencing and targeted Sanger sequencing. Studies of patient-derived cells and control cells showed that the mutations caused increased phosphorylation of AKT (164730) compared to wildtype PIK3CD, consistent with a gain of function. Patient CD8+ T cells had an effector memory phenotype and were more activated compared to controls, suggesting that a large proportion of these cells are in a terminally differentiated state with a corresponding low proliferative capacity. Patient T cells showed hyperphosphorylation of the downstream mTOR (601231) signaling pathway, which resulted in increased glucose usage in the cells and predisposition to differentiation and senescence. Treatment of 1 patient with rapamycin, which inhibits mTOR, resulted in a reduction in CD8+ T cells to normal numbers and an increase in naive T cells.
In 3 patients from 2 unrelated families with IMD14A manifest as hyper-IgM and B-cell lymphoma, Crank et al. (2014) identified 2 heterozygous gain-of-function mutations in the PIK3CD gene (602839.0001 and 602839.0004).
Avery et al. (2018) studied a large cohort of patients with PIK3CD gain-of-function mutations and established a mouse model with a heterozygous activating Pik3cd mutation (E1020K, which is orthologous to the human E1021K mutation). In both species, hyperactivation of PI3K-dependent signaling pathways led to decreased mature B cells in bone marrow and in the periphery. Further analysis showed impaired Ig class switching, but no effect on proliferation and affinity maturation of B cells. Intrinsic defects in Ig class-switch recombination (CSR) in B-cell differentiation were caused by reduction in activation-induced cytidine deaminase (AID; 605257) expression in B cells and by failure to acquire a plasmablast gene signature and phenotype. These defects in B-cell differentiation could be partially overcome by treatment with a specific PIK3CD inhibitor, which restored CSR, AID expression, and Ig secretion.
Roifman-Chitayat Syndrome
In 2 sibs, born of consanguineous parents, with Roifman-Chitayat syndrome (ROCHIS; 613328) originally reported by Roifman and Chitayat (2009), Sharfe et al. (2018) identified homozygous loss-of-function mutations in 2 different genes: PIK3CD (602839.0005) and SKAP (KNSTRN; 614718.0001). The mutations, which were found by whole-genome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed no detectable PIK3CD or KNSTRN proteins, consistent with a loss of function of both genes. Patient cells showed a near absence of AKT (164730) phosphorylation compared to controls, revealing defective PIK3CD function. Detailed in vitro studies showed that patient-derived B and T lymphocytes failed to cluster or aggregate properly, similar to abnormalities noted in SKAP-null cells, suggesting that SKAP deficiency was responsible for this feature. In addition, T cells showed reduced spontaneous migration and inefficient cell-cell contact formation due to limited cell spreading. These abnormalities were associated with aberrant MAP4 (157132) distribution and localized altered microtubule acetylation, which was attributed to loss of SKAP. Sharfe et al. (2018) concluded that the complex phenotype resulted from the concurrent loss of 2 different genes, each of which contributed to the disease manifestations.
Autosomal Recessive Immunodeficiency 14B
In 2 brothers, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; 619281), Sogkas et al. (2018) identified a homozygous frameshift mutation in the PIK3CD gene (602839.0006). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells showed impaired AKT phosphorylation after stimulation with an anti-CD3 antibody, suggesting a loss of PIK3CD function.
In a boy, born of consanguineous Pakistani parents, with IMD14B, Cohen et al. (2019) identified a homozygous frameshift mutation in the PIK3CD gene (602839.0007). The mutation, which was found by whole-exome sequencing, was predicted to disrupt the ATP binding site in the catalytic domain. The mutation was not found in the 1000 Genomes Project, ExAC, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the truncated protein was expressed, but lacked kinase activity, consistent with a loss of function. Patient T cells showed decreased calcium flux after CD3 stimulation compared to controls, suggesting impaired cellular immunity. Noting that dominant gain-of-function mutations in the PIK3CD gene can cause IMD14A, both Sogkas et al. (2018) and Cohen et al. (2019) concluded that precise regulation of PIK3CD activity is required for proper immune function.
Rodriguez et al. (2019) reported a 14-year-old boy, born of consanguineous Pakistani parents, with recurrent infections beginning in infancy who later developed chronic T-cell EBV infection with high EBV loads associated with hepatosplenomegaly and lymphadenopathies. At 14 years of age, he developed an acute episode of hemophagocytic lymphohistiocytosis (HLH) and died of the disease. His 6-year-old sister had an elevated blood EBV load in the absence of clinical symptoms. Whole-exome sequencing of the proband identified a homozygous frameshift variant (c.170delG) in the TNFRSF9 (CD137) gene (602250) that was also present in the homozygous state in his sister and in the heterozygous state in other unaffected family members. Studies of patient T cells showed lack of CD137 expression, suggesting that the variant results in a loss-of-function effect. Further studies identified a homozygous missense variant (R821H) in the PIK3CD gene that was present only in the proband; it was heterozygous in other family members, including the asymptomatic sister. The R821H variant was associated with reduced but residual kinase activity, consistent with a functional deficit. The authors suggested that CD137 deficiency likely accounts for the impaired immune control of EBV-infected T cells, whereas the mutation in the PIK3CD gene may act as a driver mutation allowing EBV-infected T cells to persist and proliferate uncontrollably.
Okkenhaug et al. (2002) generated mice expressing a catalytically inactive form of Pik3cd (asp910 to ala). They observed impaired signaling and attenuated immune responses by antigen receptors of B and T cells from these mice. The presence of Pik3ca and Pik3cb did not compensate for Pik3cd in immune function. The mutant mice also developed inflammatory bowel disease. Since the IBD7 susceptibility locus (605225) maps to chromosome 1p36, the authors suggested that PIK3CD may be a candidate susceptibility gene.
In a Taiwanese boy of Chinese descent with primary immunodeficiency-14A (IMD14A; 615513), Jou et al. (2006) identified a heterozygous G-to-A transition in exon 24 of the PIK3CD gene, resulting in a glu1021-to-lys (E1021K) substitution at a highly conserved residue in the catalytic domain. The mutation was not found in his parents or in 112 control individuals. Functional studies of the variant were not performed. The patient had had a primary B-cell deficiency with hypogammaglobulinemia and recurrent sinopulmonary infections since 7 months of age. The PIK3CD gene was chosen for study because Pik3cd-null mice show a B-cell immunodeficiency; the patient was the only one of 15 probands with immunodeficiency who was found to carry a pathogenic PIK3CD mutation.
In 17 individuals from 7 unrelated families with IMD14A, Angulo et al. (2013) identified a heterozygous G-to-A transition at nucleotide 3061 of the PIK3CD gene that resulted in a glutamic acid-to-lysine substitution at codon 1021 (E1021K) of the p110-delta protein. All affected individuals carried this mutation. This mutation was not identified among 3,346 healthy subjects. In 1 affected individual the mutation occurred as a de novo event; otherwise inheritance was autosomal dominant. The E1021K mutation in the catalytic subunit results in gain of function causing enhanced membrane association and kinase activity. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT (164730) protein and were prone to activation-induced cell death.
In 6 patients from 3 families with IMD14A, Lucas et al. (2014) identified a heterozygous E1021K mutation in the C-lobe of the kinase domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the E1021K substitution may enhance the recruitment of the protein to the plasma membrane and increase catalytic activity.
Crank et al. (2014) identified an E1021K mutation in a 21-year-old Caucasian woman with IMD14A who had increased serum IgM and developed a large B-cell lymphoma.
In a 12-year-old girl with autosomal dominant immunodeficiency-14A (IMD14A; 615513), Lucas et al. (2014) identified a heterozygous c.1002C-A transversion in the PIK3CD gene, resulting in an asn334-to-lys (N334K) substitution in the C2 domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the N334K substitution may disrupt inhibitory contacts between PIK3CD and the regulatory subunit (PIK3R1; 171833).
In 7 patients from 3 families with autosomal dominant immunodeficiency-14A (IMD14A; 615513), Lucas et al. (2014) identified a heterozygous c.1573G-A transition in the PIK3CD gene, resulting in a glu525-to-lys (E525K) substitution in the helical domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the N334K substitution may disrupt inhibitory contacts between PIK3CD and the regulatory subunit (PIK3R1; 171833).
In 2 affected members of a family with autosomal dominant immunodeficiency-14A (IMD14A; 615513), Crank et al. (2014) identified a heterozygous c.1246T-C transition in the PIK3CD gene, resulting in a cys416-to-arg (C416R) substitution. The mutation was demonstrated to result in a gain of function with hyperphosphorylation of AKT (164730). Both patients had recurrent infections, lymphadenopathy, and increased serum IgM, and both developed B-cell lymphoma.
In 2 sisters, born of consanguineous parents, with Roifman-Chitayat syndrome (ROCHIS; 613328) originally reported by Roifman and Chitayat (2009), Sharfe et al. (2018) identified a homozygous c.2161C-T transition in the PIK3CD gene, resulting in a gln721-to-ter (Q721X) substitution at the beginning of the kinase domain. The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed absence of the full-length protein, and near absence of AKT (164730) phosphorylation compared to controls, consistent with a loss of function. The patients were also homozygous for a loss-of-function mutation in the KNSTRN gene (614718.0001). Loss of both genes contributed to the phenotype.
In 2 brothers, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; 619281), Sogkas et al. (2018) identified a homozygous 1-bp deletion (c.1653delG) in the PIK3CD gene, resulting in a frameshift and premature termination (Val552SerfsTer26). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells showed impaired AKT phosphorylation after stimulation with an anti-CD3 antibody, suggesting a loss of PIK3CD function.
In a boy, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; 619281), Cohen et al. (2019) identified a homozygous 2-bp deletion (c.2558_2559delAT) in the PIK3CD gene, resulting in a frameshift and premature termination (Asp853GlyfsTer20). The mutation, which was found by whole-exome sequencing, was predicted to disrupt exons 20 to 24 encoding 171 residues of the ATP binding site in the catalytic domain. The mutation was not found in the 1000 Genomes Project, ExAC, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the truncated protein was expressed, but lacked kinase activity, consistent with a loss of function. Patient T cells showed decreased calcium flux after CD3 stimulation compared to controls, suggesting impaired cellular immunity.
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