Alternative titles; symbols
HGNC Approved Gene Symbol: PIK3R1
Cytogenetic location: 5q13.1 Genomic coordinates (GRCh38): 5:68,215,756-68,301,821 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q13.1 | ?Agammaglobulinemia 7, autosomal recessive | 615214 | Autosomal recessive | 3 |
| Immunodeficiency 36 | 616005 | Autosomal dominant | 3 | |
| SHORT syndrome | 269880 | Autosomal dominant | 3 |
Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates the inositol ring of phosphatidylinositol and related compounds at the 3-prime position. The products of these reactions are thought to serve as second messengers in growth signaling pathways. The kinase itself is made up of a catalytic subunit of molecular mass 110 kD (p110; e.g., PIK3CA, 171834) and a regulatory subunit, often of molecular mass 85 kD (p85), such as PIK3R1 (summary by Hoyle et al., 1994).
Otsu et al. (1991) showed that the bovine PI3K p85 subunit consists of 2 closely related proteins, p85-alpha and p85-beta (PIK3R2; 603157). They cloned cDNAs encoding both p85 subunits, each of which is a 724-amino acid polypeptide. The 2 subunits shared 62% amino acid sequence identity across their entire length. Both sequences contained an N-terminal SH3 region, 2 SH2 regions, and a region of homology to the C-terminal region of BCR (151410). Functional expression studies showed that both p85 subunits lacked PI3-kinase activity, but both bound to tyrosine kinase receptors. Volinia et al. (1992) stated that human p85-alpha contains all the peptide sequence found in bovine p85-alpha.
Skolnik et al. (1991) developed a novel method for expression cloning of receptor tyrosine kinase target proteins (called CORT for 'cloning of receptor targets') and illustrated the method by cloning cDNA for GRB1, the gene encoding phosphatidylinositol 3-kinase-associated p85-alpha.
The PIK3R1 gene encodes 3 regulatory isoforms of PI3K: p85, p55, and p50. The 9 3-prime exons are shared by all 3 isoforms with 2 distinct promoters, and 2 exon 1 sequences upstream of these 9 exons control the production of p55 and p50 (summary by Conley et al., 2012).
Conley et al. (2012) found variable expression of the 3 regulatory isoforms in hematopoietic cells: normal T cells expressed almost equal amounts of p85 and p50, and activated T cells also contained trace amounts of p55. In contrast, normal B cells contained p85, but no detectable p50 or p55; EBV-transformed B cells expressed low levels of p50 and p55. NK cells and neutrophils contained p85 and low levels of p50.
Skolnik et al. (1991) showed that the product of the GRB1 gene associates with activated growth factor receptors. p85-alpha modulates the interaction between PI3 kinase and platelet-derived growth factor receptor.
Simoncini et al. (2000) showed that the estrogen receptor isoform ER-alpha (133430) binds in a ligand-dependent manner to the p85-alpha regulatory subunit of PI3K. Stimulation with estrogen increases ER-alpha-associated PI3K activity, leading to the activation of protein kinase B/AKT (164730) and endothelial nitric oxide synthase (eNOS; 163729). Recruitment and activation of PI3K by ligand-bound ER-alpha are independent of gene transcription, do not involve phosphotyrosine adaptor molecules or src-homology domains of p85-alpha, and extend to other steroid hormone receptors. Mice treated with estrogen showed increased eNOS activity and decreased vascular leukocyte accumulation after ischemia and reperfusion injury. This vascular protective effect of estrogen was abolished in the presence of PI3K or eNOS inhibitors. Simoncini et al. (2000) concluded that their findings defined a physiologically important nonnuclear estrogen-signaling pathway involving the direct interaction of ER-alpha with PI3K.
Niswender et al. (2001) demonstrated that systemic administration of leptin (164160) in rat activates the enzyme phosphatidylinositol-3-hydroxykinase in the hypothalamus and that intracerebroventricular infusion of inhibitors of this enzyme prevents leptin-induced anorexia. They concluded that phosphatidylinositol-3-hydroxykinase is a crucial enzyme in the signal transduction pathway that links hypothalamic leptin to reduced food intake.
He et al. (2002) determined that the hepatitis C virus nonstructural 5A (NS5A) protein interacts directly with GRB2 (108355) and with the p85 subunit of PI3K following stimulation with epidermal growth factor (EGF; 131530). The in vivo association of NS5A with p85 PI3K increased tyrosine phosphorylation of p85 PI3K. Downstream effects of the EGF-induced interaction included tyrosine phosphorylation of AKT and serine phosphorylation of BAD (603167). Both of these events would tend to inhibit apoptosis and were consistent with the antiapoptotic properties of NS5A.
Ectopic activation of fibroblast growth factor receptor-3 (FGFR3; 134934) is associated with several cancers, including multiple myeloma (254500). Salazar et al. (2009) identified the PI3K regulatory subunit PIK3R1 as a novel interactor of FGFR3 by yeast 2-hybrid screen and confirmed an interaction between FGFR3 and PIK3R1 and PIK3R2 in mammalian cells. The interaction of FGFR3 with PIK3R1 was dependent upon receptor activation. In contrast to the Gab1 (604439)-mediated association of FGFRs with PIK3R1, the FGFR3-PIK3R1 interaction required FGFR3 tyr760, previously identified as a PLC-gamma (PLCG1; 172420)-binding site. Interaction of PIK3R1 with FGFR3 did not require PLC-gamma, suggesting that PIK3R1 interaction was direct and independent of PLC-gamma binding. FGFR3 and PIK3R1/PIK3R2 proteins also interacted in multiple myeloma cell lines, which consistently express PIK3R1 p85 isoforms but not p50 or p55 isoforms, or PIK3R3 (606076). siRNA knockdown of PIK3R2 in multiple myeloma cells caused an increased ERK response to FGF2 stimulation. Salazar et al. (2009) suggested that an endogenous negative regulatory role for the PIK3R-FGFR3 interaction on the Ras/ERK/MAPK pathway may exist in response to FGFR3 activity.
Using mouse embryonic fibroblasts, Park et al. (2010) showed that, in addition to regulating PI3K function, p85-alpha and p85-beta regulated the function of Xbp1s (XBP1; 194355), a transcription factor that orchestrates the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress. Both p85-alpha and p85-beta bound Xbp1s and increased its nuclear translocation, and it appeared that the p110 PI3K catalytic subunit and Xbp1s competed for binding of these regulatory subunits. p85-alpha and p85-beta formed an inactive dimer that was disrupted by insulin in a time-dependent manner, which promoted their association with Xbp1s. Refeeding of wildtype mice after fasting induced ER stress that was quickly resolved, as measured by Xbp1s levels. In contrast, obese and insulin-resistant ob/ob (LEP; 164160) mice could not resolve the ER stress induced during refeeding, and nuclear translocation of Xbp1s was absent in ob/ob mice. Overexpression of p85-alpha or p85-beta in livers of ob/ob mice increased glucose tolerance and reduced blood glucose concentrations.
Independently, Winnay et al. (2010) found that p85-alpha interacted with Xbp1 in an ER stress-dependent manner in mice and that this interaction was essential in the ER stress response. Cells deficient in p85-alpha or mouse livers with selective inactivation of p85-alpha showed reduced ER stress-dependent accumulation of nuclear Xbp1s and attenuated induction of UPR target genes.
Using yeast 2-hybrid analysis, pull-down assays, and immunofluorescence analysis, Chiu et al. (2014) found that human BRD7 (618489) interacted with p85-alpha and induced its nuclear translocation. Formation of the BRD7-p85-alpha complex depended on a p85-binding domain in the highly conserved C terminus of BRD7, whereas the nuclear localization of the BRD7-p85-alpha complex depended on the nuclear localization signal of BRD7. The BRD7-p85-alpha complex associated with chromatin. The BRD7-binding region of p85-alpha was the same region used for interaction with p110. Consequently, BRD7 competed with p110 for binding and interacted with free p85-alpha, but not with p85/p110 complexes, and BRD7 did not translocate p110 into the nucleus with BRD7. BRD7 removed p85-alpha from the cytosol to prevent formation of the p85/p110 complex, thereby destabilizing p110 proteins and reducing PI3K signaling. Knockdown of BRD7 increased p110 protein levels, decreased the fraction of p85-alpha in nucleus, and enhanced PI3K signaling.
Crystal Structure
Miled et al. (2007) used crystallographic and biochemical approaches to gain insight into activating mutations in 2 noncatalytic p100-alpha domains--the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110-alpha (171834) in a complex with the p85-alpha inter-Src homology 2 (inter-SH2) domains shows that the oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. The authors also examined helical domain mutations and found that the glu545-to-lys (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. Miled et al. (2007) concluded that their studies extended understanding of the architecture of the phosphatidylinositol 3-kinases and provided insight into how 2 classes of mutations that cause a gain of function can lead to cancer.
Cannizzaro et al. (1991) demonstrated that the GRB1 gene is located at 5q13 by analysis of its segregation in rodent-human hybrids and by chromosome in situ hybridization. Cannizzaro et al. (1991) observed that the RASA gene (139150), encoding another receptor-associated signal transducing protein, is also located in 5q13. Volinia et al. (1992) confirmed the mapping of PIK3R1 to chromosome 5q12-q13. Hoyle et al. (1994) demonstrated that the homologous gene in the mouse, Pik3r1, maps to chromosome 13.
Agammaglobulinemia 7, Autosomal Recessive
In a patient with autosomal recessive agammaglobulinemia-7 (AGM7; 615214), Conley et al. (2012) identified a homozygous truncating variant in the PIK3R1 gene (W298X; 171833.0001). The mutation, which was identified by exome sequencing, segregated with the disorder and was not found in 1,000 in-house control alleles. Screening of the PIK3R1 gene in 55 additional patients with defects in B-cell development did not identify any other mutations.
SHORT Syndrome, Autosomal Dominant
By whole-exome sequencing in 2 unrelated patients with SHORT syndrome (269880), Thauvin-Robinet et al. (2013) identified de novo mutations in the PIK3R1 gene (171833.0002 and 171833.0003). Screening PIK3R1 for mutations in 4 more affected individuals from 3 families revealed a recurrent substitution (R649W; 171833.0004) in all 4 patients. Sequencing PIK3R1 in a heterogeneous clinical group of 14 additional unrelated individuals with severe insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation, who had not previously been diagnosed with SHORT syndrome and who were negative for mutation in known lipodystrophy-associated genes, identified 3 with mutations in PIK3R1, including 1 with the recurrent R649W substitution and another with a 1-bp duplication at R649 (171833.0005). Thauvin-Robinet et al. (2013) noted that the c.1945C-T (R649W) mutation occurred within the context of a CpG dinucleotide, which might explain its recurrence.
In a 3-generation Norwegian family and in a German mother and son with SHORT syndrome, Chudasama et al. (2013) identified heterozygosity for the R649W missense mutation in the PIK3R1 gene. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events.
Dyment et al. (2013) performed whole-exome sequencing in a girl with SHORT syndrome and her unaffected parents and identified a frameshift mutation in the PIK3R1 gene (171833.0006) that segregated with disease. Analysis of PIK3R1 in 3 more SHORT probands revealed the presence of the R649W mutation in an affected mother and 2 sons from an English family and in another patient. A PIK3R1 nonsense mutation was identified in the third patient.
Immunodeficiency 36 With Lymphoproliferation, Autosomal Dominant
In 4 patients from 3 unrelated families with autosomal dominant immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Deau et al. (2014) identified heterozygous mutations in the PIK3R1 gene (171833.0007 and 171833.0008). The mutations, which were found by whole-exome sequencing, affected the same nucleotide and resulted in the same splicing defect. The mutations were predicted to cause a loss of p85-mediated inhibition of p110 activity, and patient lymphocytes showed increased PI3K activity and enhanced phosphorylation of AKT, consistent with a gain of function. The phenotype was similar to that of patients with IMD14 (615513) carrying gain-of-function mutations in the PIK3CD gene (602839). Patients had decreased amounts of naive T cells and memory B cells, as well as hypogammaglobulinemia. The findings suggested that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies.
In 4 patients from 3 unrelated families with immunodeficiency, Lucas et al. (2014) identified heterozygosity for point mutations in the PIK3R1 gene at the same splice donor site that was previously reported in immunodeficient patients by Deau et al. (2014): c.1425+1G-C (171833.0008) in 3 patients from 2 families, and c.1425+1G-A (171833.0009) in the remaining proband.
In 4 unrelated children with immunodeficiency and a hyper-IGM (see 308230)-like phenotype, who also exhibited poor growth and lymphoproliferation, Lougaris et al. (2015) identified heterozygosity for de novo mutations in the PIK3R1 gene at the same previously reported splice site, c.1425+1G (see 171833.0007 and 171833.0009).
Petrovski et al. (2016) reported 4 unrelated children with immunodeficiency and elevated IgM levels, lymphadenopathy, and short stature, who all carried the c.1425+1G-A mutation in the PIK3R1 gene (171833.0009). One of the patients exhibited features of SHORT syndrome; the authors noted that no results of immune studies had been reported for SHORT syndrome patients. Functional analysis showed that the splice site mutation results in deletion of exon 11 and constitutive activation of PI3K signaling. The authors noted that despite the limited allelic heterogeneity, there was considerable phenotypic heterogeneity in clinical and immunologic abnormalities in patients with PIK3R1-associated immunodeficiency.
Elkaim et al. (2016) studied 36 patients with PIK3R1-associated immunodeficiency, including 8 previously reported patients (Deau et al., 2014; Lucas et al., 2014), and noted that the previously described substitutions at c.1425+1 were detected in 84% of patients, with G-A identified in 42%, G-C in 29%, and G-T in 13%. Four additional patients had mutations involving c.1425+2, including 2 with a T-A substitution (171833.0010), 1 with a T-G substitution (171833.0011), and 1 with a TG deletion (171833.0012). Another patient had a G-C substitution at the -1 position of the splice acceptor site of exon 11 (171833.0013). Analysis of patient mRNA demonstrated that all of the mutations cause skipping of exon 11 (coding exon 10).
Associations Pending Confirmation
Phosphatidylinositol 3-kinase is a key step in the metabolic actions of insulin. Two amino acid polymorphisms have been identified in the regulatory subunit of p85-alpha, met326 to ile and asn330 to asp. The former is associated with alterations in glucose/insulin homeostasis. Almind et al. (2002) presented observations indicating that the met326-to-ile variant of p85-alpha is functional for intracellular signaling and adipocyte differentiation but has small alterations in protein expression and activity that could play a role in modifying insulin action. These conclusions were based on studies where the 4 human p85-alpha proteins encoded by these 4 alleles were expressed in yeast.
Somatic Mutations
The Cancer Genome Atlas Research Network (2008) reported the interim integrative analysis of DNA copy number, gene expression, and DNA methylation aberrations in 206 glioblastomas and nucleotide sequence alterations in 91 of the 206 glioblastomas. The authors observed that the RTK/RAS/PI3K signaling pathway was altered in 88% of glioblastomas. Somatic mutation in the PI3K complex was frequently identified. In particular, novel somatic mutations were identified in the PIK3R1 gene that resulted in disruption of the important C2-iSH2 interaction between PIK3R1 and PIK3CA (171834).
Phosphoinositide 3-kinase (PI3K) activation is implicated in many responses, including fibroblast growth, transformation, survival, and chemotaxis. Although PI3K is activated by several agents that stimulate T and B cells, the role of PI3K in lymphocyte function remained to be clarified. Fruman et al. (1999) disrupted the mouse gene encoding the PI3K adaptor subunit p85-alpha and its splice variants p55-alpha and p50-alpha. Most mice homozygous for disruption for all 3 variants died within days after birth. Lymphocyte development and function were studied with the use of the RAG2-deficient blastocyst complementation system. Chimeric mice had reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and lipopolysaccharide stimulation, as well as decreased survival after incubation with interleukin-4. In contrast, T-cell development and proliferation were normal. This phenotype was similar to defects observed in mice lacking the tyrosine kinase Btk and in patients with Bruton X-linked agammaglobulinemia (300300).
Suzuki et al. (1999) found that mice with a targeted gene disruption of p85-alpha had impaired B-cell development at the pro-B cell stage, reduced numbers of mature B cells and peritoneal CD5+ Ly-1 B cells, reduced B-cell proliferative responses, and no T cell-independent antibody production. These phenotypes were nearly identical to those of the mutant X-linked immunodeficiency (xid) mouse and of mice in whom the Btk gene has been disrupted. These results provided evidence that p85-alpha is functionally linked to the Btk pathway in antigen receptor-mediated signal transduction and is pivotal in B-cell development and functions.
Terauchi et al. (1999) reported that Pik3r1 -/- mice show increased insulin sensitivity and hypoglycemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates was mediated by full-length p85-alpha in wildtype mice, but by the p50-alpha alternative splicing isoform of the same gene in Pik3r1 -/- mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate in Pik3r1 -/- adipocytes and facilitation of Glut4 (138190) translocation from the low density microsome fraction to the plasma membrane. This mechanism seemed to be responsible for the phenotype of the homozygous deficient mice, namely increased glucose transport and hypoglycemia. This work provided the first direct evidence that PI3K and its regulatory subunits have a role in glucose homeostasis in vivo.
Taniguchi et al. (2006) found that mice with a liver-specific deletion of Pik3r1 showed increased hepatic and peripheral insulin sensitivity. Pik3r1 ablation resulted in improved Akt activation, in part, because of decreased activity of the (3,4,5)-trisphosphate phosphatase Pten (601728). The authors concluded that Pik3r1 is a critical modulator of insulin sensitivity not only because of its effect on PI3K activation, but also as a regulator of PTEN activity.
Fukao et al. (2002) found that mice lacking p85-alpha were severely deficient in gastrointestinal and peritoneal mast cells, whereas dermal mast cells were present in the skin. The p85-alpha -/- mice were susceptible to acute septic peritonitis. However, they were also susceptible to systemic anaphylaxis, reflecting the absence of peritoneal mast cells but the presence of mast cells at other anatomic sites. Reconstitution of the mutant mice with bone marrow-derived mast cells (BMMCs) restored antibacterial immunity but not immunity to an intestinal nematode. Treatment of the BMMCs with Th2 lymphocyte-derived cytokines, i.e. IL4 (147780) and IL10 (124092), induced immunity to the parasitic worm, probably because mesenteric lymph node cells from the p85-alpha -/- mice produced reduced amounts of these cytokines. Fukao et al. (2002) concluded that PI3K plays an essential role in the development and induction of mast cells in normal and pathogenic immune responses.
Fukao et al. (2002) found that Pik3r1-deficient mice showed enhanced Th1-type responses after Leishmania major infection. Normal splenic dendritic cells (DCs) responded to IL12 (see 161561) production-inducing stimuli with concomitant Pi3k activation. Splenic DCs from mutant mice or normal DCs treated with a Pi3k inhibitor showed increased IL12 production and reduced Th2 cytokine production. Because Pi3k inhibition and Pik3r1 deficiency resulted in enhanced IL12 production, Fukao et al. (2002) proposed that Pi3k is a negative regulator of IL12 production and that Pi3k inhibition may prevent potential immunopathologic effects of strong Th1 responses resulting from excessive IL12 production.
Oak et al. (2006) crossed mice with a floxed Pik3r1 allele and a null Pik3r2 allele with Lck (153390)-Cre transgenic mice to generate a strain in which class IA Pi3k expression and function were essentially abrogated in T cells beginning at the double-negative stage. Histopathologic analysis of these mice showed development of organ-specific autoimmunity resembling Sjogren syndrome (SS; 270150). By 3 to 8 months of age, mutant mice developed corneal opacity and eye lesions due to irritation and constant scratching. Mutant mice showed marked lymphocytic infiltration of lacrimal glands and serum antinuclear and anti-Ssa (SSA1; 109092) antibodies, but no kidney pathology. Cd4-positive T cells, which were the predominant infiltrating cells in lacrimal glands of mutant mice, exhibited aberrant differentiation in vitro. Oak et al. (2006) concluded that impaired class IA PI3K signaling in T cells can lead to organ-specific autoimmunity, and they proposed that class IA Pi3k-deficient mice manifest the cardinal features of human primary SS.
In a 19-year-old girl with agammaglobulinemia-7 (AGM7; 615214) and a severe defect in early B-cell development, Conley et al. (2012) identified a homozygous G-to-A transition in exon 6 of the PIK3R1 gene, resulting in a trp298-to-ter (W298X) substitution in the Rac binding domain. The patient was from a consanguineous family of Chinese/Peruvian descent and had previously been reported by de la Morena et al. (1995) as having an autosomal recessive immunodeficiency reminiscent of Bruton agammaglobulinemia (300755). Each unaffected parent was heterozygous for the mutation, which was found by whole-exome sequencing and was not present in 1,000 in-house control alleles. The mutation resulted in absence of p85 expression, but normal p55 and p50 expression. The patient presented at 3.5 months of age with pneumonia and gastroenteritis. Laboratory studies showed panhypogammaglobulinemia, neutropenia, and decreased NK cells. T cells were essentially normal. As a teenager, she developed erythema nodosum, juvenile idiopathic arthritis, recurrent Campylobacter bacteremia, and inflammatory bowel disease, suggesting disordered cytokine production. The family history was positive for 2 older brothers and 2 maternal uncles who died of acute infections between 9 and 18 months of age. Flow cytometric analysis showed that the patient had near absence of B cells in peripheral blood, and bone marrow aspiration showed normal cellularity with almost complete absence of B lineage cells. However, there were normal percentages of very early CD34+,CD19- B-cell precursors. The patient had no p85 in T cells, neutrophils, or dendritic cells. There was decreased expression of p110 in patient immune cells, indicating that the N-terminal end of p85 contributes to binding and stabilization of p110. Overall, the findings suggested that mutations in the N-terminal region of p85 can result in failure of B-cell development at a very early stage, even earlier than in mouse models. Screening of the PIK3R1 gene in 55 additional patients with defects in B-cell development did not identify any other mutations.
In a 7-year-old boy with SHORT syndrome (269880), Thauvin-Robinet et al. (2013) identified heterozygosity for a de novo 3-bp deletion (c.1615_1617delATT) at chr5:67,591,018 (GRCh37) in the PIK3R1 gene, resulting in deletion of ile539 in the inter-Src homology 2 (iSH2) domain. The mutation was not present in his unaffected parents and was not found in the NHLBI Exome Variant Server, dbSNP (build 137), or 1000 Genomes Project databases. Functional studies on patient fibroblasts revealed a 70 to 90% reduction in the effect of insulin on AKT (see 164730) activation, glycogen synthesis, and glucose uptake, indicating severe insulin resistance for both proximal and distal PI3K-dependent signaling.
In a 7-year-old boy with SHORT syndrome (269880), Thauvin-Robinet et al. (2013) identified heterozygosity for a de novo c.1465G-A transition at chr5:67,590,403 (GRCh37) in the PIK3R1 gene, resulting in a glu489-to-lys (E489K) substitution at a highly conserved residue in the inter-Src homology 2 (iSH2) domain. The mutation was not present in his unaffected parents and was not found in the NHLBI Exome Variant Server, dbSNP (build 137), or 1000 Genomes Project databases. Functional studies on patient fibroblasts revealed a 70 to 90% reduction in the effect of insulin on AKT (see 164730) activation, glycogen synthesis, and glucose uptake, indicating severe insulin resistance for both proximal and distal PI3K-dependent signaling.
In 5 patients from 4 families with SHORT syndrome (269880), including a patient previously reported by Bonnel et al. (2000), Thauvin-Robinet et al. (2013) identified heterozygosity for a c.1945C-T transition at chr5:67,592,129 (GRCh37) in the PIK3R1 gene, resulting in an arg649-to-trp (R649W) substitution at a highly conserved residue in the cSH2 domain. In the 1 family for which parental DNA was available, the mutation was shown to be de novo. Thauvin-Robinet et al. (2013) noted that the c.1945C-T mutation occurred within the context of a CpG dinucleotide, which might explain its recurrence.
In affected members of a 3-generation Norwegian family with SHORT syndrome, originally described by Aarskog et al. (1983), and a German mother and son with SHORT syndrome, originally reported by Koenig et al. (2003), Chudasama et al. (2013) identified heterozygosity for the R649W missense mutation in the PIK3R1 gene. The mutation was not found in 340 Norwegian controls. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events. Analysis of patient fibroblasts and reconstituted Pik3r1-knockout preadipocytes demonstrated impaired interaction between p85-alpha and IRS1 (147545) and reduced AKT (see 164730)-mediated insulin signaling.
In a mother and 2 sons from an English family with SHORT syndrome, originally reported by Bankier et al. (1995) and restudied by Reardon and Temple (2008), and in an unrelated male patient, Dyment et al. (2013) identified heterozygosity for the R649W mutation in the PIK3R1 gene.
In a 60-year-old woman with severe insulin resistance, generalized lipoatrophy, and facial dysmorphism consistent with SHORT syndrome (269880), Thauvin-Robinet et al. (2013) identified heterozygosity for a 1-bp duplication (c.1943dupT) in the PIK3R1 gene, causing a frameshift predicted to result in a premature termination codon (Arg649ProfsTer5).
In a 2-year-old girl with SHORT syndrome (269880), Dyment et al. (2013) identified heterozygosity for a de novo 1-bp insertion (c.1906_1907insC) in exon 14 of the PIK3R1 gene, causing a frameshift predicted to generate a premature termination codon (Asn636ThrfsTer18). The mutation was not found in her unaffected parents. Functional analysis of patient lymphoblastoid cells showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT (see 164730)-mTOR (601231) pathway.
In a patient with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Deau et al. (2014) identified a de novo heterozygous G-to-T transversion in intron 10 of the PIK3R1 gene, resulting in an in-frame deletion of exon 10 and removal of a peptide sequence (amino acid residues 434-475) that is part of an alpha-helix involved in p110 binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in an in-house control database. The same splice site mutation, resulting from a different nucleotide change (171833.0008), was found in 3 additional patients with a similar disorder. Both mutations resulted in a loss of p85-mediated inhibition and caused increased phosphorylation of downstream signaling pathways, consistent with a gain of function. Immunologic studies showed a defect in both B- and T-cell differentiation.
Lucas et al. (2014) designated the c.1425+1 splice site as occurring in intron 11 of the PIK3R1 gene (c.1425+1G-T, NM_181523.2).
In a 19-month-old Italian girl with recurrent respiratory infections and poor growth, who had hypogammaglobulinemia with elevated serum IgM levels and lymphoproliferation, Lougaris et al. (2015) identified heterozygosity for the c.1425+1G-T splice site mutation in the PIK3R1 gene. The mutation occurred de novo.
In 3 patients from 2 unrelated families with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Deau et al. (2014) identified a heterozygous G-to-C transversion in intron 10 of the PIK3R1 gene, resulting in an in-frame deletion of exon 10 and removal of a peptide sequence (amino acids 434-475) that is part of an alpha-helix involved in p110 binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in an in-house control database. In 1 family, a mother and child were affected. The same splice site mutation, resulting from a different nucleotide change (171833.0007), was found in another patient with a similar disorder. Both mutations resulted in a loss of p85-mediated inhibition and caused increased phosphorylation of downstream signaling pathways, consistent with a gain of function. Immunologic studies showed a defect in both B- and T-cell differentiation.
In a 32-year-old Turkish woman and a Caucasian American mother and son with immunodeficiency, Lucas et al. (2014) identified heterozygosity for the c.1425+1G-C mutation, which they designated as occurring in intron 11 of the PIK3R1 gene (c.1425+1G-C, NM_181523.2). Sequencing of patient cDNA demonstrated that the mutation causes skipping of exon 11, resulting in an in-frame deletion of residues 434 to 475 of the p85-alpha regulatory subunit. Analysis of PI3K signaling in patient T-cell blasts showed increased phosphorylation of AKT (164730) and downstream targets compared to controls, indicating constitutive hyperactivation of PI3K and AKT. The mutant p85-alpha protein was detected at low levels in patient cells, and overexpression of the mutant in control T cells demonstrated a dominant gain-of-function effect on PI3K signaling. In addition, the authors showed that this hyperactivation is due to qualitatively and quantitatively different binding to, and impaired inhibition of, the p110-delta catalytic subunit (PIK3CD; 602839).
In a 5-year-old Chinese boy with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), who also exhibited lymphadenopathy, hepatomegaly, and severe juvenile rheumatoid arthritis, Lucas et al. (2014) identified heterozygosity for a c.1425+1G-A mutation (c.1425+1G-A, NM_181523.2) in intron 11 of the PIK3R1 gene.
In a 9-month-old Albanian girl, a 3-year-old Italian boy, and a 3.5-year-old Swedish girl with recurrent respiratory infections and poor growth, who had hypogammaglobulinemia with elevated serum IgM levels and lymphoproliferation, Lougaris et al. (2015) identified heterozygosity for the c.1425+1G-A mutation in the PIK3R1 gene. The mutation was shown to have occurred de novo in 2 of the patients; the genotype of the Swedish parents was unknown.
In 4 unrelated children (patients 1-4) with immunodeficiency and elevated IgM levels, lymphadenopathy, and short stature, Petrovski et al. (2016) identified heterozygosity for the c.1425+1G-A mutation in PIK3R1. The mutation was confirmed to have arisen de novo in 3 of the patients; it was not found in the fourth child's unaffected mother, but DNA was unavailable from the father. Analysis of PCR products from patient 1 and his parents demonstrated that the mutation causes skipping of exon 11, with direct exon 10 to exon 12 splicing. Results of functional analysis using patient cells were consistent with constitutive activation of the PI3K-mTOR (601231) signaling. Patient 4, a 5-year-old Caucasian girl, also exhibited features of SHORT syndrome (269880); the authors noted that no results of immune studies had been reported for SHORT syndrome patients.
In 2 patients with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Elkaim et al. (2016) identified heterozygosity for a c.1425+2T-A transversion (c.1425+2T-A, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha.
In a patient (P8) with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Elkaim et al. (2016) identified heterozygosity for a c.1425+2T-G transversion (c.1425+2T-G, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha.
In a patient (P10) with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Elkaim et al. (2016) identified heterozygosity for a 2-bp deletion (c.1425+2delTG, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha.
In a patient (P19) with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Elkaim et al. (2016) identified heterozygosity for a c.1300-1G-C transversion (c.1300-1G-C, NM_181523.2) in intron 10 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha.
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