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aPIK3R1 gene with splice site mutation and transcript variant. PIK3R1 is located in chromosome 5q13.1 and consists of 16 exons (exons are represented as boxes). The gene undergoes alternative splicing, which results in four main transcript variants, one of which encodes for p85α. The mutations c.1425 + 1G > A/C/T affect a splice site located in the first intronic nucleotide following exon 11. b p85α protein structure. The splice site mutations result in the deletion of amino acid residues 434–475 of the inter-Src homology 2 region (Inter-SH2). The Inter-SH2 region is found between the N-terminal Src homology 2 (N-SH2) and the C-terminal Src homology 2 (C-SH2) regions. At the N-terminus of p85α, resides the Src homology region 3 domain (SH3). This is followed by the breakpoint cluster region homology (BH). aa amino acids
Source publication
Activated PI3K δ syndrome (APDS) is a primary immunodeficiency caused by heterogeneous germline gain-of-function mutations which ultimately lead to the hyperactivation of the phosphoinositide-3-kinase δ (PI3K δ). PI3K δ exists as a heterodimer composed of a catalytic and a regulatory subunit. APDS type 2 is caused by mutations in the PIK3R1 gene af...
Citations
... Through this review of the medical literature, 193 individuals diagnosed with APDS1 through molecular genetic testing and pathogenic variant present in PIK3CD were extracted from the literature for whom age was reported [1,2,6,8,. In addition, 63 individuals diagnosed with APDS2 through molecular genetic testing and pathogenic variant present in PIK3R1 were extracted from the literature for whom age was reported [3,4,7,8,26,44,[55][56][57][58][59][60][61][62][63][64][65][66]. ...
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan–Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.
... 45 However, patients with overlapping clinical features have been reported. [46][47][48] These clinical observations are relevant for the patient management and for research studies that further investigate pathophysiological differences between the catalytic and regulatory kinase components encoded by the mutated genes. Indeed, a recent work could identify relevant differences in B-cell abnormalities between APDS1 and APDS2 and highlight an increased perinatal mortality in APDS2 mice, but not in the APDS1 counterpart. ...
Background:
Activated phosphoinositide-3-kinase (PI3K) δ Syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.
Objectives:
Report the extended spectrum of disease manifestations in APDS1 versus APDS2, compare these to CTLA-4 deficiency, NFκB1 deficiency, and STAT3 gain-of-function (GOF) disease; identify predictors of severity in APDS.
Methods:
Data collection with the European Society for Immunodeficiencies (ESID)-APDS registry. Comparison with published cohorts of the other IEIs.
Results:
The analysis of 170 APDS patients outlines high penetrance and early-onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA-4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS.
Conclusion:
APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEI is substantial. Some specific features distinguish APDS1 from APDS2. Early-onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.
... The PIK3R1 mutations that cause SHORT syndrome are typically found in the inter-SH2 or C-terminal SH2 domains of p85α (Avila et al., 2016;Chudasama et al., 2013;Dyment et al., 2013;Thauvin-Robinet et al., 2013). Interestingly, several patients with APDS2 due to the canonical PIK3R1 exon 11 skipping splice site mutations have also been described to have features of the SHORT syndrome (Bravo García-Morato et al., 2017;Petrovski et al., 2016;Ramirez et al., 2020), consistent with these mutations also affecting the inter-SH2 domain of p85. Notably, most of the patients reported here displayed at least some features of the SHORT syndrome (Table S1). ...
Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients’ immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies.
... Another rare but significant clinical phenotype that can be associated with mutations in the PIK3R1 gene is Short Syndrome (short stature, hyperextensibility, hernias, ocular depression [deeply set eyes], Rieger anomaly, teething delay, partial lipodystrophy, insulin resistance, and facial dysmorphic signs). [18][19][20][21][22][23][24][25][26] In a limited number of cases, patients can present with the two clinical phenotypes of PIK3R1 gene mutations APDS2 and SHORT syndrome. 27 Based on all previously mentioned findings we recommend that patients with mutations in the PIK3R1 gene should be seen by both clinical immunologists and clinical geneticists. ...
We report a rare case of a 14-year-old boy diagnosed with Activated phosphoinositide 3-kinase delta syndrome Type 2 (APDS2). Based on a typical clinical presentation (Delayed teething, Prominent lymphadenopathy and recurrent characteristic infections started early in life and including multiple episodes of bilateral conjunctivitis, an extensive herpes skin infection in addition to recurrent upper sinopulmonary infections) along with suggestive laboratory immunological findings, and positive confirmatory genetic testing. After diagnosis, the patient was commenced on prophylactic antibiotics which resulted in a reduction in the frequency of his infections and hospitalizations. The targeted therapy of mTOR inhibition with Sirolimus and the possibility of hematopoietic stem cells transplantation are considered and discussed with the family, and he is on regular follow-up with the Allergy/Immunology team. APDS is a rare but increasingly reported inborn error of immunity. Gain-of-function and loss-of-function mutations in phosphoinositide 3-kinase (PIK3CD (encoding P 110 δ ) and PIK3R1 (encoding p 85 α , p 55 α , a n d p 50 α )) lead to APDS1 and APDS2, respectively. Our aim in reporting our case is to allow room for more elaboration of the different genotypes and clinical presentations of both types of APDS, in which early and accurate diagnosis will subsequently help in the initiation of outcome-improving therapy.
... [14][15][16][17] In APDS2, also known as p85α-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI-R1), the defects in PI3K signaling pathways are leading to immunodeficiency and immune dysregulation, with B and T cell lymphopenia, lymphocyte maturational and functional defects, and antibody deficiency, frequently presented as the hyper-IgM immunoglobulin profile. [18][19][20] The individual patient's immunophenotype is determined by the mutation in PIK3R1, as mono-allelic LOF mutations cause activation of the PI3K-AKT-mTOR pathway with defects in lymphocyte development and variable immunoglobulin deficiency and have been noted in patients with both APDS2 and SHORT syndrome, [11][12][13] whereas biallelic LOF mutations impair the PI3K pathway, resulting in more profound abnormalities in B cells and agammaglobulinemia. 21 To expand the clinical and immunological phenotype of an extremely rare association of APDS2 and mild phenotypic features of the SHORT syndrome in a pediatric patient who shows unique and previously unreported dysmorphology features with a congenital deformity of the chest, a stellate pattern of the iris, accompanied by IgE-mediated cow's milk allergy, and antibody deficiency, in the context of a frameshift mutation in PIK3R1 with reduced penetrance. ...
... This result might be consistent with a clinical diagnosis of autosomal dominant PIK3R1-related condition, activated PI3Kδ syndrome, and also with the SHORT syndrome, albeit coexisting phenotypic features of both APDS2 and the SHORT syndrome is exceptional. [11][12][13] The variant was also found in the patient's mother, who is a healthy individual, not affected with any comorbidities. She did not hitherto suffer from recurrent infections and did not present autoimmune, atopic, or lymphoproliferative diseases appearing in APDS2. ...
... The combination of APDS2 and SHORT syndrome has been described in medical literature only in four cases so far, [11][12][13] suggesting a rarity of this clinical phenotypic and genetic phenotypic features in the form of CCWD, pectus excavatum, a stellate pattern of the iris, and dysplastic nails to the clinical set of symptoms of the SHORT syndrome. Likewise, hyperimmunoglobulinemia E and hypersensitivity to cow's milk allergens have not been identified either in patients affected with the SHORT syndrome or APDS2. ...
Monoallelic loss-of-function (LOF) mutations in the phosphatidylinositol 3-kinase (PIK3R1) gene affecting the inter-Src homology 2 domain of the p85α regulatory subunit of phosphoinositide-3-kinase δ (PI3Kδ) cause the activated PI3K δ syndrome (APDS2). APDS2 is defined as a primary antibody deficiency, developmental abnormalities within the B and T lymph cell compartments, and immune dysregulation. The genetic defect of APDS2 is shared with that of the SHORT syndrome, characterized by short stature, joint hyperextensibility, ocular depression, Rieger anomaly, and delayed tooth eruption. LOF variants in an intronic splice site (c.1425+1G.C/A/T) in the PI3KR1 gene have been identified in patients affected with both APDS2 and SHORT syndrome. Herein, we report a novel c.1644-1648del (p.Asp548Glufs*6) variant in a pediatric patient with the APDS2-related immunodeficiency, who presents with mild phenotypic fea-tures of the SHORT syndrome, congenital chest wall deformity, and IgE-mediated food allergy. The same variant was also identified in the patient’s hitherto asymptomatic mother, implicating an incomplete penetrance. Regular monitoring by a multidisciplinary team under the pediatric clinical immunologist’s supervision to implement appropriate diagnostic procedures and treatment modalities is of paramount importance. Further studies are required to better define the genotype-phenotype correlation in patients with the PIK3R1 gene mutations and to better delineate the mutual relationship between APDS2 and the SHORT syndrome.
... A potential difference between type 1 and type 2 APDS is the notion of growth retardation more commonly associated to APDS2 (26,32). A few reports relate APDS2 patients associated to a SHORT syndrome (47). SHORT syndrome is a rare genetic congenital disease characterized by short stature, hyperextensibility, ocular depression, Rieger anomaly and teething delay, with no reported immunodeficiency. ...
Autosomal dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic subunit p110δ of phosphoinositide 3-kinase-δ (PI3K-δ) or autosomal dominant loss-of-function mutations in the PIK3R1 gene encoding the p85α, p55α and p50α regulatory subunits cause Activated PI3-kinase-δ syndrome (APDS; referred as type 1 APDS and type 2 APDS, respectively). Consequences of these mutations are PI3K-δ hyperactivity. Clinical presentation described for both types of APDS patients is very variable, ranging from mild or asymptomatic features to profound combined immunodeficiency. Massive lymphoproliferation, bronchiectasis, increased susceptibility to bacterial and viral infections and, at a lesser extent, auto-immune manifestations and occurrence of cancer, especially B cell lymphoma, have been described for both types of APDS patients. Here, we review clinical presentation and treatment options as well as fundamental immunological and biological features associated to PI3K-δ increased signaling.
... APDS2 patients also experience lymphadenopathy, splenome-190 galy, severe or persistent EBV/CMV infections, lymphoma, and autoimmunity [17,18,39,[42][43][44][45][46]. A small number of APDS2 patients have received additional diagnoses of a separate disorder called SHORT syndrome (Short stature, Hyperextensibility of the joints, Ocular depression, Rieger anomaly of the eyes, 195 Teething Delays), which involves growth retardation and metabolic disease features [42,45,47]. The typical genetic lesion in SHORT syndrome is heterozygous variants in the more distal exons of PIK3R1 [48-50], rather than the common splice variant that causes exon 11 splicing resulting in APDS2. ...
Introduction
Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that plays a key role in fundamental aspects of cell biology including survival, metabolism, proliferation and differentiation. Thus, balanced PI3K signalling is critical for multiple aspects of human health. The initial discovery that germline variants in genes in the PI3K pathway resulted in inborn errors of immunity highlighted the non-redundant role of these signalling proteins in the human immune system. The subsequent identification and characterisation of >250 individuals with a novel immune dysregulatory disorder, termed activated PI3K-delta syndrome (APDS), has reinforced the status of PI3K as a key pathway regulating immune function. Studies of APDS have demonstrated that dysregulated PI3K function is disruptive for many immune cell processes including development, activation, differentiation, effector function and self-tolerance, which are all important in supporting effective, long-term immune responses.
Areas covered
In this review, we recount recent findings regarding humans with germline variants in PI3K genes and discuss the underlying cellular and molecular pathologies, with a focus on the implications of these findings for therapy in APDS patients.
Expert Opinion
Fine tuning immune signalling by modulating PI3K offers opportunities for therapeutic interventions in settings of immunodeficiency, autoimmunity and malignancy, but also highlights potential adverse events that may result from overt pharmacological or intrinsic inhibition of PI3K function.
PIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have short stature or SHORT syndrome, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes.
Activated Phosphoinositide 3-kinase Delta Syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function (GOF) variants in the PIK3CD gene while loss of function (LOF) variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 was 87%, age 30 was 74%, age 40 and 50 were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The mortality data suggests that the standard of care treatment for APDS, immunoglobulin replacement therapy, appears to prevent most deaths due to severe infection, however, new treatments are needed to mitigate the risk of death from lymphoma and other cancers. This analysis based on real world evidence gathered from the medical literature is the largest study of survival for APDS to date.
Activated PI3K-delta Syndrome (APDS), also called PI3K-delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is an autosomal dominant disorder caused by inherited or de novo gain-of-function mutations in one of two genes encoding subunits of the phosphoinositide-3-kinase delta (PI3Kδ) complex. This largely leukocyte-restricted protein complex regulates cell growth, activation, proliferation, and survival. Patients who harbor these mutations have early onset immunodeficiency with recurrent infections, lymphadenopathy, and autoimmunity. The most common infection susceptibilities are sinopulmonary (encapsulated bacteria) and herpesviruses. Multiple defects in both innate and adaptive immune function are responsible for this phenotype. Apart from anti-microbial prophylaxis and immunoglobulin replacement, patients are treated with a variety of immunomodulatory agents and some have needed hematopoietic stem cell transplants. Here, we highlight the spectrum of infections, immune defects, and therapy options in this inborn error of immunity.
