Novel  PIK3CD  mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans

Takeda, Andrew J.; Yu, Zhongxin; Dornan, Gillian L.; Siempelkamp, Braden D.; Jenkins, Meredith L.; Matthews, Helen; McElwee, Joshua; Bi, Weimin; Seeborg, Filiz O.; Su, Helen C.; Burke, John E.; Lucas, Carrie L.

doi:10.1016/j.jaci.2017.03.026

Cited by 61 publications

(48 citation statements)

References 28 publications

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“…Perturbations of the interaction between the p110 catalytic subunits and regulatory subunits through activating mutations is causative of multiple human diseases, including cancer (Fruman et al, 2017;Samuels et al, 2004), primary immunodeficiencies (Angulo et al, 2013;Dornan and Burke, 2018;Lucas et al, 2016), and developmental disorders (Goncalves and Cantley, 2018;Lindhurst et al, 2012;Rivière et al, 2012;Venot et al, 2018). Mutations mediate activation of PI3K activity through disruption of key inhibitory interfaces or through induction of allosteric conformational changes that mimic natural activation mechanisms of class IA PI3Ks (Burke et al, 2012;Dornan et al, 2017;Takeda et al, 2017). Class IA regulatory subunits can interact with all p110 catalytic subunits, so mutations in the genes that encode these subunits could be expected to perturb signalling through all p110 isotypes.…”

Section: Discussionmentioning

confidence: 99%

Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases

Dornan

Stariha

Rathinaswamy

et al. 2019

Preprint

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The class IA PI3Ks are key signalling enzymes composed of a heterodimer of a p110 catalytic subunit and a p85 regulatory subunit, with PI3K mutations being causative of multiple human diseases including cancer, primary immunodeficiencies, and developmental disorders.Mutations in the p85α regulatory subunit encoded by PIK3R1 can both activate PI3K through oncogenic truncations in the iSH2 domain, or inhibit PI3K through developmental disorder mutations in the cSH2 domain. Using a combined biochemical and hydrogen deuterium exchange mass spectrometry approach we have defined the molecular basis for how these mutations activate both the p110α/p110δ catalytic subunits. We find that the oncogenic Q572* truncation of PIK3R1 disrupts all inhibitory inputs, with p110α being hyper-activated compared to p110δ. In addition, we find that the R649W mutation in the cSH2 of PIK3R1 decreases sensitivity to activation by receptor tyrosine kinases. This work reveals novel insight into isoform specific regulation of p110s by p85α.Keywords: PI3K, p110, p85, phosphoinositide 3-kinase, PI3K-Akt, HDX-MS, hydrogen exchange, phosphoinositides, PIK3CA, PIK3R1Defining the p85 mechanisms that mediate the inhibition and activation of PI3K Highlights-An oncogenic variant of p85α, Q572*, leads to hyper-activation of p110α compared to p110δ -HDX-MS revealed that Q572* leads to disruption of all inhibitory interfaces in p110α -A SHORT syndrome mutation in p85α leads to decreased sensitivity to RTKs for p110α/δ Defining the p85 mechanisms that mediate the inhibition and activation of PI3K

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Section: Discussionmentioning

confidence: 99%

Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases

Dornan

Stariha

Rathinaswamy

et al. 2019

Preprint

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“…PBMCs were isolated from healthy anonymous blood donors obtained from the Australian Red Cross Service and patients with PIK3CD GOF mutations (Table I). 19,23,24 Viral infection history of healthy donors was unknown. Whole blood was collected from Australian-based patients and sent immediately to the Garvan Institute of Medical Research.…”

Section: Clinical Evaluationmentioning

confidence: 99%

“…19,31 The other mutations identified in patients in this study (ie, G124D, N334K, E525K, and E1025G) have been reported previously and confirmed to be GOF mutations. 19,23,24 Patients' ages ranged from 4.5 to 67 years (mean, 20.1 years), with patients originating from a variety of ethnicities (Table I). As control subjects, we analyzed PBMCs from 38 healthy donors whose ages ranged from 10 to 71 years (mean, 38.0 years).…”

Section: Patients With Pik3cd Gof Mutations Present With Features Of mentioning

confidence: 99%

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

Edwards

Bier

Cole

et al. 2019

Journal of Allergy and Clinical Immunology

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“…According to literature, patients with APDS 1 may also present with gastrointestinal infections [6,7]. Another clinical manifestation are local and systemic lymphoproliferative disorders and hepatosplenomegaly observed since early childhood [3,[7][8][9]. Abnormalities in laboratory results include immune cytopenia and altered distribution of lymphocyte subpopulations [1,5,7,8].…”

mentioning

confidence: 99%

“…Another clinical manifestation are local and systemic lymphoproliferative disorders and hepatosplenomegaly observed since early childhood [3,[7][8][9]. Abnormalities in laboratory results include immune cytopenia and altered distribution of lymphocyte subpopulations [1,5,7,8]. Because of the tendency to lymphoproliferation, patients with APDS are at increased risk of neoplastic transformation, mainly to hematologic malignancies [1,3,9].…”

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confidence: 99%

Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys

Ewertowska

Grześk

Urbańczyk

et al. 2020

Allergy Asthma Clin Immunol

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Background: Activated PI3K delta syndrome (APDS) belongs to the heterogeneous group of primary immunodeficiency disorders (PIDs). Progress in next-generation sequencing (NGS) enabled identification of gain-offunction mutations in phosphoinositide 3-kinase (PI3K) genes. Depending on the type of causative mutation, APDS is classified into two types: APDS 1 and APDS 2. To date, less than 100 cases of APDS have been reported. Clinical symptoms of APDS result from impaired immune regulation and are clinically manifested by recurrent infections, allergies, lymphoproliferation and autoimmunity. They show similarity to other PIDs. Therefore, many patients were diagnosed incorrectly. The availability of genetic testing has allowed establishing the correct diagnosis in increasing number of patients suffering from APDS. Case presentations:The first male patient presented in infancy with recurrent infections. Subsequently he was found to suffer from hepatosplenomegaly, early portal hypertension, massive lymphoproliferation and hypogammaglobulinemia. The common E1021K mutation in the PI3KCD gene was identified. The patient underwent successful hematopoietic stem cell transplantation with resolution of most symptoms. The second patient suffered from persistent growth retardation since early life, facial dysmorphism and recurrent respiratory infections from early childhood. He was found to have systemic lympho-proliferation, panhypoglobulinemia and impaired antibody responses to vaccines. The introduction of NGS in Poland enabled rapid identification of a mutation in the PI3KR1 gene. Growth hormone administration seemed to have worsened the lymphoproliferation. Conclusions:Patients with suspected common variable immunodeficiency (CVID) and additional symptoms, such as allergy, facial dysmorphia, short stature, enhanced lymphoproliferation and lack of adequate response to human immunoglobulin replacement therapy, should be considered for NGS-based genetic testing. It may substantially shorten the time needed to establish the correct diagnosis, direct appropriate treatment and avoid potentially harmful therapies. To date, few cases of APDS have been described. It is important to report each of them to establish clinical indices and laboratory biomarkers of APDS 1 and APDS 2, to develop the standards of care in these conditions.

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Novel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans

Cited by 61 publications

References 28 publications

Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases

Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys

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