期刊
SCIENCE
卷 342, 期 6160, 页码 866-871出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1243292
关键词
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资金
- European Research Council (ERC) [260477]
- European Union (EU) [261441]
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- Swiss National Science Foundation [PA00P3_134202]
- European Commission [275880]
- Medical Research Council [U105184308]
- National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
- Wellcome Trust
- Medical Research Council UK
- British Lung Foundation
- Biotechnology and Biological Sciences Research Council [BB/J004456/1]
- Institut National de la Sante et de la Recherche Medicale
- EU FP7 EUROPAD [201549]
- Association Contre Le Cancer
- Agence Nationale de la Recherche [2010-CSRD]
- EU FP7 ERC PIDIMMUNE [249816]
- PASPA-DGAPA-UNAM
- GlaxoSmithKline
- Roche
- Novartis
- Karus Therapeutics Ltd
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0411, BBS/E/B/0000H260, BBS/E/B/0000H329] Funding Source: researchfish
- Medical Research Council [MC_U105184308] Funding Source: researchfish
- Swiss National Science Foundation (SNF) [PA00P3_134202] Funding Source: Swiss National Science Foundation (SNF)
- BBSRC [BBS/E/B/0000H260, BBS/E/B/0000H329, BBS/E/B/000C0411] Funding Source: UKRI
- MRC [MC_U105184308] Funding Source: UKRI
Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-delta syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110 delta protein, the catalytic subunit of phosphoinositide 3-kinase delta (PI3K delta), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110 delta. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110 delta inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.
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