Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17.
Angulo I , Vadas O,Garçon F,Banham-Hall E,Plagnol V,Leahy TR,Baxendale H,Coulter T,Curtis J,Wu C, Blake-Palmer K , Perisic O,Smyth D,Maes M,Fiddler C,Juss J,Cilliers D,Markelj G,Chandra A,Farmer G,Kielkowska A,Clark J,Kracker S,Debré M,Picard C,Pellier I,Jabado N, Morris JA, Barcenas-Morales G , Fischer A,Stephens L,Hawkins P,Barrett JC,Abinun M,Clatworthy M,Durandy A,Doffinger R,Chilvers ER,Cant AJ,Kumararatne D,Okkenhaug K,Williams RL,Condliffe A, Nejentsev S.
Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), 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 p110δ. 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 p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.