Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage

Ivan Angulo, Oscar Vadas, Fabien Garçon, Edward Banham-Hall, Vincent Plagnol, Timothy R Leahy, Helen Baxendale, Tanya Coulter, James Curtis, Changxin Wu, Katherine Blake-Palmer, Olga Perisic, Deborah Smyth, Mailis Maes, Christine Fiddler, Jatinder Juss, Deirdre Cilliers, Gašper Markelj, Anita Chandra, George FarmerAnna Kielkowska, Jonathan Clark, Sven Kracker, Marianne Debré, Capucine Picard, Isabelle Pellier, Nada Jabado, James A Morris, Gabriela Barcenas-Morales, Alain Fischer, Len Stephens, Phillip Hawkins, Jeffrey C Barrett, Mario Abinun, Menna Clatworthy, Anne Durandy, Rainer Doffinger, Edwin R Chilvers, Andrew J Cant, Dinakantha Kumararatne, Klaus Okkenhaug, Roger L Williams, Alison Condliffe, Sergey Nejentsev

Research output: Contribution to journalArticleAcademicpeer-review

448 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)866-71
Number of pages6
Issue number6160
Publication statusPublished - 15 Nov 2013
Externally publishedYes


  • Class I Phosphatidylinositol 3-Kinases
  • Genetic Predisposition to Disease
  • Humans
  • Immunologic Deficiency Syndromes/genetics
  • Lymphocytes/immunology
  • Mutation
  • Pedigree
  • Phosphatidylinositol 3-Kinases/genetics
  • Phosphatidylinositol Phosphates/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism
  • Respiratory Tract Infections/genetics

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