title: Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.
abstract: 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.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Angulo
authors.forename: Oscar
authors.initials: O
authors.lastname: Vadas
authors.forename: Fabien
authors.initials: F
authors.lastname: Garçon
authors.forename: Edward
authors.initials: E
authors.lastname: Banham-Hall
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Leahy
authors.forename: Helen
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authors.lastname: Baxendale
authors.forename: Tanya
authors.initials: T
authors.lastname: Coulter
authors.forename: James
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authors.lastname: Curtis
authors.forename: Changxin
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authors.lastname: Wu
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authors.lastname: Blake-Palmer
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authors.lastname: Perisic
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authors.initials: D
authors.lastname: Smyth
authors.forename: Mailis
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authors.lastname: Maes
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authors.initials: C
authors.lastname: Fiddler
authors.forename: Jatinder
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authors.lastname: Juss
authors.forename: Deirdre
authors.initials: D
authors.lastname: Cilliers
authors.forename: Gašper
authors.initials: G
authors.lastname: Markelj
authors.forename: Anita
authors.initials: A
authors.lastname: Chandra
authors.forename: George
authors.initials: G
authors.lastname: Farmer
authors.forename: Anna
authors.initials: A
authors.lastname: Kielkowska
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clark
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.forename: Marianne
authors.initials: M
authors.lastname: Debré
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pellier
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: James A
authors.initials: JA
authors.lastname: Morris
authors.forename: Gabriela
authors.initials: G
authors.lastname: Barcenas-Morales
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Len
authors.initials: L
authors.lastname: Stephens
authors.forename: Phillip
authors.initials: P
authors.lastname: Hawkins
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.forename: Menna
authors.initials: M
authors.lastname: Clatworthy
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cant
authors.forename: Dinakantha
authors.initials: D
authors.lastname: Kumararatne
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Roger L
authors.initials: RL
authors.lastname: Williams
authors.forename: Alison
authors.initials: A
authors.lastname: Condliffe
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases; D020022:Genetic Predisposition to Disease; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology; D009154:Mutation; D010375:Pedigree; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology*
chemical_list: D018129:Phosphatidylinositol Phosphates; C547378:phosphatidylinositol 3,4,5,6-tetrakisphosphate; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D051057:Proto-Oncogene Proteins c-akt