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Phosphoinositide 3-kinase ? 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-? 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? protein, the catalytic subunit of phosphoinositide 3-kinase ? (PI3K?), 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?. 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? inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.

SUBMITTER: Angulo I 

PROVIDER: S-EPMC3930011 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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

Angulo Ivan I   Vadas Oscar O   Garçon Fabien F   Banham-Hall Edward E   Plagnol Vincent V   Leahy Timothy R TR   Baxendale Helen H   Coulter Tanya T   Curtis James J   Wu Changxin C   Blake-Palmer Katherine K   Perisic Olga O   Smyth Deborah D   Maes Mailis M   Fiddler Christine C   Juss Jatinder J   Cilliers Deirdre D   Markelj Gašper G   Chandra Anita A   Farmer George G   Kielkowska Anna A   Clark Jonathan J   Kracker Sven S   Debré Marianne M   Picard Capucine C   Pellier Isabelle I   Jabado Nada N   Morris James A JA   Barcenas-Morales Gabriela G   Fischer Alain A   Stephens Len L   Hawkins Phillip P   Barrett Jeffrey C JC   Abinun Mario M   Clatworthy Menna M   Durandy Anne A   Doffinger Rainer R   Chilvers Edwin R ER   Cant Andrew J AJ   Kumararatne Dinakantha D   Okkenhaug Klaus K   Williams Roger L RL   Condliffe Alison A   Nejentsev Sergey S  

Science (New York, N.Y.) 20131017 6160


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  ...[more]

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