Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage

被引：477

作者：

Angulo, Ivan ^{[1
]}

Vadas, Oscar ^{[2
]}

Garcon, Fabien ^{[3
]}

Banham-Hall, Edward ^{[3
]}

Plagnol, Vincent ^{[4
]}

Leahy, Timothy R. ^{[5
,6
]}

Baxendale, Helen ^{[7
]}

Coulter, Tanya ^{[6
,8
]}

Curtis, James ^{[1
]}

Wu, Changxin ^{[1
]}

Blake-Palmer, Katherine ^{[1
]}

Perisic, Olga ^{[2
]}

Smyth, Deborah ^{[9
]}

Maes, Mailis ^{[1
]}

Fiddler, Christine ^{[1
]}

Juss, Jatinder ^{[1
]}

Cilliers, Deirdre ^{[10
]}

Markelj, Gasper ^{[11
]}

Chandra, Anita ^{[7
]}

Farmer, George ^{[12
]}

Kielkowska, Anna ^{[13
]}

Clark, Jonathan ^{[13
]}

Kracker, Sven ^{[14
,15
]}

Debre, Marianne ^{[16
]}

Picard, Capucine ^{[15
,16
,17
]}

Pellier, Isabelle ^{[18
]}

Jabado, Nada ^{[19
,20
]}

Morris, James A. ^{[21
]}

Barcenas-Morales, Gabriela ^{[22
]}

Fischer, Alain ^{[14
,15
,16
]}

Stephens, Len ^{[3
]}

Hawkins, Phillip ^{[3
]}

Barrett, Jeffrey C. ^{[21
]}

Abinun, Mario ^{[5
]}

Clatworthy, Menna ^{[1
]}

Durandy, Anne ^{[14
,15
,16
,17
]}

Doffinger, Rainer ^{[7
]}

Chilvers, Edwin R. ^{[1
]}

Cant, Andrew J. ^{[5
]}

Kumararatne, Dinakantha ^{[7
]}

Okkenhaug, Klaus ^{[3
]}

Williams, Roger L. ^{[2
]}

Condliffe, Alison ^{[1
]}

Nejentsev, Sergey ^{[1
]}

机构：

[1] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England

[2] MRC, Mol Biol Lab, Cambridge CB2 2QH, England

[3] Babraham Inst, Cambridge, England

[4] UCL, Univ Coll London Genet Inst, London, England

[5] Newcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[6] Our Ladys Childrens Hosp, Dublin, Ireland

[7] Addenbrookes Hosp, Dept Clin Biochem & Immunol, Cambridge, England

[8] Trinity Coll Dublin, Sch Med, Dept Immunol, Dublin, Ireland

[9] Univ Cambridge, Juvenile Diabet Res Fdn, Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge, England

[10] Oxford Univ Hosp, Dept Clin Genet, Oxford, England

[11] Univ Med Ctr, Univ Childrens Hosp, Dept Allergol Rheumatol & Clin Immunol, Ljubljana, Slovenia

[12] Raigmore Hosp, Inverness, Scotland

[13] Babraham Biosci Technol Ltd, Cambridge, England

[14] Necker Childrens Hosp, INSERM, U768, Natl Inst Hlth & Med Res, Paris, France

[15] Descartes Sorbonne Paris Cite Univ Paris, Imagine Inst, Paris, France

[16] Necker Childrens Hosp, AP HP, Dept Immunol & Hematol, Paris, France

[17] Necker Childrens Hosp, AP HP, Ctr Primary Immunodeficiencies CEDI, Paris, France

[18] CHU Angers, Dept Pediat, Angers, France

[19] McGill Univ, Dept Pediat, Montreal, PQ H3A 2T5, Canada

[20] McGill Univ Hlth Ctr, Montreal, PQ, Canada

[21] Wellcome Trust Sanger Inst, Hinxton, England

[22] Lab Inmunol, Fes Cuautitlan, Mexico

来源：

SCIENCE | 2013年 / 342卷 / 6160期

基金：

英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会; 瑞士国家科学基金会; 欧洲研究理事会;

关键词：

PTEN; ACTIVATION; PI3K; IMMUNODEFICIENCY;

D O I：

10.1126/science.1243292

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：866 / 871

页数：6

共 25 条

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