Publication Date:
2013-10-19
Description:
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 p110delta protein, the catalytic subunit of phosphoinositide 3-kinase delta (PI3Kdelta), 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 p110delta. 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 p110delta inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930011/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930011/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Angulo, Ivan -- Vadas, Oscar -- Garcon, Fabien -- Banham-Hall, Edward -- Plagnol, Vincent -- Leahy, Timothy R -- Baxendale, Helen -- Coulter, Tanya -- Curtis, James -- Wu, Changxin -- Blake-Palmer, Katherine -- Perisic, Olga -- Smyth, Deborah -- Maes, Mailis -- Fiddler, Christine -- Juss, Jatinder -- Cilliers, Deirdre -- Markelj, Gasper -- Chandra, Anita -- Farmer, George -- Kielkowska, Anna -- Clark, Jonathan -- Kracker, Sven -- Debre, Marianne -- Picard, Capucine -- Pellier, Isabelle -- Jabado, Nada -- Morris, James A -- Barcenas-Morales, Gabriela -- Fischer, Alain -- Stephens, Len -- Hawkins, Phillip -- Barrett, Jeffrey C -- Abinun, Mario -- Clatworthy, Menna -- Durandy, Anne -- Doffinger, Rainer -- Chilvers, Edwin R -- Cant, Andrew J -- Kumararatne, Dinakantha -- Okkenhaug, Klaus -- Williams, Roger L -- Condliffe, Alison -- Nejentsev, Sergey -- 095198/Wellcome Trust/United Kingdom -- 095198/Z/10/Z/Wellcome Trust/United Kingdom -- 095691/Wellcome Trust/United Kingdom -- BB/J004456/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184308/Medical Research Council/United Kingdom -- U105184308/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Cambridge, Cambridge, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24136356" target="_blank"〉PubMed〈/a〉
Keywords:
Class I Phosphatidylinositol 3-Kinases
;
*Genetic Predisposition to Disease
;
Humans
;
Immunologic Deficiency Syndromes/*genetics/immunology/*pathology
;
Lymphocytes/immunology
;
Mutation
;
Pedigree
;
Phosphatidylinositol 3-Kinases/*genetics
;
Phosphatidylinositol Phosphates/metabolism
;
Proto-Oncogene Proteins c-akt/metabolism
;
Respiratory Tract Infections/*genetics/immunology/*pathology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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