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Review
. 2018 Feb 27:9:369.
doi: 10.3389/fimmu.2018.00369. eCollection 2018.

Activated PI3 Kinase Delta Syndrome: From Genetics to Therapy

David Michalovich  1 , Sergey Nejentsev  2
Affiliations
Review

Activated PI3 Kinase Delta Syndrome: From Genetics to Therapy

David Michalovich et al. Front Immunol. .

Abstract

Activated PI3 kinase delta syndrome (APDS) is a primary immunodeficiency caused by dominant mutations that increase activity of phosphoinositide-3-kinase δ (PI3Kδ). APDS can be caused by mutations in the PIK3CD gene that encodes PI3Kδ catalytic subunit p110δ (APDS1) or mutations in the PIK3R1 gene that encodes regulatory subunit p85α (APDS2). APDS research advanced rapidly after the initial discovery in 2013. More than 200 APDS patients have been identified around the world. Multiple novel APDS mutations were reported and molecular mechanisms leading to PI3Kδ activation have been elucidated. The finding of APDS significantly increased our understanding of the role of PI3Kδ in the human immune system. Perhaps most importantly, discovery of the molecular basis of this primary immunodeficiency suggested that APDS patients, who previously received only non-specific therapy, could be treated by a novel class of drugs that inhibits PI3Kδ activity. This led to the ongoing clinical trials of selective PI3Kδ inhibitors in APDS patients. Overall, the APDS story provides an excellent example of translational research, beginning with patients who had an unknown disease cause and leading to a novel specific knowledge-based treatment.

Keywords: activated PI3 kinase delta syndrome; inhibitor; mutation; phosphoinositide-3-kinase δ; primary immunodeficiency.

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Figures

Figure 1
Figure 1
(A) Domain structure of the p110δ and p85α proteins and positions of mutations. ABD, adaptor-binding domain; RBD, Ras-binding domain; BH, breakpoint cluster region homology domain; P, proline-rich regions. (B) Activated PI3 kinase delta syndrome mutations in the PIK3CD (, , –15, 19) and PIK3R1 (7, 8, 14, 20) genes. 1—NM_005026; 2—NM_181523 (RefSeq); 3—O00329; 4—P27986 (UniProt).
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References

    1. Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol (2018) 38(1):129.10.1007/s10875-017-0465-8 - DOI - PMC - PubMed
    1. Burke JE, Williams RL. Synergy in activating class I PI3Ks. Trends Biochem Sci (2015) 40(2):88.10.1016/j.tibs.2014.12.003 - DOI - PubMed
    1. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kdelta and primary immunodeficiencies. Nat Rev Immunol (2016) 16(11):702.10.1038/nri.2016.93 - DOI - PMC - PubMed
    1. Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol (2013) 31:675.10.1146/annurev-immunol-032712-095946 - DOI - PMC - PubMed
    1. Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science (2013) 342(6160):866.10.1126/science.1243292 - DOI - PMC - PubMed

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