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.
Highlights
Primary immunodeficiencies (PIDs) are a group of disorders that cause immune dysfunction and manifest with increased susceptibility to infections
Each class IA PI3K is composed of a catalytic subunit: p110α, p110β, or p110δ, and one of the five regulatory subunits: p85α, p55α, p50α, p85β, or p55γ
Activated PI3 kinase delta syndrome (APDS) mutations were shown to appear de novo among children, while being absent in their parents [5, 6, 10, 20], and long-range haplotype analysis in families with the E1021K mutation showed no founder effect [5]. These findings indicate that APDS mutations appear recurrently in human populations
Summary
Primary immunodeficiencies (PIDs) are a group of disorders that cause immune dysfunction and manifest with increased susceptibility to infections. Mutations in more than 300 genes have been shown to cause various PIDs [1]. Activated PI3 kinase delta syndrome (APDS) is a PID that results from gain-of-function mutations in genes encoding the phosphoinositide-3-kinase δ (PI3Kδ). Each class IA PI3K is composed of a catalytic subunit: p110α, p110β, or p110δ (encoded by genes PIK3CA, PIK3CB, and PIK3CD, respectively), and one of the five regulatory subunits: p85α, p55α, p50α (all encoded by different transcripts of the PIK3R1 gene), p85β (encoded by the PIK3R2 gene), or p55γ (encoded by the PIK3R3 gene). PIP3 produced by PI3Ks activates kinases PDK1 and AKT, leading to the activation of mTOR complex 1 and inhibition of FOXO family of transcription factors.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
