Human Disorders of PI3K Biology

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Background

Studies of inherited mutations underlying rare human disorders elucidate genes and pathways of fundamental importance to human health. The phosphoinositide 3-kinase (PI3K) pathway has recently been highlighted as a driver of disease when either hyperactivated or inactivated due to germline mutations. In particular, the class I PI3Ks, which phosphorylate the phosphoinositol-4,5-bisphosphate lipid to produce the phosphoinositol-3,4,5-trisphosphate (PIP3) second messenger, have become the focus of intense investigation in recent years due to germline mutations identified in several diseases affecting the immune system, tissue growth, brain, metabolism, and cancers. Class I PI3Ks are comprised of a complex of two proteins, a catalytic subunit and a regulatory subunit. There are three class IA (activated by tyrosine phosphorylation events) catalytic subunits, p110α, p110β, and p110δ, and these interact with the p85α/p55α/p50α (all from the PIK3R1 gene), p85β, or p55γ regulatory subunit. Class IB (activated by G protein-coupled receptor signaling) PI3K has a single catalytic subunit, p110γ, which interacts with either the p101 or p101 regulatory subunit. Both p110δ and p110γ are expressed predominantly in leukocytes, while the other catalytic subunits are more ubiquitously expressed.

Immunodeficiency disorders have been attributed to both loss- and gain-of-function mutations in the genes encoding p110δ or p85α. There is also now evidence that some of the features caused by p110δ hyperactivation are recapitulated in patients with loss-of-function mutations in the PTEN phosphatase, which functions to dephosphorylate the PIP3 second messenger and suppress PI3K signaling. Very recent data have also emerged indicating pro-inflammatory effects of p110γ inhibition in animals, highlighting a potential negative regulatory function of p110γ predominantly in myeloid cells. Outside the immune system, class I PI3K gene mutations have been found as the cause of a spectrum of rare tissue overgrowth disorders and multi-system syndromes. Integrating knowledge gleaned from these diverse disorders and the wealth of information on fundamental PI3K biology offers the potential to gain a more complete picture of this important pathway and potential effects of its therapeutic manipulation for treatment of a vast array of pathologies.

This Research Topic will provide a comprehensive overview of disorders of PI3K biology and will cover various aspects of the primary immunodeficiency disorder called Activated PI3Kδ Syndrome (APDS), or PASLI disease, caused by mutations in the genes encoding p110δ or p85α. It will also cover the physiological consequences of PTEN deficiency, p110γ inhibition, p85α deficiency, p110δ deficiency, and inherited non-immune overgrowth and metabolic disorders from mutations in PI3K genes.

Keywords: PI3K, Monogenic Disorders, Immunodeficiency, Overgrowth

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