Hyper-activated PI3K-δ in immunodeficiency

The class I phosphoinositide 3-kinases (PI3Ks) are especially involved in the cell response to extracellular signals and convert phosphatidylinositol-(4,5)-bisphosphate (PIP2) into phosphatidylinositol-(3,4,5)-triphosphate (PIP3), an important intracellular " second messenger " , activating many different intracellular enzymes, including Akt also known as protein-kinase B. Class IA PI3Ks are heterodimeric molecules consisting of a catalytic subunit (p110α, p110β or p110δ) and a regulatory subunit (p85α, p85β, p85γ, p50α or p55α). Each of the catalytic subunits can bind to any of the regulatory subunits. The p110δ catalytic subunit is expressed predominantly in leukocytes, whereas the other subunits present with an ubiquitously expression pattern. Class IA PI3Ks activation in lymphocytes occurs downstream of the antigen receptor (B or T cell receptor) and co-stimulatory molecules. Crosslinking of antigen receptors leads to phosphorylation of tyrosine residues, which then recruits class IA PI3Ks [1]. A homozygous nonsense mutation in PIK3R1 causing loss of p85α was identified in an immunodeficient patient presenting with agammaglobulinemia [2]. More recently heterozygous gain-of-function mutations in the PIK3CD gene encoding p110δ have been described (N334K, C416R, E525K and E1021K with the majority of cases carrying E1021K) as a cause for primary immunodeficiency [3-5]. The disease was called activated PI3K-δ syndrome (APDS) [3]. Frequent symptoms were recurrent respiratory infections since childhood, bronchiectasis, lymphoproliferation, adenopathy and hypogammaglobulinemia or Hyper-IgM syndrome. Abnormalities of lymphocyte subpopulations were observed in the B (higher frequency of transitional, decrease of mature B) and T lymphocyte compartments (decreased naïve CD4 T and naïve CD8 T and increased frequency of effector memory CD8 T cells) indicating a combined immunodeficiency. APDS appears to predispose to B cell lymphomagenesis especially diffuse large B cell lymphomas and Hodgkin lymphoma. A combination of aberrant immune surveillance due to disturbed T cell function and B cell intrinsic defects could be responsible for the increased B cell lymphoma frequency. We identified by using the whole-exome sequencing approach a novel cause for hyper-activated PI3K-δ signaling: splice site mutations in PIK3R1 [6]. PIK3R1 encodes the most abundantly expressed regulatory subunit p85α and two additional isoforms (p55α and p50α), the production of which is regulated by two distinct promoters and an alternative exon 1. These mutations located at the splice donor site of the coding exon 10 lead to exon skipping and affect the mRNAs of all PIK3R1 encoded isoforms. Splicing from exon 9 to exon 11 occurs in frame thus these mutations lead to a shortened p85α protein which was …