title: A human immunodeficiency caused by mutations in the PIK3R1 gene.
abstract: Recently, patient mutations that activate PI3K signaling have been linked to a primary antibody deficiency. Here, we used whole-exome sequencing and characterized the molecular defects in 4 patients from 3 unrelated families diagnosed with hypogammaglobulinemia and recurrent infections. We identified 2 different heterozygous splice site mutations that affect the same splice site in PIK3R1, which encodes the p85α subunit of PI3K. The resulting deletion of exon 10 produced a shortened p85α protein that lacks part of the PI3K p110-binding domain. The hypothetical loss of p85α-mediated inhibition of p110 activity was supported by elevated phosphorylation of the known downstream signaling kinase AKT in patient T cell blasts. Analysis of patient blood revealed that naive T and memory B cell counts were low, and T cell blasts displayed enhanced activation-induced cell death, which was corrected by addition of the PI3Kδ inhibitor IC87114. Furthermore, B lymphocytes proliferated weakly in response to activation via the B cell receptor and TLR9, indicating a B cell defect. The phenotype exhibited by patients carrying the PIK3R1 splice site mutation is similar to that of patients carrying gain-of-function mutations in PIK3CD. Our results suggest that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies.
authors.forename: Marie-Céline
authors.initials: MC
authors.lastname: Deau
authors.forename: Lucie
authors.initials: L
authors.lastname: Heurtier
authors.forename: Pierre
authors.initials: P
authors.lastname: Frange
authors.forename: Felipe
authors.initials: F
authors.lastname: Suarez
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
mesh_terms: D058543:Class Ia Phosphatidylinositol 3-Kinase; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D008213:Lymphocyte Activation; D008297:Male; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C588001:PIK3R1 protein, human