A human immunodeficiency caused by mutations in the PIK3R1 gene.
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Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, Cavazzana M, Picard C, Durandy A, Fischer A, Kracker S
A human immunodeficiency caused by mutations in the PIK3R1 gene.
J Clin Invest. 2014 Sep;124(9):3923-8. doi: 10.1172/JCI75746. Epub 2014 Aug 18.
- PubMed ID
- 25133428 [ View in PubMed]
- 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 p85alpha subunit of PI3K. The resulting deletion of exon 10 produced a shortened p85alpha protein that lacks part of the PI3K p110-binding domain. The hypothetical loss of p85alpha-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 PI3Kdelta 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.