期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 9, 页码 3923-3928出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI75746
关键词
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资金
- INSERM
- Fondation pour la Recherche Medicale [ING20130526624]
- Ligue Contre le Cancer - Comite de Paris
- EUFP7 European Research Council PIDIMMUNE program [249816]
- French Agence Nationale de la Recherche as part of the Investments for the Future program [ANR-10-IAHU-01]
Recently, patient mutations that activate PI3K signaling have beer 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 hypogarnmaglobulinemia and recurrent infections. We identified 2 different heterozygous splice site mutations that affect the same splice site in PIK3R1, which encodes the p85 alpha subunit of PI3K. The resulting deletion of exon 10 produced a shortened p85 alpha protein that lacks part of the PI3K110-binding domain. The hypothetical loss of p85 alpha-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 PI3K delta 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.
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