A human immunodeficiency caused by mutations in the PIK3R1
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Authors: | Marie-Céline Deau Lucie Heurtier Pierre Frange Felipe Suarez Christine Bole-Feysot Patrick Nitschke Marina Cavazzana Capucine Picard Anne Durandy Alain Fischer Sven Kracker |
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Institution: | 1.INSERM UMR 1163, Human Lymphohematopoiesis Laboratory, and 2.Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France. 3.Unité d’Immunologie et Hématologie Pédiatrique, 4.Service d’Hématologie Adultes, and 5.Center for Primary Immunodeficiencies, Assistance Publique–Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France. 6.Collège de France, Paris, France. |
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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. |
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