case_images: PMC8266209_01
case_images: Molecular APDS2 characteristics. (A) Schematic representation of the PIK3R1 gene and illustrated localization of identified mutation. (B) RT-PCR of PIK3R1 mRNA from T-cell blast of a control, a patient with APDS2, and the investigated patient. (C) Schematic representation of mutations affecting splicing of exon 11 annotated in ClinVAR. In red is the mutation of investigated patient. (D) AKT phosphorylation analysis in T-cell blasts (cultured for 13 days) from a healthy control, an APDS2 patient, and the investigated patient. The analysis was performed as described by Deau et al.. Mean fluorescence intensity (MFI) is indicated for each sample.
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case_images: PMC8266209_01_fped-09-688022-g0001.jpg
case_images: F1
case_images: APDS2. Analysis of patients' derived T-cell blast mRNA indicated exon skipping of coding exon11 (Figures 1A-C). T-cell blasts (Figure 1D). Treatment with a p110 delta-specific inhibitor (IC87114) abrogated those differences, indicating that increased PI3K delta-signaling at basal level was responsible for the high level of AKT phosphorylation at Ser473 (Figure 1D). Together, our functional analysis demonstrated that the de novo c.1425+3delGA mutation causes exon skipping of exon 11 and subsequent activation of PI3K delta-signaling in lymphocytes. Since the discovery of APDS2, administration of immunomodulatory agents such as rapamycin and p110delta-specific inhibitor has been under consideration.