Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K

Whole exome sequencing was used to determine the causative gene in patients with B cell defects of unknown etiology. A homozygous premature stop codon in exon 6 of PIK3R1 was identified in a young woman with colitis and absent B cells. The mutation results in the absence of p85 alpha but normal expression of the p50 alpha and p55 alpha regulatory subunits of PI3K. Bone marrow aspirates from the patient showed <0.1% CD19(+) B cells with normal percentages of TdT(+)VpreB(+)CD19(-) B cell precursors. This developmental block is earlier than that seen in patients with defects in the B cell receptor signaling pathway or in a strain of engineered mice with a similar defect in p85 alpha. The number and function of the patient's T cells were normal. However, Western blot showed markedly decreased p110 delta, as well as absent p85 alpha, in patient T cells, neutrophils, and dendritic cells. The patient had normal growth and development and normal fasting glucose and insulin. Mice with p85 alpha deficiency have insulin hypersensitivity, defective platelet function, and abnormal mast cell development. In contrast, the absence of p85 alpha in the patient results in an early and severe defect in B cell development but minimal findings in other organ systems.