Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients - a nonsense, a frameshift duplication and five different missense - cause autosomal dominant ICA by haploinsufficiency. Population genetic studies showed that RPSA was subject to purifying selection. RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.

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Background During IgE-mediated immediate hypersensitivity reactions, vascular endothelial cells permeabilize in response to mast cell mediators. We have previously demonstrated that patients and mice with STAT3 mutations (autosomal dominant-hyper IgE syndrome; AD-HIES) are partially protected from anaphylaxis. Objectives To further study the mechanism by which STAT3 contributes to anaphylaxis, and determine whether small molecule inhibition of STAT3 can prevent anaphylaxis. Methods Using unaffected and STAT3-inhibited or genetic loss of function samples, we performed histamine skin prick testing, investigated the contribution of STAT3 to animal models of anaphylaxis, measured endothelial cell permeability, gene and protein expression, and histamine receptor-mediated signaling. Results While mouse mast cell degranulation was minimally affected by STAT3 blockade, mast cell mediator-induced anaphylaxis was blunted in Stat3 mutant AD-HIES mice and in wild-type mice subjected to small molecule STAT3 inhibition. Histamine skin prick responses were diminished in AD-HIES patients. Human umbilical vein vascular endothelial cells (HUVECs) derived from patients with AD-HIES or treated with a STAT3 inhibitor failed to properly signal through Src or to appropriately dissolute the adherens junctions made up of the proteins vascular endothelial (VE)-cadherin and β-catenin. Further, we found that diminished STAT3-target mir17–92 expression in AD-HIES HUVECS is associated with increased PTEN expression, which inhibits Src, and increased E2F1 expression, which regulates β-catenin cellular dynamics. Conclusions These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions thus permitting vascular permeability.

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