Development of IgA nephropathy-like glomerulonephritis associated with Wiskott–Aldrich syndrome protein deficiency

Wiskott–Aldrich syndrome (WAS) is a rare X-linked disorder caused by mutations in the WAS gene. Glomerulonephritis is a frequent complication, however, histopathological data from affected patients is scarce because the thrombocytopenia that affects most patients is a contraindication to renal biopsies. We found that WASp-deficient mice develop proliferative glomerulonephritis reminiscent of human IgA nephropathy (IgAN). We examined whether increased aberrant IgA production is associated with the development of glomerulonephritis in WASp-deficient mice. Serum IgA and IgA production by splenic B cells was increased in WASp-deficient mice compared to wild-type (WT) mice. A lectin-binding study revealed a reduced ratio of sialylated and galactosylated IgA in the sera from old WASp-deficient mice. Circulating IgA-containing immune complexes showed significantly higher titers in WASp-deficient mice compared to WT mice. These results indicate that the increased IgA production and aberrant glycosylation of IgA may be critically involved in the pathogenesis of glomerulonephritis in WAS.

► Renal diseases are a frequent complication associated with Wiskott–Aldrich syndrome. ► WASp-deficient mice develop glomerulonephritis reminiscent of IgA nephropathy. ► Aberrant glycosylation of IgA is critically involved in the pathogenesis of IgAN. ► Aberrant glycosylation of IgA is involved in WAS associated glomerulonephritis.