Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene

AnN -ethyl-N -nitrosourea mutagenesis screen in mice was performed to isolate regulators of circulating platelet number. We report here recessive thrombocytopenia and kidney disease inplt1 mice, which is the result of a severe but partial loss-of-function mutation in the gene encoding glycoprotein-N -acetylgalactosamine-3-β-galactosyltransferase (C1GalT1), an enzyme essential for the synthesis of extended mucin-type O-glycans. Platelet half-life and basic hemostatic parameters were unaffected inplt1/plt1 mice, and the thrombocytopenia and kidney disease were not attenuated on a lymphocyte-deficientrag1 -null background. gpIbα and podocalyxin were found to be major underglycosylated proteins inplt1/plt1 platelets and the kidney, respectively, implying that these are key targets for C1GalT1, appropriate glycosylation of which is essential for platelet production and kidney function. Compromised C1GalT1 activity has been associated with immune-mediated diseases in humans, most notably Tn syndrome and IgA nephropathy. The disease inplt1/plt1 mice suggests that, in addition to immune-mediated effects, intrinsic C1Gal-T1 deficiency in megakaryocytes and the kidney may contribute to pathology.