Thrombocytopenia and Kidney Disease in Mice with a Mutation in the C1galt1 Gene

An N-ethyl-N-nitrosourea mutagenesis screen in mice was performed to isolate regulators of circulating platelet number. We report here recessive thrombocytopenia and kidney disease in pit1 mice, which is the result of a severe but partial loss-of-function mutation in the gene encoding glycoprotein-N-acetylgalactosamine-3-β-galactosyltransferase (CIGalT1), an enzyme essential for the synthesis of extended mucin-type O-glycans. Platelet half-life and basic hemostatic parameters were unaffected in pltl/pltl mice, and the thrombocytopenia and kidney disease were not attenuated on a lymphocyte-deficient ragl-null background. gplba and podocalyxin were found to be major underglycosylated proteins in pltl/pltl platelets and the kidney, respectively, implying that these are key targets for CIGalT1, appropriate glycosylation of which is essential for platelet production and kidney function. Compromised CIGalT1 activity has been associated with immune-mediated diseases in humans, most notably Tn syndrome and IgA nephropathy. The disease in pltl/pltl mice suggests that, in addition to immune-mediated effects, intrinsic C1Gal-T1 deficiency in megakaryocytes and the kidney may contribute to pathology.