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

Warren Alexander, Elizabeth M Viney, Jianguo Zhang, Donald Metcalf, Maria Kauppi, Craig D Hyland, Marina Carpinelli, William Stevenson, Ben Croker, Adrienne A Hilton, Sarah L Ellis, Carly Selan, Harshal Nandurkar, Chris Goodnow, Benjamin T Kile, Nicos A Nicola, Andrew W Roberts, Douglas Hilton

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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 plt1 mice, which is the result of a severe but partial loss-of-function mutation in the gene encoding glycoprotein-N-acetylgalactosamine-3-?-galactosyltransferase (C1GalT1), an enzyme essential for the synthesis of extended mucin-type O-glycans. Platelet half-life and basic hemostatic parameters were unaffected in plt1/plt1 mice, and the thrombocytopenia and kidney disease were not attenuated on a lymphocyte-deficient ragi-null background, gplba and podocalyxin were found to be major underglycosylated proteins in plt1/plt1 platelets and the kidney, respectively, implying that these are key targets for CIGaITI, 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 in plt1/plt1 mice suggests that, in addition to immune-mediated effects, intrinsic C1Gal-T1 deficiency in megakaryocytes and the kidney may contribute to pathology. ? 2006 by The National Academy of Sciences of the USA.
Original languageEnglish
Pages (from-to)16442 - 16447
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
Publication statusPublished - 2006

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