title: Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene.
abstract: 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-beta-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 rag1-null background. gpIbalpha and podocalyxin were found to be major underglycosylated proteins in plt1/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 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. alexandw@wehi.edu.au
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Viney
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Maria
authors.initials: M
authors.lastname: Kauppi
authors.forename: Craig D
authors.initials: CD
authors.lastname: Hyland
authors.forename: Marina R
authors.initials: MR
authors.lastname: Carpinelli
authors.forename: William
authors.initials: W
authors.lastname: Stevenson
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
authors.forename: Adrienne A
authors.initials: AA
authors.lastname: Hilton
authors.forename: Sarah
authors.initials: S
authors.lastname: Ellis
authors.forename: Carly
authors.initials: C
authors.lastname: Selan
authors.forename: Harshal H
authors.initials: HH
authors.lastname: Nandurkar
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D015996:Survival Rate; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C515597:C1galt1 protein, mouse; D005700:Galactosyltransferases