Mutant mice provide new insight into the role of (mis-)glycation in IgA nephropathy and other glomerular diseases

Abstract

Keywords: aminopeptidase N; glomerular;glomerulonephritis; glycosylation; IgA; podocalyxinIn the 24 October 2006 issue of PNAS, Alexander andcolleagues [1] describe the results of a systematic searchfor thrombocytopenic mice generated by large-scalemutagenesis. Amongst 3523 mice, one pedigree indeedexhibited 50% reduction in platelet counts. Apartfrom thrombocytopenia, the only other notablefeature of these mice was prominent renal disease(albuminuria/proteinuria, glomerulosclerosis andtubulointerstitial inflammatory infiltration) leadingto uraemia and death at around 200 days afterbirth. This renal disease was not immune mediated,since it persisted in mutant mice crossed to B- andT-cell deficient mice and since no glomerularimmune deposits were detected. Serum IgA levelswere normal.The genetic defect in the above mice was identifiedas a point mutation in the enzyme core1-b1,3-galactosyltransferase, C1GalT1 (EC 2.4.1.122). Thisled to minimal (<5%) residual enzymatic activity.However, the small amount of enzyme activity thatwas preserved related to preserved interaction ofmutated C1GalT1 with its chaperone C1GalT2, alsoknown as Cosmc. Reduced C1GalT1 enzyme activityresulted in the appearance of the Tn-antigen on variousproteins, most prominently glycoprotein Ib-a onplatelets and aminopeptidase N as well as podocalyxinin kidneys.