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

Extract

In the 24 October 2006 issue of PNAS , Alexander and colleagues [ 1 ] describe the results of a systematic search for thrombocytopenic mice generated by large-scale mutagenesis. Amongst 3523 mice, one pedigree indeed exhibited ∼50% reduction in platelet counts. Apart from thrombocytopenia, the only other notable feature of these mice was prominent renal disease (albuminuria/proteinuria, glomerulosclerosis and tubulointerstitial inflammatory infiltration) leading to uraemia and death at around 200 days after birth. This renal disease was not immune mediated, since it persisted in mutant mice crossed to B- and T-cell deficient mice and since no glomerular immune deposits were detected. Serum IgA levels were normal.

The genetic defect in the above mice was identified as a point mutation in the enzyme core1-β1,3-galactosyltransferase, C1GalT1 (EC 2.4.1.122). This led to minimal (<5%) residual enzymatic activity. However, the small amount of enzyme activity that was preserved related to preserved interaction of mutated C1GalT1 with its chaperone C1GalT2, also known as Cosmc. Reduced C1GalT1 enzyme activity resulted in the appearance of the Tn-antigen on various proteins, most prominently glycoprotein Ib-α on platelets and aminopeptidase N as well as podocalyxin in kidneys.