Mucin-type O-linked glycosylation, a posttranslational modification affecting 
the stability and biophysical characteristics of proteins, requires C1GalT1 (T 
synthase) and its obligate, X-linked chaperone Cosmc. Hypomorphic C1GalT1 
mutations cause renal failure via not yet established mechanisms. We hypothesize 
that impaired Cosmc-dependent O-glycosylation in podocytes is sufficient to 
cause disease. Podocyte-specific Cosmc knockout mice were generated and 
phenotyped to test this hypothesis. Female heterozygous mice displaying mosaic 
inactivation of Cosmc in podocytes due to random X-linked inactivation were also 
examined. Mice with podocyte-specific Cosmc deletion develop profound 
albuminuria, foot process effacement, glomerular sclerosis, progressive renal 
failure, and impaired survival. Glomerular transcriptome analysis reveals early 
changes in cell adhesion, extracellular matrix organization, and 
chemokine-mediated signaling pathways, coupled with podocyte loss. Expression of 
the O-glycoprotein podoplanin was lost, while Tn antigen, representing immature 
O-glycans, was most abundantly found on podocalyxin. In contrast to hemizygous 
male and homozygous female animals, heterozygous female mosaic animals developed 
only mild albuminuria, focal foot process effacement, and nonprogressive kidney 
disease. Ultrastructurally, Cosmc-deficient podocytes formed Tn antigen-positive 
foot processes interdigitating with those of normal podocytes but not with other 
Cosmc-deficient cells. This suggests a cell nonautonomous mechanism for 
mucin-type O-glycoproteins in maintaining podocyte function. In summary, our 
findings demonstrated an essential and likely cell nonautonomous role for 
mucin-type O-glycosylation for podocyte function.