Role of Polypeptide GalNAc-transferase T3 in Familial Tumoral Calcinosis: The Importance of a Single GalNAc-transferase Isoform

Abstract

UDP-GalNAc: polypeptide N-acetylgalactosaminyl transferase (GalNAc-transferase, GalNAc-T) is the enzyme catalyzing mucin-type O-glycosylation (GalNAcα1-O-Ser/Thr) of proteins. Mutations in the gene encoding the GalNAc-T3 isoform were recently identified as a cause of the autosomal recessive metabolic disorder familial tumoral calcinosis (FTC) (OMIM 211900). FTC is associated with hyperphosphatemia and massive ectopic calcifications. We recently demonstrated that the secretion of the phosphaturic factor FGF23 requires O-glycosylation, and that GalNAc-T3 selectively directs O-glycosylation in a subtilisin-like proprotein convertase recognition sequence motif, which blocks furin protease processing of FGF23. These results suggest a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation and protease processing to produce intact FGF23.