Abstract
Mucin-type O-glycosylation involves the attachment of glycans to an initial O-linked N-acetylgalactosamine (GalNAc) on serine and threonine residues on proteins. This process in mammals is initiated and regulated by a large family of 20 UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) (EC 2.4.1.41). The enzymes are encoded by a large gene family (GALNTs). Two of these genes, GALNT2 and GALNT3, are known as monogenic autosomal recessive inherited disease genes with well characterized phenotypes, whereas a broad spectrum of phenotypes is associated with the remaining 18 genes. Until recently, the overlapping functionality of the 20 members of the enzyme family has hindered characterizing the specific biological roles of individual enzymes. However, recent evidence suggests that these enzymes do not have full functional redundancy and may serve specific purposes that are found in the different phenotypes described. Here, we summarize the current knowledge of GALNT and associated phenotypes.
Highlights
Initiation of mucin-type O-glycosylation is controlled by a large family of UDPGalNAc: polypeptide N-acetylgalactosaminyltransferases (EC 2.4.1.41; referred to as glycans to an initial O-linked Nacetylgalactosamine (GalNAc)-Ts, ppGalNAc-Ts, and ppGaNTases) in animals
Hyperostosis-hyperphosphatemia syndrome (HHS) is another clinical feature of GALNT3 deficiency; as concluded by Ichikawa et al [49], we consider hyperphosphatemic familial tumoral calcinosis (HFTC) and HHS to be a continuous spectrum of the same disease and we describe both conditions as HFTC in this review
Recent genome-wide association studies (GWASs) have shown that GALNT12 is negatively associated with serum galactosedeficient IgA1 levels resulting in IgA nephropathy [114], and a single nucleotide polymorphism (SNP)—rs2295926, belonging to GALNT12—is strongly associated with rapid radiographic joint destruction in patients with rheumatoid arthritis [115], but the underlying molecular mechanisms are unclear
Summary
Initiation of mucin-type O-glycosylation is controlled by a large family of UDPGalNAc: polypeptide N-acetylgalactosaminyltransferases (EC 2.4.1.41; referred to as GalNAc-Ts, ppGalNAc-Ts, and ppGaNTases) in animals. These enzymes catalyze formation of GalNAcα1-serine (Ser)/threonine (Thr) linkages in glycoproteins. Isoforms of GalNAc-Ts have been identified and several reviews have described these enzymes in detail [1,2,3]. More recent studies have described GALNT mutation-related phenotypes in mammals. The purpose of this review is to summarize these phenotypes and to correct unintentional errors and nomenclature in the literature
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