The role of the GlcNAcβ1,2Manα- moiety in mammalian development. Null mutations of the genes encoding UDP-N-acetylglucosamine: α-3-D-mannoside β-1,2-N-acetylglucosaminyltransferase I and UDP-N-acetylglucosamine:α-D-mannoside β-1,2-N-acetylgluco

摘要

The GlcNAcβ1,2Manα- moiety can be synthesized by at least two mammalian glycosyltransferases, UDP-GlcNAc:α-3-D-mannoside β-1,2-N-acetylglucosaminyltransferase I (GnT I, EC 2.4.1.101) and UDP-GlcNAc:α-D-mannoside β-1,2-N-acetylglucosaminyltransferase I.2 (GnT I.2). GnT I adds a GlcNAc residue in β-1,2 glycosidic linkage to the Manα1,3 arm of the N-glycan core to initiate the biosynthesis of hybrid and complex N-glycans. GnT I.2 can add (GlcNAc in β1,2 linkage to any α-linked terminal Man residue but has a strong preference for the Manα1-O-Thr- moiety which occurs in α-dystroglycan and other O-mannosylated glycoproteins. Mouse embryos lacking a functional GnT I gene (MgatI) were unable to synthesize complex N-glycans and none survived past 10.5 days after fertilization. The embryos showed multisystemic defects in various morphogenic processes such as neural tube formation, vascularization and the determination of left-right body plan asymmetry. Six human patients with muscle-eye-brain disease (MEB) were recently shown to have point mutations in the gene encoding GnT I.2 (MGATI.2). MEB is an autosomal recessive disease characterized by congenital muscular dystrophy, ocular abnormalities, brain malformations and other multisystemic defects. Both the MGATI.2 gene and MEB disease have been mapped to chromosome 1p32-p34. At least one of the biochemical sites affected by the MGATI.2 mutations is probably the interaction between laminin in the extracellular matrix and the peripheral membrane glycoprotein α-dystroglycan since this interaction is believed to require the presence of the sialylα2,3Galβ1,4GlcNAcβ1,2Manα1-O-Ser/Thr moiety on α-dystroglycan. It can be concluded that the GlcNAcβ1,2Manα- moiety is important for mammalian development due to an essential role in two distinct biochemical pathways.