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-acetylglucosaminyltransferase I.2 cause embryonic lethality and congenital muscular dystrophy in mice and men, respectively

The GlcNAcbeta1,2Manalpha moiety can be synthesized by at least two mammalian glycosyltransferases, UDP-GlcNAc:alpha-3-D-mannoside beta1,2-N-acetylglucosaminyltransferase I (GnT 1, EC 2.4.1.101) and UDP-GIcNAc:alpha-D-mannoside 1,2-N-acetylglucosaminyltransferase 1.2 (GnT 1.2). GnT I adds a GlcNAc residue in beta1,2 glycosidic linkage to the Manalpha,3 arm of the N-glycan core to initiate the biosynthesis of hybrid and complex N-glycans. GnT 1.2 can add GlcNAc in beta1,2 linkage to any alpha-linked terminal Man residue but has a strong preference for the Manalpha1-O-Thr- moiety which occurs in alpha-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 1.2 (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 alpha-dystroglycan since this interaction is believed to require the presence of the sialylalpha2,3 Galbeta1,4GIcNAcbeta1,2Manalpha1-O-Ser/Thr moiety on alpha-dystroglycan. It can be concluded that the GIcNAcbeta1,2Manalpha moiety is important for mammalian development due to an essential role in two distinct biochemical pathways. (C) 2002 Elsevier Science B.V. All rights reserved.