Mice with a homozygous deletion of the Mgat2 gene encoding UDP-N-acetylglucosamine:alpha-6-D-mannoside beta1,2-N-acetylglucosaminyltransferase II: a model for congenital disorder of glycosylation type IIa.

Mice homozygous for a deletion of the Mgat2 gene encoding UDP-N-acetylglucosamine:alpha-6-D-mannoside beta1,2-N-acetylglucosaminyltransferase II (GlcNAcT-II, EC 2.4.1.143) have been reported. GlcNAcT-II is essential for the synthesis of complex N-glycans. The Mgat2-null mice were studied in a comparison with the symptoms of congenital disorder of glycosylation type IIa (CDG-IIa) in humans. Mutant mouse tissues were shown to be deficient in GlcNAcT-II enzyme activity and complex N-glycan synthesis, resulting in severe gastrointestinal, hematologic and osteogenic abnormalities. All mutant mice died in early post-natal development. However, crossing the Mgat2 mutation into a distinct genetic background resulted in a low frequency of survivors exhibiting additional and novel disease signs of CDG-IIa. Analysis of N-glycan structures in the kidneys of Mgat2-null mice showed a novel bisected hybrid N-glycan structure in which the bisecting GlcNAc residue was substituted with a beta1,4-linked galactose or the Lewis(x) structure. These studies suggest that some of the functions of complex N-glycan branches are conserved in mammals and that human disease due to aberrant protein N-glycosylation may be modeled in the mouse, with the expectation in this case of gaining insights into CDG-IIa disease pathogenesis. Further analyses of the Mgat2-deficient phenotype in the mouse have been accomplished involving cells in which the Mgat2 gene is dispensable, as well as other cell lineages in which a severe defect is present. Pre-natal defects appear in a significant number of embryos, and likely reflect a limited window of time in which a future therapeutic approach might effectively operate.