title: Modeling human congenital disorder of glycosylation type IIa in the mouse: conservation of asparagine-linked glycan-dependent functions in mammalian physiology and insights into disease pathogenesis.
abstract: The congenital disorders of glycosylation (CDGs) are recent additions to the repertoire of inherited human genetic diseases. Frequency of CDGs is unknown since most cases are believed to be misdiagnosed or unrecognized. With few patients identified and heterogeneity in disease signs noted, studies of animal models may provide increased understanding of pathogenic mechanisms. However, features of mammalian glycan biosynthesis and species-specific variations in glycan repertoires have cast doubt on whether animal models of human genetic defects in protein glycosylation will reproduce pathogenic events and disease signs. We have introduced a mutation into the mouse germline that recapitulates the glycan biosynthetic defect responsible for human CDG type IIa (CDG-IIa). Mice lacking the Mgat2 gene were deficient in GlcNAcT-II glycosyltransferase activity and complex N-glycans, resulting in severe gastrointestinal, hematologic, and osteogenic abnormalities. With use of a lectin-based diagnostic screen for CDG-IIa, we found that all Mgat2-null mice died in early postnatal development. However, crossing the Mgat2 mutation into a distinct genetic background resulted in a low frequency of survivors. Mice deficient in complex N-glycans exhibited most CDG-IIa disease signs; however, some signs were unique to the aged mouse or are prognostic in human CDG-IIa. Unexpectedly, analyses of N-glycan structures in Mgat2-null mice revealed a novel oligosaccharide branch on the "bisecting" N-acetylglucosamine. These genetic, biochemical, and physiologic studies indicate conserved functions for N-glycan branches produced in the Golgi apparatus among two mammalian species and suggest possible therapeutic approaches to GlcNAcT-II deficiency. Our findings indicate that human genetic disease due to aberrant protein glycosylation can be modeled in the mouse to gain insights into N-glycan-dependent physiology and the pathogenesis of CDG-IIa.
authors.affiliation: Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, Glycobiology Research and Training Center, 9500 Gilman Drive-0625, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.forename: M
authors.initials: M
authors.lastname: Sutton-Smith
authors.forename: D
authors.initials: D
authors.lastname: Ditto
authors.forename: M
authors.initials: M
authors.lastname: Panico
authors.forename: R M
authors.initials: RM
authors.lastname: Campbell
authors.forename: N M
authors.initials: NM
authors.lastname: Varki
authors.forename: J M
authors.initials: JM
authors.lastname: Long
authors.forename: J
authors.initials: J
authors.lastname: Jaeken
authors.forename: S R
authors.initials: SR
authors.lastname: Levinson
authors.forename: A
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: H R
authors.initials: HR
authors.lastname: Morris
authors.forename: D
authors.initials: D
authors.lastname: Le
authors.forename: A
authors.initials: A
authors.lastname: Dell
authors.forename: H
authors.initials: H
authors.lastname: Schachter
authors.forename: J D
authors.initials: JD
authors.lastname: Marth
mesh_terms: D000015:Abnormalities, Multiple / Q000209:etiology; D000818:Animals; D001216:Asparagine / Q000737:chemistry / Q000378:metabolism*; D001851:Bone Diseases, Metabolic / Q000209:etiology; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000209:etiology / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity; D013737:Testis / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D011134:Polysaccharides; D001216:Asparagine; D017351:N-Acetylglucosaminyltransferases