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| 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 |
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| Author(s): Wang Y, Tan J, Sutton-Smith M, Ditto D, Panico M, Campbell RM, Varki NM, Long JM, Jaeken J, Levinson SR, Wynshaw-Boris A, Morris HR, Le D, Dell A, Schachter H, Marth JD |
| Source: GLYCOBIOLOGY Volume: 11 Issue: 12 Pages: 1051-1070 Published: DEC 2001 |
| Times Cited: 59 References: 48 |
| 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Marth, JD (reprint author), Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, Glycobiol Res & Training Ctr, 9500 Gilman Dr 0625, La Jolla, CA 92093 USA |
Addresses:
1. Univ Calif San Diego, Howard Hughes Med Inst, Dept Cellular & Mol Med, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA
2. Univ Toronto, Dept Biochem, Toronto, ON Canada
3. Hosp Sick Children, Program Struct Biol & Biochem, Toronto, ON Canada
4. Univ London Imperial Coll Sci Technol & Med, Dept Biochem, London, England
5. Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
6. Univ Calif San Diego, Dept Med, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA
7. Univ Calif San Diego, Superfund Basic Res Ctr, La Jolla, CA 92093 USA
8. Univ Leuven, Dept Paediat, Ctr Metab Dis, Louvain, Belgium
9. Univ Colorado, Hlth Sci Ctr, Dept Cellular & Struct Biol, Denver, CO 80262 USA |
| Publisher: OXFORD UNIV PRESS INC, JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 515EQ |
| ISSN: 0959-6658 |
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