title: Human disorders in N-glycosylation and animal models.
abstract: Genes that cause human disorders in N-linked oligosaccharide biosynthesis have appeared much faster than animal model systems to study them. In most models, a single gene is altered or deleted while other genes and the environment are held constant. Since humans have variable genetic backgrounds and environments, model systems may only partially mimic the actual disorders. Mutations in seven of the 30-40 genes needed for the synthesis and transfer of oligosaccharides from the lipid donor to the nascent protein acceptors in the endoplasmic reticulum cause Type I Congenital Disorders of Glycosylation (CDG). Since all of these gene products ultimately contribute to the same final step, one might suspect that all the diseases would be very similar. However, even patients with mutations in the same gene show considerable phenotypic variability. Modifier, or susceptibility genes in the background likely explain some variations of the "primary" gene chosen for study. Add to this the stress of infections, dietary insufficiencies, and the demands of growth itself. These issues are particularly important during development when the temporal and spatial specific interplay of cell adhesions and signals has only a single opportunity. Multiple hypomorphic alleles of genes in the same pathway may have synergistic effects. Investigators designing model systems to study human glycosylation disorders may want to construct strains with several heterozygous hypomorphic alleles in rate-limiting steps in the glycosylation pathway.
authors.affiliation: Glycobiology and Carbohydrate Chemistry Program, The Burnham Institute, La Jolla, CA 92037, USA. hudson@burnham.org
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
mesh_terms: D000818:Animals; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D023421:Models, Animal; D009844:Oligosaccharides / Q000096:biosynthesis
chemical_list: D009844:Oligosaccharides