title: Modeling a congenital disorder of glycosylation type I in C. elegans: a genome-wide RNAi screen for N-glycosylation-dependent loci.
abstract: Inefficient glycosylation caused by defective synthesis of lipid-linked oligosaccharide donor results in multi-systemic syndromes known as congenital disorders of glycosylation type I (CDG-I). Strong loss of function mutations are embryonic lethal, patients with partial losses of function are occasionally born but are very ill, presenting with defects in virtually every tissue. CDG-I clinical expression varies considerably and ranges from very mild to severe, and the underlying cause of the variable clinical features is not yet understood. We postulate that accompanying defects in an individual's genetic background enhance the severity of CDG-I clinical phenotypes. Since so many protein structures and functions are compromised in CDG-I illnesses, the gene products that are dependent on N-linked glycosylation which cause lethality or particular symptoms are difficult to resolve. The power of genetic silencing that is a characteristic of C. elegans has allowed us to systematically dissect the complex glycosylation phenotype observed in CDG-I patients into specific glycan-dependent gene products. To accomplish this, we inhibited glycosylation with a sub-phenotypic dose of tunicamycin, reduced single genes by RNA interference, and then sought loci where the combination caused a synthetic or dramatically enhanced phenotype. This screen has identified genes in C. elegans that require N-linked glycans to function properly as well as candidate gene homologues that may enhance the clinical severity of CDG-I disorders in humans.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of New Hampshire, Durham, NH 03824, USA. weston.struwe@nibrt.ie
authors.forename: Weston B
authors.initials: WB
authors.lastname: Struwe
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Hughes
authors.forename: David W
authors.initials: DW
authors.lastname: Osborn
authors.forename: Erica D
authors.initials: ED
authors.lastname: Boudreau
authors.forename: Kristin M D
authors.initials: KM
authors.lastname: Shaw
authors.forename: Charles E
authors.initials: CE
authors.lastname: Warren
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology*; D002874:Chromosome Mapping / Q000379:methods*; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics; D056426:Genetic Loci; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D010641:Phenotype; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D034741:RNA, Small Interfering; D014415:Tunicamycin