title: Genome-wide analysis of the unfolded protein response in fibroblasts from congenital disorders of glycosylation type-I patients.
abstract: Congenital disorders of glycosylation (CDG) are a family of diseases characterized by defects of N-linked glycosylation. In CDG-I, several genetic defects cause a shortage of dolichol-linked oligosaccharides, which leads to underglycosylation of nascent glycoproteins. N-linked glycosylation is important for proper folding and trafficking of glycoproteins. Inhibition of glycosylation results in the buildup of misfolded proteins in the endoplasmic reticulum, which induces a protective reaction known as the unfolded protein response (UPR). To investigate whether UPR components are induced in CDG, we have performed a transcriptome analysis of primary fibroblasts from unaffected control subjects and from CDG-I patients using oligonucleotide gene expression arrays. The stress imposed by CDG was also compared with the stress induced by tunicamycin and glucose deprivation. Whereas tunicamycin elicited a strong transcriptional response typical for the UPR, CDG fibroblasts displayed a qualitatively similar yet moderate induction of genes encoding components of the UPR. Among these genes, the PERK kinase inhibitor DNAJC3/P58(IPK) gene showed the highest induction throughout all CDG-I types tested. This was paralleled by elevated expression of genes involved in amino acid biosynthesis and transport, which defined a new component of the cellular response to glycosylation stress.
authors.affiliation: Institute of Physiology, University of Zürich, Switzerland.
authors.forename: M Rita
authors.initials: MR
authors.lastname: Lecca
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wagner
authors.forename: Andrea
authors.initials: A
authors.lastname: Patrignani
authors.forename: Eric G
authors.initials: EG
authors.lastname: Berger
authors.forename: Thierry
authors.initials: T
authors.lastname: Hennet
mesh_terms: D002478:Cells, Cultured; D000013:Congenital Abnormalities / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D015894:Genome, Human; D006031:Glycosylation; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D017510:Protein Folding; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics