Genome-wide analysis of the unfolded protein response in fibroblasts from congenital disorders of glycosylation type-I patients.

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.