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Genome‐wide analysis of the unfolded protein response in fibroblasts from congenital disorders of glycosylation type‐I patients
Author(s) -
Rita Lecca M.,
Wagner Ulrich,
Patrignani Andrea,
Berger Eric G.,
Hennet Thierry
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2397fje
Subject(s) - tunicamycin , unfolded protein response , glycosylation , endoplasmic reticulum , gene , glycoprotein , transcriptome , n linked glycosylation , biology , microbiology and biotechnology , integrated stress response , gene expression , biochemistry , translation (biology) , messenger rna , glycan
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.