Timal, Sharita and Hoischen, Alexander and Lehle, Ludwig and Adamowicz, Maciej and Huijben, Karin and Sykut-Cegielska, Jolanta and Paprocka, Justyna and Jamroz, Ewa and van Spronsen, Francjan J. and Koerner, Christian and Gilissen, Christian and Rodenburg, Richard J. and Eidhof, Ilse and Van den Heuvel, Lambert and Thiel, Christian and Wevers, Ron A. and Morava, Eva and Veltman, Joris and Lefeber, Dirk J. (2012) Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. HUMAN MOLECULAR GENETICS, 21 (19). pp. 4151-4161. ISSN 0964-6906,
Full text not available from this repository. (Request a copy)Abstract
Congenital disorders of glycosylation type I (CDG-I) form a growing group of recessive neurometabolic diseases. Identification of disease genes is compromised by the enormous heterogeneity in clinical symptoms and the large number of potential genes involved. Until now, gene identification included the sequential application of biochemical methods in blood samples and fibroblasts. In genetically unsolved cases, homozygosity mapping has been applied in consanguineous families. Altogether, this time-consuming diagnostic strategy led to the identification of defects in 17 different CDG-I genes. Here, we applied whole-exome sequencing (WES) in combination with the knowledge of the protein N-glycosylation pathway for gene identification in our remaining group of six unsolved CDG-I patients from unrelated non-consanguineous families. Exome variants were prioritized based on a list of 76 potential CDG-I candidate genes, leading to the rapid identification of one known and two novel CDG-I gene defects. These included the first X-linked CDG-I due to a de novo mutation in ALG13, and compound heterozygous mutations in DPAGT1, together the first two steps in dolichol-PP-glycan assembly, and mutations in PGM1 in two cases, involved in nucleotide sugar biosynthesis. The pathogenicity of the mutations was confirmed by showing the deficient activity of the corresponding enzymes in patient fibroblasts. Combined with these results, the gene defect has been identified in 98% of our CDG-I patients. Our results implicate the potential of WES to unravel disease genes in the CDG-I in newly diagnosed singleton families.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DOLICHOL; DEFICIENCY; MUTATIONS; TRANSFERASE; YEAST; BIOSYNTHESIS; ENZYMES; STEPS; SERUM; CDG; |
| Subjects: | 500 Science > 580 Botanical sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Pflanzenwissenschaften > Lehrstuhl für Zellbiologie und Pflanzenphysiologie (Prof. Dr. Klaus Grasser) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 May 2020 05:52 |
| Last Modified: | 05 May 2020 05:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18014 |
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