A glycogene mutation map for discovery of diseases of glycosylation

Research output: Contribution to journalJournal articleResearchpeer-review

Lars Hansen, Allan Lind-Thomsen, Hiren J Joshi, Nis Borbye Pedersen, Christian Theil Have, Yun Kong, Shengjun Wang, Thomas Sparso, Niels Grarup, Malene Bech Vester-Christensen, Katrine Schjoldager, Hudson H Freeze, Torben Hansen, Oluf Pedersen, Bernard Henrissat, Ulla Mandel, Henrik Clausen, Hans H Wandall, Eric P Bennett

Glycosylation of proteins and lipids involves over 200 known glycosyltransferases, and deleterious defects in many of the genes encoding these enzymes cause disorders collectively classified as Congenital Disorders of Glycosylation (CDGs). Most known CDGs are caused by defects in glycogenes that effects glycosylation globally. Many glycosyltransferases are members of homologous isoenzyme families and deficiencies in individual isoenzymes may not affect glycosylation globally. In line with this there appears to be an underrepresentation of disease-causing glycogenes among these larger isoenzyme homologous families. However, Genome-Wide-Association Studies (GWAS) have identified such isoenzyme genes as candidates for different diseases, but validation is not straightforward without biomarkers. Large-scale whole exome sequencing (WES) provides access to mutations in e.g. glycosyltransferase genes in populations, which can be used to predict and/or analyze functional deleterious mutations. Here, we constructed a draft of a Functional Mutational Map of glycogenes, GlyMAP, from WES of a rather homogenous population of 2,000 Danes. We catalogued all missense mutations and used prediction algorithms, manual inspection, and in case of CAZy family GT27 experimental analysis of mutations to map deleterious mutations. GlyMAP provides a first global view of the genetic stability of the glycogenome and should serve as a tool for discovery of novel CDGs.

Original languageEnglish
JournalGlycobiology
Volume25
Issue number2
Pages (from-to)211-224
Number of pages14
ISSN0959-6658
DOIs
Publication statusPublished - 2015

ID: 124783749