Journal
GLYCOBIOLOGY
Volume 25, Issue 2, Pages 211-224Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/glycob/cwu104
Keywords
damaging mutations; glycogenes; nonsynonymous mutations; nsSNV; MAF
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Funding
- Kirsten og Freddy Johansen Fonden
- A. P. Moller og Hustru Chastine Mc-Kinney Mollers Fond til Almene Formaal
- Carlsberg Foundation
- Novo Nordisk Foundation
- Danish Research Councils
- program of excellence from the University of Copenhagen
- Danish National Research Foundation [DNRF107]
- Rocket Fund [R01DK99551]
- Lundbeck Foundation (The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care [LuCamp])
- Danish Council for Independent Research
- NNF Center for Basic Metabolic Research [Grarup Group] Funding Source: researchfish
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Glycosylation of proteins and lipids involves over 200 known glycosyltransferases (GTs), 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 affect glycosylation globally. Many GTs 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 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, for example, GT 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 2000 Danes. We cataloged all missense mutations and used prediction algorithms, manual inspection and in case of carbohydrate-active enzymes family GT27 experimental analysis of mutations to map deleterious mutations. GlyMAP (http://glymap.glycomics.ku.dk) provides a first global view of the genetic stability of the glycogenome and should serve as a tool for discovery of novel CDGs.
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