title: A glycogene mutation map for discovery of diseases of glycosylation.
abstract: 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.
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences lah@sund.ku.dk epb@sund.ku.dk.
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.affiliation: Wilhelm Johannsen Center for Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen N DK-2200, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Lind-Thomsen
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Hiren J
authors.initials: HJ
authors.lastname: Joshi
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Nis Borbye
authors.initials: NB
authors.lastname: Pedersen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Metabolics Genetics, Universitetsparken, Copenhagen Ø DK-2100, Denmark.
authors.forename: Christian Theil
authors.initials: CT
authors.lastname: Have
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Yun
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Shengjun
authors.initials: S
authors.lastname: Wang
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Metabolics Genetics, Universitetsparken, Copenhagen Ø DK-2100, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sparso
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Metabolics Genetics, Universitetsparken, Copenhagen Ø DK-2100, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Malene Bech
authors.initials: MB
authors.lastname: Vester-Christensen
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Katrine
authors.initials: K
authors.lastname: Schjoldager
authors.affiliation: Human Genetics Program, Sanford Children's Health Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Metabolics Genetics, Universitetsparken, Copenhagen Ø DK-2100, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Metabolics Genetics, Universitetsparken, Copenhagen Ø DK-2100, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences Architecture et Fonction des Macromolécules Biologiques, UMR 7257, Centre National de la Recherche Scientifique, Aix-Marseille Université, Marseille 13288, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Henrissat
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Ulla
authors.initials: U
authors.lastname: Mandel
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Henrik
authors.initials: H
authors.lastname: Clausen
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Wandall
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, Faculty of Health Sciences lah@sund.ku.dk epb@sund.ku.dk.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Bennett
mesh_terms: D002874:Chromosome Mapping; D018981:Congenital Disorders of Glycosylation / Q000235:genetics*; D030541:Databases, Genetic; D056726:Genetic Association Studies; D015894:Genome, Human; D042822:Genomic Instability; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics*; D006801:Humans; D058977:Molecular Sequence Annotation; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational
chemical_list: D016695:Glycosyltransferases
keywords: MAF; damaging mutations; glycogenes; nonsynonymous mutations; nsSNV