TY - JOUR

T1 - A glycogene mutation map for discovery of diseases of glycosylation

AU - Hansen, Lars

AU - Lind-Thomsen, Allan

AU - Joshi, Hiren J

AU - Pedersen, Nis Borbye

AU - Have, Christian Theil

AU - Kong, Yun

AU - Wang, Shengjun

AU - Sparso, Thomas

AU - Grarup, Niels

AU - Vester-Christensen, Malene Bech

AU - Schjoldager, Katrine

AU - Freeze, Hudson H

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Henrissat, Bernard

AU - Mandel, Ulla

AU - Clausen, Henrik

AU - Wandall, Hans H

AU - Bennett, Eric P

N1 - © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1093/glycob/cwu104

DO - 10.1093/glycob/cwu104

M3 - Journal article

C2 - 25267602

VL - 25

SP - 211

EP - 224

JO - Glycobiology

JF - Glycobiology

SN - 0959-6658

IS - 2

ER -