title: Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man.
abstract: Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
authors.forename: Adriaan G
authors.initials: AG
authors.lastname: Holleboom
authors.forename: Helen
authors.initials: H
authors.lastname: Karlsson
authors.forename: Ruei-Shiuan
authors.initials: RS
authors.lastname: Lin
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Beres
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Sierts
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Herman
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Motazacker
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: Johannes H M
authors.initials: JH
authors.lastname: Levels
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Stefan
authors.initials: S
authors.lastname: Ljunggren
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Fritz
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Tabak
authors.forename: Mats
authors.initials: M
authors.lastname: Lindahl
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
mesh_terms: D000328:Adult; D000368:Aged; D053305:Apolipoprotein C-III / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006031:Glycosylation; D006579:Heterozygote; D006801:Humans; D008049:Lipase / Q000097:blood*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D019518:Postprandial Period / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D053305:Apolipoprotein C-III; D002784:Cholesterol; D008049:Lipase; D008071:Lipoprotein Lipase; D017350:N-Acetylgalactosaminyltransferases; D010455:Peptides; D000097763:Polypeptide N-acetylgalactosaminyltransferase