title: A combined defect in the biosynthesis of N- and O-glycans in patients with cutis laxa and neurological involvement: the biochemical characteristics.
abstract: Based on our preliminary observation of abnormal glycosylation in a cutis laxa patient, nine cutis laxa patients were analyzed for congenital defects of glycosylation (CDG). Isoelectric focusing of plasma transferrin and apolipoproteinC-III showed that three out of nine patients had a defect in the biosynthesis of N-glycans and core 1 mucin type O-glycans, respectively. Mass spectrometric N-glycan analyses revealed a relative increase of glycans lacking sialic acid and glycans lacking sialic acid and galactose residues. Mutation analysis of the fibulin-5 gene (FBLN5), which has been reported in cases of autosomal recessive cutis laxa, revealed no mutations in the patients' DNA. Evidence is presented that extracellular matrix (ECM) proteins of skin are likely to be highly glycosylated with N- and/or mucin type O-glycans by using algorithms for predicting glycosylation. The conclusions in this study were that the clinical phenotype of autosomal recessive cutis laxa seen in three patients is not caused by mutations in the FBLN5 gene. Our findings define a novel form of CDG with cutis laxa and neurological involvement due to a defect in the sialylation and/or galactosylation of N- and O-glycans. Improper glycosylation of ECM proteins of skin may form the pathophysiological basis for the cutis laxa phenotype.
authors.affiliation: Radboud University Nijmegen Medical Center, Laboratory of Pediatrics and Neurology, Institute of Neurology, Reinier Postlaan 4, 6525 GC Nijmegen, The Netherlands.
authors.forename: Suzan
authors.initials: S
authors.lastname: Wopereis
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grünewald
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Winchester
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Karin M L C
authors.initials: KM
authors.lastname: Huijben
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
mesh_terms: D001056:Apolipoproteins C / Q000378:metabolism; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics*; D002675:Child, Preschool; D003241:Consanguinity; D003483:Cutis Laxa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005808:Genes, Recessive; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007525:Isoelectric Focusing; D013058:Mass Spectrometry; D009422:Nervous System Diseases / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D011134:Polysaccharides / Q000096:biosynthesis* / Q000737:chemistry; D014168:Transferrin / Q000378:metabolism
chemical_list: D001056:Apolipoproteins C; D016326:Extracellular Matrix Proteins; D011134:Polysaccharides; D014168:Transferrin