title: Defective protein glycosylation in patients with cutis laxa syndrome.
abstract: Congenital cutis laxa is a genetically heterogeneous condition presenting with loose and redundant skin folds, decreased elasticity of the skin, connective tissue involvement and a highly variable spectrum of associated features. The most common forms are inherited in an autosomal recessive or dominant fashion. Fibulin 5 and elastin mutations were detected in a limited number of patients, but in most cases the etiology is not known. Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, we performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome, including a recently developed test for defective O-glycosylation. Here, we describe five patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay and neurological findings. Three of these five children have an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were found in the FBLN5 gene. In conclusion, we have identified a new combined glycosylation defect with a distinct clinical phenotype. Our results suggest that a combined defect of glycosylation might be a causative factor in congenital cutis laxa. This is the first report where abnormal N- and O-linked glycosylation is implicated in the etiology of cutis laxa syndrome.
authors.affiliation: Department of Pediatrics, University Medical Centre Nijmegen, Nijmegen, The Netherlands. e.morava@cukz.umcn.nl
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Suzan
authors.initials: S
authors.lastname: Wopereis
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Jan
authors.initials: J
authors.lastname: Smeitink
authors.forename: Ron
authors.initials: R
authors.lastname: Wevers
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grünewald
mesh_terms: D001056:Apolipoproteins C / Q000378:metabolism; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D003241:Consanguinity; D003483:Cutis Laxa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D007231:Infant, Newborn; D007525:Isoelectric Focusing; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011134:Polysaccharides / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D014168:Transferrin / Q000378:metabolism
chemical_list: D001056:Apolipoproteins C; D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D011134:Polysaccharides; D011994:Recombinant Proteins; D014168:Transferrin