title: Abnormal cartilage development and altered N-glycosylation in Tmem165-deficient zebrafish mirrors the phenotypes associated with TMEM165-CDG.
abstract: The congenital disorders of glycosylation (CDG), a group of inherited diseases characterized by aberrant glycosylation, encompass a wide range of defects, including glycosyltransferases, glycosidases, nucleotide-sugar transporters as well as proteins involved in maintaining Golgi architecture, pH and vesicular trafficking. Mutations in a previously undescribed protein, TMEM165, were recently shown to cause a new form of CDG, termed TMEM165-CDG. TMEM165-CDG patients exhibit cartilage and bone dysplasia and altered glycosylation of serum glycoproteins. We utilized a morpholino knockdown strategy in zebrafish to investigate the physiologic and pathogenic functions of TMEM165. Inhibition of tmem165 expression in developing zebrafish embryos caused craniofacial abnormalities, largely attributable to fewer chondrocytes. Decreased expression of several markers of cartilage and bone development suggests that Tmem165 deficiency alters both chondrocyte and osteoblast differentiation. Glycomic analysis of tmem165 morphants also revealed altered initiation, processing and extension of N-glycans, paralleling some of the glycosylation changes noted in human patients. Collectively, these findings highlight the utility of zebrafish to elucidate pathogenic mechanisms associated with glycosylation disorders and suggest that the cartilage and bone dysplasia manifested in TMEM165-CDG patients may stem from abnormal development of chondrocytes and osteoblasts.
authors.affiliation: Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Riet
authors.initials: R
authors.lastname: Bammens
authors.affiliation: Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Nickita
authors.initials: N
authors.lastname: Mehta
authors.affiliation: Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Race
authors.affiliation: CNRS-UMR 8576, Structural and Functional Glycobiology Unit, IFR 147, University of Lille 1, 59655 Villeneuve d'Ascq, France.
authors.forename: François
authors.initials: F
authors.lastname: Foulquier
authors.affiliation: Center for Metabolic Disease, University Hospital Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.affiliation: Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tiemeyer
authors.affiliation: Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Steet
authors.affiliation: Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium heatherfs@ccrc.uga.edu gert.matthijs@med.kuleuven.be.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA heatherfs@ccrc.uga.edu gert.matthijs@med.kuleuven.be.
authors.forename: Heather
authors.initials: H
authors.lastname: Flanagan-Steet
mesh_terms: D000818:Animals; D017920:Antiporters; D002356:Cartilage / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology*; D027682:Cation Transport Proteins; D018981:Congenital Disorders of Glycosylation / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D006031:Glycosylation; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015027:Zebrafish / Q000378:metabolism*
chemical_list: D017920:Antiporters; D027682:Cation Transport Proteins; D008565:Membrane Proteins; C575014:TMEM165 protein, human
keywords: N-glycosylation; cartilage; congenital disorders of glycosylation; zebrafish