title: COG8 deficiency causes new congenital disorder of glycosylation type IIh.
abstract: We describe a new Type II congenital disorder of glycosylation (CDG-II) caused by mutations in the conserved oligomeric Golgi (COG) complex gene, COG8. The patient has severe psychomotor retardation, seizures, failure to thrive and intolerance to wheat and dairy products. Analysis of serum transferrin and total serum N-glycans showed normal addition of one sialic acid, but severe deficiency in subsequent sialylation of mostly normal N-glycans. Patient fibroblasts were deficient in sialylation of both N- and O-glycans, and also showed slower brefeldin A (BFA)-induced disruption of the Golgi matrix, reminiscent of COG7-deficient cells. Patient fibroblasts completely lacked COG8 protein and had reduced levels and/or mislocalization of several other COG proteins. The patient had two COG8 mutations which severely truncated the protein and destabilized the COG complex. The first, IVS3 + 1G > A, altered the conserved splicing site of intron 3, and the second deleted two nucleotides (1687-1688 del TT) in exon 5, truncating the last 47 amino acids. Lentiviral-mediated complementation with normal COG8 corrected mislocalization of other COG proteins, normalized sialylation and restored normal BFA-induced Golgi disruption. We propose to call this new disorder CDG-IIh or CDG-II/COG8.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Kranz
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.forename: Liangwu
authors.initials: L
authors.lastname: Sun
authors.forename: Vandana
authors.initials: V
authors.lastname: Sharma
authors.forename: Erik A
authors.initials: EA
authors.lastname: Eklund
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miura
authors.forename: Daniel
authors.initials: D
authors.lastname: Ungar
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lupashin
authors.forename: R Dennis
authors.initials: RD
authors.lastname: Winkel
authors.forename: John F
authors.initials: JF
authors.lastname: Cipollo
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
authors.forename: Eva
authors.initials: E
authors.lastname: Loh
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002648:Child; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D000077614:Golgi Matrix Proteins; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C522290:COG8 protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D011134:Polysaccharides; D014168:Transferrin; C087574:macrogolgin; D020126:Brefeldin A