COG8 deficiency causes new congenital disorder of glycosylation type IIh.
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.
Kranz
Christian
C
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Ng
Bobby G
BG
Sun
Liangwu
L
Sharma
Vandana
V
Eklund
Erik A
EA
Miura
Yoshiaki
Y
Ungar
Daniel
D
Lupashin
Vladimir
V
Winkel
R Dennis
RD
Cipollo
John F
JF
Costello
Catherine E
CE
Loh
Eva
E
Hong
Wanjin
W
Freeze
Hudson H
HH
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
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