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Human Molecular Genetics Advance Access originally published online on March 1, 2007
Human Molecular Genetics 2007 16(7):731-741; doi:10.1093/hmg/ddm028
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

COG8 deficiency causes new congenital disorder of glycosylation type IIh

Christian Kranz1,{dagger}, Bobby G. Ng1,{dagger}, Liangwu Sun1, Vandana Sharma1, Erik A. Eklund1,{ddagger}, Yoshiaki Miura1,¶, Daniel Ungar2, Vladimir Lupashin3, R. Dennis Winkel4, John F. Cipollo5, Catherine E. Costello5, Eva Loh6, Wanjin Hong6 and Hudson H. Freeze1,*

1 Burnham Institute for Medical Research, La Jolla, CA 92037, USA, 2 Princeton University, Department of Molecular Biology, Princeton, NJ 08544, USA, 3 University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA, 4 Highland Park Professional Building, Kalispell, MT 59901, USA, 5 Boston University School of Medicine, Boston, MA 02118-2526, USA and 6 Institute of Molecular & Cell Biology, 61 Biopolis Drive, Singapore 138671, Singapore

* To whom correspondence should be addressed at: Glycobiology and Carbohydrate Chemistry Program, Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd, La Jolla, CA92037, USA. Tel: +1 8586463142; Fax: +1 8587136281; Email: hudson{at}burnham.org

Received February 9, 2007; Accepted February 12, 2007

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.

{dagger} These authors contributed equally.

{ddagger} Present address: Lund University, Department for Cell and Molecular Biology, BMC C13, 221 84 Lund, Sweden.

Present address: Hokkaido University, Sapporo, Japan.


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