Human Molecular Genetics Advance Access published online on January 12, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddl476
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation
1 Laboratory for Molecular Diagnostics, University of Leuven, Herestraat 49, B-3000, Leuven 2 Department of Molecular Biology, Princeton University, Princeton, NJ 08544 USA, Belgium 3 Laboratory of Membrane Trafficking and VIB11, Center for Human Genetics, University of Leuven, Herestraat 49, B-3000, Leuven 4 Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1 N 1EH, UK 5 Departamento de Pediatría, Unidad de Enfermedades Mitocondriales – Enfermedades Metabólicas Hereditarias, Hospital 12 de Octubre, Avda. de Córdoba s/n, 28041, Madrid, Spain 6 Instituto de Bioquímica Clínica, Corporació Sanitària Clínic y CSIC, Barcelona, Spain 7 Laboratory of structural and functional glycobiology, UMR 8576 CNRS, University of Lille I, 59655 Villeneuve d'Ascq, France 8 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Address for correspondence: Gert Matthijs, Center for Human Genetics, University of Leuven, Herestraat 49, Leuven B-3000, Belgium. Fax: 31-16-346060 E-mail: Gert.Matthijs{at}med.kuleuven.be
Received October 16, 2006; Revised December 28, 2006; Accepted December 28, 2006
The hetero-octameric Conserved Oligomeric Golgi (COG) complex is essential for the structure/function of the Golgi apparatus through regulation of membrane trafficking. Here we describe a patient with a mild form of a Congenital Disorder of Glycosylation type II (CDG-II) that is caused by a homozygous nonsense mutation in the hCOG8 gene. This leads to a premature stop codon resulting in a truncated Cog8 subunit lacking the 76 C-terminal amino acids. Mass spectrometric analysis of the N- and O-glycan structures identified a mild sialylation deficiency. We showed that the molecular basis of this defect in N- and O-glycosylation is caused by the disruption of the Cog1-Cog8 interaction, due to the truncation. As a result, Cog1 deficiency accompanies the Cog8 deficiency, preventing assembly of the intact, stable complex and resulting in the appearance of smaller subcomplexes. Moreover, levels of ß1,4-galactosytransferase were significantly reduced. The defects in O-glycosylation could be fully restored by transfecting patient's fibroblasts with full length hemagglutinin-tagged Cog8. The Cog8 defect described here represents a novel type of CDG-II, which we propose to name it CDG-IIh or CDG caused by Cog8 deficiency (CDG-II/Cog8).
Wim Annaert and Gert Matthijs contributed equally to this work.
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