Human Molecular Genetics Advance Access originally published online on January 12, 2007
Human Molecular Genetics 2007 16(7):717-730; doi:10.1093/hmg/ddl476
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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 and 2 Laboratory of Membrane Trafficking and VIB11, Center for Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium, 3 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA, 4 Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 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, 08028, Barcelona, Spain, 7 Laboratory of Structural and Functional Glycobiology, UMR 8576 CNRS, University of Lille I, 59655 Villeneuve d'Ascq, France and 8 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
* To whom correspondence should be addressed at: Fax: +32 3116346060; Email: gert.matthijs{at}med.kuleuven.be
Received October 16, 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), which 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 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 the patient's fibroblasts with full-length Cog8. The Cog8 defect described here represents a novel type of CDG-II, which we propose to name as CDG-IIh or CDG caused by Cog8 deficiency (CDG-II/Cog8).
These authors contributed equally to this work.
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