A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation

Laboratory for Molecular Diagnostics, Center for Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Human Molecular Genetics (Impact Factor: 6.68). 05/2007; 16(7):717-30. DOI: 10.1093/hmg/ddl476
Source: PubMed

ABSTRACT 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 beta1,4-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).

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Available from: Bryan Winchester, Jul 08, 2015
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    • "Of these proteins, the COG complex is of considerable interest because of its association with a group of inherited autosomal recessive human diseases called congenital disorders of glycosylation (CDG). Mutations of the COG complex subunits 1, 4, 5, 6, 7 and 8 cause CDGs in humans (Wu et al. 2004; Spaapen et al. 2005; Foulquier et al. 2006, 2007; Kranz et al. 2007; Paesold-Burda et al. 2009; Reynders et al. 2009; Lubbehusen et al.). The severity of the disease varies and symptoms that include mental retardation, perinatal asphyxia, acute encephalopathy, alternating esotropia, pseudoptosis, hypotonia, hepatosplenomegaly, ventricular hypertrophy, growth retardation, progressive microcephaly, epileptic seizures and failure to thrive. "
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    ABSTRACT: The conserved oligomeric Golgi complex (COG) is a hetero-octomeric peripheral membrane protein required for retrograde vesicular transport and glycoconjugate biosynthesis within the Golgi. Mutations in subunits 1, 4, 5, 6, 7 and 8 are the basis for a rare inheritable human disease termed congenital disorders of glycosylation type-II. Defects to COG complex function result in aberrant glycosylation, protein trafficking and Golgi structure. The cellular function of the COG complex and its role in protein glycosylation are not completely understood. In this study, we report the first detailed structural analysis of N-glycans from a COG complex-deficient organism. We employed sequential ion trap mass spectrometry of permethylated N-glycans to demonstrate that the COG complex is essential for the formation of fucose-rich N-glycans, specifically antennae fucosylated structures in Caenorhabditis elegans. Our results support the supposition that disruption to the COG complex interferes with normal protein glycosylation in the medial and/or trans-Golgi.
    Glycobiology 02/2012; 22(6):863-75. DOI:10.1093/glycob/cws053 · 3.75 Impact Factor
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    • "Results COG complex depletions alter the N-linked glycosylation of plasma membrane-localized glycoconjugates Recently published characterization of human fibroblasts obtained from patients with CDG-II that are deficient for the COG complex subunits demonstrated that the plasma membrane of these mutant cells is positively stained with fluorescently labeled PNA (Foulquier et al. 2006, 2007). The PNA binds specifically to terminal galactosyl residues (Lotan et al. 1975) and therefore PNA-positive staining indicates that there is an increase in the amount of terminal galactoses in plasma membrane O-linked glycoconjugates in COG-deficient cells. "
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    ABSTRACT: Cell surface lectin staining, examination of Golgi glycosyltransferases stability and localization, and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis were employed to investigate conserved oligomeric Golgi (COG)-dependent glycosylation defects in HeLa cells. Both Griffonia simplicifolia lectin-II and Galanthus nivalus lectins were specifically bound to the plasma membrane glycoconjugates of COG-depleted cells, indicating defects in activity of medial- and trans-Golgi-localized enzymes. In response to siRNA-induced depletion of COG complex subunits, several key components of Golgi glycosylation machinery, including MAN2A1, MGAT1, B4GALT1 and ST6GAL1, were severely mislocalized. MALDI-TOF analysis of total N-linked glycoconjugates indicated a decrease in the relative amount of sialylated glycans in both COG3 KD and COG4 KD cells. In agreement to a proposed role of the COG complex in retrograde membrane trafficking, all types of COG-depleted HeLa cells were deficient in the Brefeldin A- and Sar1 DN-induced redistribution of Golgi resident glycosyltransferases to the endoplasmic reticulum. The retrograde trafficking of medial- and trans-Golgi-localized glycosylation enzymes was affected to a larger extent, strongly indicating that the COG complex regulates the intra-Golgi protein movement. COG complex-deficient cells were not defective in Golgi re-assembly after the Brefeldin A washout, confirming specificity in the retrograde trafficking block. The lobe B COG subcomplex subunits COG6 and COG8 were localized on trafficking intermediates that carry Golgi glycosyltransferases, indicating that the COG complex is directly involved in trafficking and maintenance of Golgi glycosylation machinery.
    Glycobiology 03/2011; 21(12):1554-69. DOI:10.1093/glycob/cwr028 · 3.75 Impact Factor
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    • "Further support for COG being involved in retrograde membrane trafficking of Golgi resident proteins is provided by data showing that mutations in COG subunits lead in humans to congenital disorders of glycosylation (CDG Type II)[3] [37] [38] [39] [40] [41] [42] [43] [44] [45]. Mutations in COG subunits severely alter the localization and function of Golgi glycosylation machinery [1] [13] [37] [39] [46] [47] [48], resulting in defects in the processing of N-linked glycan chains (for review, see [49]). "
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    ABSTRACT: Tethers are a diverse group of loosely related proteins and protein complexes grouped into three families based on structural and functional similarities. A well-accepted role for tethering factors is the initial attachment of transport carriers to acceptor membranes prior to fusion. However, accumulating evidence indicates that tethers are more than static bridges. Tethers have been shown to interact with components of the fusion machinery and with components involved in vesicle formation. Tethers belonging to the three families act at the same stage of traffic, suggesting that they mediate distinct events during vesicle tethering. Thus, multiple tether-facilitated events are required to provide selectivity to vesicle fusion. In this review, we highlight findings that support this model.
    FEBS letters 11/2009; 583(23):3770-83. DOI:10.1016/j.febslet.2009.10.083 · 3.34 Impact Factor