A new enborn error of glycosylation due to a COG8 deficiency reveals a critical role for the COG1-COG8 interaction in COG complex formation

Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States
Human Molecular Genetics (Impact Factor: 6.39). 05/2007; 16(7):717-30. DOI: 10.1093/hmg/ddl476
Source: PubMed


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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    • "The first described COG-related CDG was due to mutations in COG7 and entailed a severe phenotype with early lethality [4]. Subsequently, also defects in COG1, -2, -4, -5, -6, and -8 have been identified in patients with a type 2 pattern upon IEF of serum transferrin [5] [6] [7] [8] [9]. Only 3 families with COG6-deficient patients have been described so far [10] [11] [12]. "
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    ABSTRACT: The conserved oligomeric Golgi (COG) complex consists of eight subunits and plays a crucial role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been detected in patients with congenital disorders of glycosylation (CDG) of variable severity. So far, 3 families with a total of 10 individuals with biallelic COG6 mutations have been described, showing a broad clinical spectrum. Here we present 7 additional patients with 4 novel COG6 mutations. In spite of clinical variability, we delineate the core features of COG6-CDG i.e. liver involvement (9/10), microcephaly (8/10), developmental disability (8/10), recurrent infections (7/10), early lethality (6/10), and hypohidrosis predisposing for hyperthermia (6/10) and hyperkeratosis (4/10) as ectodermal signs. Regarding all COG6-related disorders a genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal CDG phenotypes. A comparison with other COG deficiencies suggests ectodermal changes to be a hallmark of COG6-related disorders. Our findings aid clinical differentiation of this complex group of disorders and imply subtle functional differences between the COG complex subunits. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Molecular Genetics and Metabolism
    • "This fine balance is required for the correct localization and distribution of the glycosylation enzymes in the Golgi (Reynders et al., 2011). The functional importance of the COG complex in human is underscored by the identification of mutations in six out of the eight subunits (COG1, COG4, COG5, COG6, COG7 and COG8) in patients with the human disease congenital disorder of glycosylation (CDG) type II (Foulquier et al., 2007; Foulquier et al., 2006; Freeze and Ng, 2011; Kranz et al., 2007; Kudlyk et al., 2013; Ng et al., 2011; Spaapen et al., 2005; Wu et al., 2004; Zeevaert et al., 2008). The patients are characterized by abnormal glycosylation, although the clinical presentations are highly heterogeneous. "
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    ABSTRACT: Searching and evaluating the Human Protein Atlas for transmembrane proteins enabled us to identify an integral membrane protein, TMEM115 that is enriched in the Golgi apparatus. Biochemical and cell biological analysis suggests that TMEM115 has 4 candidate transmembrane domains located at the N-terminal region. Both the N- and C-terminal domains are oriented towards the cytoplasm. Immunofluoresence analysis supports that TMEM115 is enriched in the Golgi cisternae. Functionally, TMEM115 knockdown or overexpression delays Brefeldin-A induced Golgi-to-ER retrograde transport, phenocopying cells with mutations or silencing of the COG complex. Co-immunoprecipitation and in vitro binding experiments reveals that TMEM115 interacts with COG complex, and may self-interact to form dimers or oligomers. A short region (residues 206-229) immediately to the C-terminal side of the 4(th) transmembrane domain is both necessary and sufficient for Golgi targeting. Knockdown of TMEM115 also reduces the binding of lectins PNA and HPA, suggesting an altered O-linked glycosylation profile. These results establish that TMEM115 is a novel integral membrane protein of the Golgi stack regulating Golgi-ER retrograde transport and is likely part of the machinery of the COG complex.
    No preview · Article · May 2014 · Journal of Cell Science
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    • "COG is an octameric complex, composed of two “lobes” (A and B) of four subunits each, connected to varying degrees in yeast and mammalian cells through the Cog1 and Cog8 subunits [87,88]. The main function of COG is to maintain proper glycosylation of proteins in the Golgi stack, through the continuous retrograde transport of relevant enzymes from endosomes to the TGN and within the Golgi itself [87,88]. In our comparative genomic analysis we found that subunit distribution was sparse. "
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    ABSTRACT: Apicomplexa are obligate intracellular parasites that cause tremendous disease burden world-wide. They utilize a set of specialized secretory organelles in their invasive process that require delivery of components for their biogenesis and function, yet the precise mechanisms underpinning such processes remain unclear. One set of potentially important components is the multi-subunit tethering complexes (MTCs), factors increasingly implicated in all aspects of vesicle-target interactions. Prompted by the results of previous studies indicating a loss of membrane trafficking factors in Apicomplexa, we undertook a bioinformatic analysis of MTC conservation. Building on knowledge of the ancient presence of most MTC proteins, we demonstrate the near complete retention of MTCs in the newly available genomes for Guillardiatheta and Bigelowiellanatans. The latter is a key taxonomic sampling point as a basal sister taxa to the group including Apicomplexa. We also demonstrate an ancient origin of the CORVET complex subunits Vps8 and Vps3, as well as the TRAPPII subunit Tca17. Having established that the lineage leading to Apicomplexa did at one point possess the complete eukaryotic complement of MTC components, we undertook a deeper taxonomic investigation in twelve apicomplexan genomes. We observed excellent conservation of the VpsC core of the HOPS and CORVET complexes, as well as the core TRAPP subunits, but sparse conservation of TRAPPII, COG, Dsl1, and HOPS/CORVET-specific subunits. However, those subunits that we did identify appear to be expressed with similar patterns to the fully conserved MTC proteins, suggesting that they may function as minimal complexes or with analogous partners. Strikingly, we failed to identify any subunits of the exocyst complex in all twelve apicomplexan genomes, as well as the dinoflagellate Perkinsus marinus. Overall, we demonstrate reduction of MTCs in Apicomplexa and their ancestors, consistent with modification during, and possibly pre-dating, the move from free-living marine algae to deadly human parasites.
    Full-text · Article · Sep 2013 · PLoS ONE
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