COG8 deficiency causes new congenital disorder of glycosylation type IIh

Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Human Molecular Genetics (Impact Factor: 6.39). 04/2007; 16(7):731-41. DOI: 10.1093/hmg/ddm028
Source: PubMed


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

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    • "The effect of TMEM115 depletion on BFA-dependent Golgi disassembly is similar to the phenotype observed in cells deficient in COG proteins (Kranz et al., 2007; Steet and Kornfeld, 2006) or upon silencing COG subunits (Laufman et al., 2011; Laufman et al., 2013; Laufman et al., 2009), indicating that TMEM115 might play certain functions in COG-dependent transport pathways. Taken together, these results strongly suggest that TMEM115 functions in regulating or directly involved in the retrograde transport from the Golgi to the ER. "
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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.
    Journal of Cell Science 05/2014; 127(13). DOI:10.1242/jcs.136754 · 5.43 Impact Factor
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    • "Mutations in the genes of six different COG-subunits have been reported, i.e. COG1 and COG4 to COG8 [8-18]. The first patient with COG5-CDG was only recently published [12]. "
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    ABSTRACT: Background The Conserved Oligomeric Golgi (COG) complex is involved in the retrograde trafficking of Golgi components, thereby affecting the localization of Golgi glycosyltransferases. Deficiency of a COG-subunit leads to defective protein glycosylation, and thus Congenital Disorders of Glycosylation (CDG). Mutations in subunits 1, 4, 5, 6, 7 and 8 have been associated with CDG-II. The first patient with COG5-CDG was recently described (Paesold-Burda et al. Hum Mol Genet 2009; 18:4350–6). Contrary to most other COG-CDG cases, the patient presented a mild/moderate phenotype, i.e. moderate psychomotor retardation with language delay, truncal ataxia and slight hypotonia. Methods CDG-IIx patients from our database were screened for mutations in COG5. Clinical data were compared. Brefeldin A treatment of fibroblasts and immunoblotting experiments were performed to support the diagnosis. Results and conclusion We identified five new patients with proven COG5 deficiency. We conclude that the clinical picture is not always as mild as previously described. It rather comprises a broad spectrum with phenotypes ranging from mild to very severe. Interestingly, on a clinical basis some of the patients present a significant overlap with COG7-CDG, a finding which can probably be explained by subunit interactions at the protein level.
    Orphanet Journal of Rare Diseases 12/2012; 7(1):94. DOI:10.1186/1750-1172-7-94 · 3.36 Impact Factor
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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 · 3.15 Impact Factor
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