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: 6.68). 04/2007; 16(7):731-41. DOI: 10.1093/hmg/ddm028
Source: PubMed

ABSTRACT 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 CDG-IIh or CDG-II/COG8.

  • [Show abstract] [Hide abstract]
    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 · 5.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The conserved oligomeric Golgi (COG) complex co-ordinates retrograde vesicle transport within the Golgi. These vesicles maintain the distribution of glycosylation enzymes between the Golgi's cisternae, and therefore COG is intimately involved in glycosylation homeostasis. Recent years have greatly enhanced our knowledge of COG's composition, protein interactions, cellular function and most recently also its structure. The emergence of COG-dependent human glycosylation disorders gives particular relevance to these advances. The structural data have firmly placed COG in the family of multi-subunit tethering complexes that it shares with the exocyst, Dsl1 and Golgi-associated retrograde protein (GARP) complexes. Here, we review our knowledge of COG's involvement in vesicle tethering at the Golgi. In particular, we consider what this knowledge may add to our molecular understanding of vesicle tethering and how it impacts on the fine tuning of Golgi function, most notably glycosylation.
    Traffic 07/2012; 13(7). DOI:10.1111/j.1600-0854.2012.01338.x · 4.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Voltage-gated ion channels are transmembrane proteins that regulate electrical excitability in cells and are essential components of the electrically active tissues of nerves, muscle and the heart. Potassium channels are one of the largest subfamilies of voltage sensitive channels and are among the most-studied of the voltage-gated ion channels. Voltage-gated channels can be glycosylated and changes in the glycosylation pattern can affect ion channel function, leading to neurological and neuromuscular disorders and congenital disorders of glycosylation (CDG). Alterations in glycosylation can also be acquired and appear to play a role in development and aging. Recent studies have focused on the impact of glycosylation and sialylation on ion channels, particularly for voltage-gated potassium and sodium channels. The terminal step of sialylation often affects channel activation and inactivation kinetics. The presence of sialic acids on O or N-glycans can alter the gating mechanism and cause conformational changes in the voltage-sensing domains due to sialic acid's negative charges. This manuscript will provide an overview of sialic acids, potassium and sodium channel function, and the impact of sialylation on channel activation and deactivation.
    Biochemical and Biophysical Research Communications 06/2014; DOI:10.1016/j.bbrc.2014.06.067 · 2.28 Impact Factor

Full-text (2 Sources)

Available from
May 26, 2014