Key features and clinical variability of COG6-CDG

Rymen, Daisy; Winter, Peter de; Hasselt, Peter M. van; Jaeken, Jaak; Kasapkara, Çiğdem Seher; Gökçay, Gülden; Haijes, Hanneke A.; Goyens, Philippe; Tokatlı, Ayşegül; Thiel, Christian; Bartsch, Oliver; Hecht, Jochen; Krawitz, Peter; Prinsen, Hubertus C.M.T.; Mildenberger, Eva; Matthijs, Gert; Kornak, Uwe

doi:10.1016/j.ymgme.2015.07.003

Cited by 49 publications

(83 citation statements)

References 24 publications

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“…78 COG6 is part of the conserved oligomeric Golgi complex, and mutations in this gene have been described in individuals with congenital disorders of glycosylation; core clinical features include recurrent infections and hyperkeratosis. 79 These observations suggest that COG6 might play a role in immune-cell function; studies that address this possibility are warranted.…”

Section: Discussionmentioning

confidence: 99%

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

Ferreira

Mathur

Vonk

et al. 2019

The American Journal of Human Genetics

201

240

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The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n ¼ 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h 2 g ¼ 25.6%) than for AOA (onset at ages between 20 and 60 years; h 2 g ¼ 10.6%). The genetic correlation (r g ) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h 2 g ¼ 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n ¼ 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA-than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n ¼ 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.

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Section: Discussionmentioning

confidence: 99%

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

Ferreira

Mathur

Vonk

et al. 2019

The American Journal of Human Genetics

201

240

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“…N-glycan mass spectrometry (MS) analysis confirmed hyposialylation of N-glycans, similar to CHO-COG mutants and COG-CDG patients (discussed in the next section). Fly COG mutants also displayed increased high-mannose, paucimannose, and Humans, COG4-CDG COG4 (R729W), COG4 (G516R) Cells: reduction in COG3 (50%), COG2 (40%), COG1 (25%), and COG5 (40%) protein levels, COG complex formation seemed to be unaffected, mild Golgi dysfunction (compared to COG7 or COG8-CDG), Golgi dilatation and fragmentationPatients: Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features [102,115] Humans, COG5-CDG COG5 (homozygous intronic substitution (c.1669-15T>C) leading to exon skipping) Cells: undersialylation of N-and O-glycansPatients: moderate psychomotor retardation with language delay, truncal ataxia and slight hypotonia [110,166,174,175] Humans, COG6-CDG COG6 (G549V) Cells: reduction in STX6 levels, glycosylation defects including reduced sialyation of O-glycans; decreased activity of B4GALT1 but normal import of UDP-galactose into the Golgi, reduced protein levels of COG5 (55%), COG6 (21%), and COG7 (62%), degradation of mRNA encoding COG6, formation of the COG complex affectedPatients: microcephaly, chronic inflammatory bowel disease, micronodular liver cirrhosis, severe neurologic disease characterized by vitamin K deficiency, vomiting, intractable focal seizures, intracranial bleedings and fatal outcome in early infancy [176][177][178][179] Humans, COG7-CDG COG7 (intronic splice site mutation (c.169+4A>C)) Cells: disruption of multiple N-and O-glycosylation pathways, completely destabilized COG complexPatients: growth retardation, microcephaly, hypotonia, adducted thumbs, feeding problems, failure to thrive, cardiac anomalies, wrinkled skin and episodes of extreme hyperthermia, skeletal anomalies and a mild liver involvement [96,101,173,180] Humans, COG8-CDG COG8 Cells: deficient in sialylation of both N-and O-glycans, slower brefeldin A induced disruption of the Golgi matrix, reduction in COG1, COG5, COG6, and COG7 protein levels but not COG2, COG3 and COG4, COG5, COG6, and COG7 were also mislocalizedPatients: cerebellar atrophy, Elevated blood creatine phosphokinase, Alternating esotropia, psychomotor retardation, failure to thrive, intolerance to wheat and dairy products, lack of bowel or bladder control, dry skin with keratosis pilaris, mild contractures of the lower extremities [99,100,103,107,108] Humans, TMED6-COG8 translocation…”

Section: Misglycosylationmentioning

confidence: 99%

Maintaining order: COG complex controls Golgi trafficking, processing, and sorting

2019

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The conserved oligomeric Golgi (COG) complex, a multisubunit tethering complex of the CATCHR (complexes associated with tethering containing helical rods) family, controls membrane trafficking and ensures Golgi homeostasis by orchestrating retrograde vesicle targeting within the Golgi. In humans, COG defects lead to severe multisystemic diseases known as COG‐congenital disorders of glycosylation (COG‐CDG). The COG complex both physically and functionally interacts with all classes of molecules maintaining intra‐Golgi trafficking, namely SNAREs, SNARE‐interacting proteins, Rabs, coiled‐coil tethers, and vesicular coats. Here, we review our current knowledge of COG‐related trafficking and glycosylation defects in humans and model organisms, and analyze possible scenarios for the molecular mechanism of the COG orchestrated vesicle targeting.

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“…The COG complex is composed of eight subunits partitioned in lobe A (including COG1–COG4) and lobe B (COG5–COG8). A total of 33 patients have been reported with defects in each subunit except COG3 . Patients present with multisystem involvement with predominant neurological morbidity.…”

Section: Introductionmentioning

confidence: 99%

“…A total of 33 patients have been reported with defects in each subunit except COG3. [6] Patients present with multisystem involvement with predominant neurological morbidity. The clinical spectrum ranges from very severe phenotypes with early lethality (as in COG6-CDG and in COG7-CDG) to moderate/mild expression.…”

Section: Introductionmentioning

confidence: 99%

MALDI‐MS profiling of serum O‐glycosylation and N‐glycosylation in COG5‐CDG

et al. 2017

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Congenital disorders of glycosylation (CDG) are due to defective glycosylation of glycoconjugates. Conserved oligomeric Golgi (COG)-CDG are genetic diseases due to defects of the COG complex subunits 1-8 causing N-glycan and O-glycan processing abnormalities. In COG-CDG, isoelectric focusing separation of undersialylated glycoforms of serum transferrin and apolipoprotein C-III (apoC-III) allows to detect N-glycosylation and O-glycosylation defects, respectively. COG5-CDG (COG5 subunit deficiency) is a multisystem disease with dysmorphic features, intellectual disability of variable degree, seizures, acquired microcephaly, sensory defects and autistic behavior. We applied matrix-assisted laser desorption/ionization-MS for a high-throughput screening of differential serum O-glycoform and N-glycoform in five patients with COG5-CDG. When compared with age-matched controls, COG5-CDG showed a significant increase of apoC-III (aglycosylated glycoform), whereas apoC-III (mono-sialylated glycoform) decreased significantly. Serum N-glycome of COG5-CDG patients was characterized by the relative abundance of undersialylated and undergalactosylated biantennary and triantennary glycans as well as slight increase of high-mannose structures and hybrid glycans. Using advanced and well-established MS-based approaches, the present findings reveal novel aspects on O-glycan and N-glycan profiling in COG5-CDG patients, thus providing an increase of current knowledge on glycosylation defects caused by impairment of COG subunits, in support of clinical diagnosis. Copyright © 2017 John Wiley & Sons, Ltd.

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Key features and clinical variability of COG6-CDG

Cited by 49 publications

References 24 publications

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

Maintaining order: COG complex controls Golgi trafficking, processing, and sorting

MALDI‐MS profiling of serum O‐glycosylation and N‐glycosylation in COG5‐CDG

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