Insights Into the Pathological Glycosylation Associated With COG6-CDG.

Zuzana Pakanová, Maroš Krchňák, Marek Nemčovič, Rebeka Kodríková, Nina Ondrušková, Hana Štufková, Mária Giertlová, Katarína Okáľová, Paula Stretavská, Slavomíra Martineková, Renáta Zemjarová Mezenská, Michaela Urminská, Martina Škopková, Andrea Andrésová, Miroslava Lysinová, Lenka Belujská, Anna Šalingová, Gábor Beke, Lucia Račková, Tomáš Honzík, Hana Hansíková, Peter Baráth

Journal: Human mutation 2025;2025():7948771

PMID: 41362306

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Abstract

BACKGROUND AND AIMS

Congenital disorders of glycosylation (CDG) are rare diseases caused by defects in protein glycosylation. We present an infant with multisystemic clinical involvement, diagnosed with COG6-CDG.

METHODS

Serum and transferrin-linked N-glycans, as well as serum and apolipoprotein CIII-linked O-glycans, were analyzed by MALDI mass spectrometry. Mutation analysis was performed by next-generation sequencing. Functional studies assessed COG6 subunit expression, cooperating subunits, and retrograde transport. GlycoWorks RapiFluor-MS-based N-glycan labeling with HPLC-FLD and ESI-Orbitrap mass spectrometry enabled further comprehensive glycoprofile analysis.

RESULTS

Aberrant glycosylation typical of combined N- and O-glycosylation defects was detected. Mutation analysis identified a novel homozygous variant in the COG6 gene: c.906_907delinsA, p.(His302GlnfsTer4), introducing a premature stop codon and producing a truncated protein of only 304 amino acids. The diagnosis of COG6-CDG was confirmed by the complete absence of the COG6 subunit, impairment of two other cooperating subunits, and delayed retrograde transport. Independent glycoprofile analyses by HPLC-FLD and ESI-Orbitrap revealed a set of potential glycobiomarkers of COG6-CDG, including underprocessed N-glycans Hex3-5HexNAc2, Hex3-5HexNAc3, Hex3-4HexNAc4, and Hex4HexNAc3-4NeuAc1.

CONCLUSION

This study describes a novel COG6 variant leading to complete loss of protein function and major glycosylation abnormalities. Multiomics analysis provided deeper insights into the molecular mechanisms of this rare disease and the function of the COG6 gene and demonstrated how the mutation results in significant alterations in the patient's (glyco)phenotype.

Address: Department of Glycobiology, Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia.; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.; Department of Neurology, Faculty of Medicine, Pavol Jozef Šafárik University, Košice, Slovakia.; Department of Clinical Neurosciences, Center of Clinical and Preclinical Research MEDIPARK, Pavol Jozef Šafárik University, Košice, Slovakia.; Ambulance of Medical Genetics, Children's Faculty Hospital and Slovak Health University, Banská Bystrica, Slovakia.; Ambulance of Medical Genetics, Unilabs Slovakia, Košice, Slovakia.; Pediatric Neurology Ambulance, Children's Faculty Hospital With Clinic Banská Bystrica, Banská Bystrica, Slovakia.; Ambulance of Medical Genetics, Unilabs Slovakia, Banská Bystrica, Slovakia.; Department of Medical Genetics, F.D. Roosevelt University Hospital With Policlinic Banská Bystrica, Banská Bystrica, Slovakia.; Department of Medical Genetics, F.D. Roosevelt University Hospital With Policlinic Banská Bystrica, Banská Bystrica, Slovakia.; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.; Laboratory of Medical Genetics, Unilabs Slovakia, Bratislava, Slovakia.; Laboratory of Medical Genetics, Unilabs Slovakia, Bratislava, Slovakia.; Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.; The Ambulance of Pediatric Endocrinology and Diabetology and Metabolic and Nutritional Disorders, Children's Faculty Hospital With Clinic Banská Bystrica, Banská Bystrica, Slovakia.; Department of Laboratory Medicine, National Institute of Children's Diseases, Bratislava, Slovakia.; Department of Glycobiology, Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia.; Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Slovakia.

DOI: 10.1155/humu/7948771

MeSH Terms: Humans, Congenital Disorders of Glycosylation, Glycosylation, Adaptor Proteins, Vesicular Transport, Mutation, Male, Infant, Polysaccharides, Transferrin, Female