Insights Into the Pathological Glycosylation Associated With COG6-CDG

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F25%3A10506115" target="_blank" >RIV/00216208:11110/25:10506115 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064165:_____/25:10506115

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=PypXEeHhNT" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=PypXEeHhNT</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1155/humu/7948771" target="_blank" >10.1155/humu/7948771</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Insights Into the Pathological Glycosylation Associated With COG6-CDG

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Insights Into the Pathological Glycosylation Associated With COG6-CDG

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30101 - Human genetics

Projekt

<a href="/cs/project/NU22-07-00474" target="_blank" >NU22-07-00474: Molekulárně-genetické příčiny a biochemické důsledky Dědičných poruch glykosylace</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Human Mutation

ISSN

1059-7794

e-ISSN

1098-1004

Svazek periodika

2025

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

7948771

Kód UT WoS článku

001626952400001

EID výsledku v databázi Scopus

2-s2.0-105023540884