Hypothesis: lobe A (COG1-4)-CDG causes a ...
Document type :
Article dans une revue scientifique
PMID :
Permalink :
Title :
Hypothesis: lobe A (COG1-4)-CDG causes a more severe phenotype than lobe B (COG5-8)-CDG
Author(s) :
Haijes, Hanneke A. [Auteur]
University Medical Center [Utrecht] [UMCU]
Jaeken, Jaak [Auteur]
University Hospital Gasthuisberg [Leuven]
Foulquier, Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
van Hasselt, Peter M. [Auteur]
University Medical Center [Utrecht] [UMCU]
University Medical Center [Utrecht] [UMCU]
Jaeken, Jaak [Auteur]
University Hospital Gasthuisberg [Leuven]
Foulquier, Francois [Auteur]

Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
van Hasselt, Peter M. [Auteur]
University Medical Center [Utrecht] [UMCU]
Journal title :
Journal of medical genetics
Abbreviated title :
J. Med. Genet.
Volume number :
55
Pages :
137-142
Publication date :
2018-02
ISSN :
1468-6244
English keyword(s) :
COG
conserved oligomeric Golgi complex
Congenital Disorders of Glycosylation
CDG
conserved oligomeric Golgi complex
Congenital Disorders of Glycosylation
CDG
HAL domain(s) :
Chimie/Chimie théorique et/ou physique
English abstract : [en]
The conserved oligomeric Golgi (COG) complex consists of eight subunits organized in two lobes: lobe A (COG1-4) and lobe B (COG5-8). The different functional roles of COG lobe A and lobe B might result in distinct clinical ...
Show more >The conserved oligomeric Golgi (COG) complex consists of eight subunits organized in two lobes: lobe A (COG1-4) and lobe B (COG5-8). The different functional roles of COG lobe A and lobe B might result in distinct clinical phenotypes in patients with COG-CDG (congenital disorders of glycosylation). This hypothesis is supported by three observations. First, knock-down of COG lobe A components affects Golgi morphology more severely than knock-down of COG lobe B components. Second, nearly all of the 27 patients with lobe B COG-CDG had bi-allelic truncating mutations, as compared with only one of the six patients with lobe A COG-CDG. This represents a frequency gap which suggests that bi-allelic truncating mutations in COG lobe A genes might be non-viable. Third, in support, large-scale exome data of healthy adults (Exome Aggregation Consortium (ExAC)) underline that COG lobe A genes are less tolerant to genetic variation than COG lobe B genes. Thus, comparable molecular defects are more detrimental in lobe A COG-CDG than in lobe B COG-CDG. In a larger perspective, clinical phenotypic severity corresponded nicely with tolerance to genetic variation. Therefore, genomic epidemiology can potentially be used as a photographic negative for mutational severity.Show less >
Show more >The conserved oligomeric Golgi (COG) complex consists of eight subunits organized in two lobes: lobe A (COG1-4) and lobe B (COG5-8). The different functional roles of COG lobe A and lobe B might result in distinct clinical phenotypes in patients with COG-CDG (congenital disorders of glycosylation). This hypothesis is supported by three observations. First, knock-down of COG lobe A components affects Golgi morphology more severely than knock-down of COG lobe B components. Second, nearly all of the 27 patients with lobe B COG-CDG had bi-allelic truncating mutations, as compared with only one of the six patients with lobe A COG-CDG. This represents a frequency gap which suggests that bi-allelic truncating mutations in COG lobe A genes might be non-viable. Third, in support, large-scale exome data of healthy adults (Exome Aggregation Consortium (ExAC)) underline that COG lobe A genes are less tolerant to genetic variation than COG lobe B genes. Thus, comparable molecular defects are more detrimental in lobe A COG-CDG than in lobe B COG-CDG. In a larger perspective, clinical phenotypic severity corresponded nicely with tolerance to genetic variation. Therefore, genomic epidemiology can potentially be used as a photographic negative for mutational severity.Show less >
Language :
Anglais
Audience :
Non spécifiée
Administrative institution(s) :
CNRS
Université de Lille
Université de Lille
Research team(s) :
Mécanismes moléculaires de la N-glycosylation et pathologies associées
Submission date :
2020-02-12T15:11:53Z
2021-03-18T13:01:45Z
2021-03-18T13:01:45Z