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Hypothesis: lobe A (COG1-4)-CDG causes a more severe phenotype than lobe B (COG5-8)-CDG

Abstract : 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.
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https://hal.univ-lille.fr/hal-03173349
Contributeur : Lilloa Université de Lille <>
Soumis le : jeudi 18 mars 2021 - 14:01:51
Dernière modification le : vendredi 19 mars 2021 - 03:32:40

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Hanneke A. Haijes, Jaak Jaeken, Francois Foulquier, Peter M. van Hasselt. Hypothesis: lobe A (COG1-4)-CDG causes a more severe phenotype than lobe B (COG5-8)-CDG. Journal of medical genetics, 2018, Journal of medical genetics, 55 (2), pp.137-142. ⟨10.1136/jmedgenet-2017-104586⟩. ⟨hal-03173349⟩

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