Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations

Vogt, Guillaume, Chapgier, Ariane, Yang, Kun, Chuzhanova, Nadia, Feinberg, Jacqueline, Fieschi, Claire, Boisson-Dupuis, Stephanie, Alcais, Alexandre, Filipe-Santos, Orchidee, Bustamante, Jacinta, Beaucoudrey, Ludovic de, Al-Mohsen, Ibrahim, Al-Hajjar, Sami, Al-Ghonaium, Abdulaziz, Adimi, Pierre, Mirsaeidi, Mehdi, Khalilzadeh, Soheila, Rosenzweig, Sergio, Martin, Oscar de la Calle, Bauer, Thomas R, Puck, Jennifer M, Ochs, Hans D, Furthner, Dieter, Engelhorn, Carolin, Belohradsky, Bernd, Mansouri, Davood, Holland, Steven M, Schrieber, Robert D, Abel, Laurent, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484, Casanova, Jean -Laurent and Soudais, Claire 2005. Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nature Genetics 37 (7) , pp. 692-700. 10.1038/ng1581

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Abstract

Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFN. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations (1.4%) in 77 genes (13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
ISSN:	1061-4036
Last Modified:	17 Oct 2022 08:26
URI:	https://orca.cardiff.ac.uk/id/eprint/180

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