Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations

Guillaume Vogt, Ariane Chapgier, Kun Yang, Nadia Chuzhanova, Jacqueline Feinberg, Claire Fieschi, Stéphanie Boisson-Dupuis, Alexandre Alcais, Orchidée Filipe-Santos, Jacinta Bustamante, Ludovic De Beaucoudrey, Ibrahim Al-Mohsen, Sami Al-Hajjar, Abdulaziz Al-Ghonaium, Parisa Adimi, Mehdi Mirsaeidi, Soheila Khalilzadeh, Sergio Rosenzweig, Oscar De La Galle Martin, Thomas R. BauerJennifer M. Puck, Hans D. Ochs, Dieter Furthner, Carolin Engelhorn, Bernd Belohradsky, Davood Mansouri, Steven M. Holland, Robert D. Schreiber, Laurent Abel, David N. Cooper, Claire Soudais, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

185 Scopus citations


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 IFNγR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNγ. 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.

Original languageEnglish
Pages (from-to)692-700
Number of pages9
JournalNature Genetics
Issue number7
StatePublished - 2005


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