Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations

• Published in: Nature genetics Vol. 37; no. 7; pp. 692 - 700
• Main Authors: Vogt, Guillaume, Chapgier, Ariane, Yang, Kun, Chuzhanova, Nadia, Feinberg, Jacqueline, Fieschi, Claire, Boisson-Dupuis, Stéphanie, Alcais, Alexandre, Filipe-Santos, Orchidée, Bustamante, Jacinta, de Beaucoudrey, Ludovic, Al-Mohsen, Ibrahim, Al-Hajjar, Sami, Al-Ghonaium, Abdulaziz, Adimi, Parisa, Mirsaeidi, Mehdi, Khalilzadeh, Soheila, Rosenzweig, Sergio, de la Calle Martin, Oscar, Bauer, Thomas R, Puck, Jennifer M, Ochs, Hans D, Furthner, Dieter, Engelhorn, Carolin, Belohradsky, Bernd, Mansouri, Davood, Holland, Steven M, Schreiber, Robert D, Abel, Laurent, Cooper, David N, Soudais, Claire, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2005; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Anti-Bacterial Agents - pharmacology; BCG Vaccine - adverse effects; BCG Vaccine - pharmacology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line; Child; Child, Preschool; Disease susceptibility; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Glycosylation; Human Genetics; Humans; Identification and classification; In Vitro Techniques; Interleukin-12 - metabolism; Leukocytes - drug effects; Leukocytes - metabolism; Leukocytes - microbiology; Mutation; Mutation, Missense; Mycobacterium Infections - genetics; Mycobacterium Infections - metabolism; Physiological aspects; Proteins; Receptors, Interferon - deficiency; Receptors, Interferon - genetics; Tunicamycin - pharmacology; United States; Pathogenic; Glycosylation; Mutation
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1581

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.