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Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations

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 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.

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Figure 1: IFNGR2 genotype and clinical phenotype of individuals with MSMD.
Figure 2: Cellular phenotype of individuals with MSMD.
Figure 3: Subcellular distribution of IFNγR2.
Figure 4: Biochemical properties of IFNγR2.
Figure 5: Pattern of IFNγR2 glycosylation.
Figure 6: Chemical complementation of the cellular phenotype.
Figure 7: Other gain-of-glycosylation mutations.

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Acknowledgements

We thank P. Stenson for provision of the HGMD data and C. Antignac, D. Cotton, C. Eidenschenk, J. Jaeken, C. Lamaze, P. de Lonlay, S. Lyonnet, A. Puel, K. Tedin, V. Tolyan, M. Vihinen and all members of the HGID laboratory for discussions. The laboratory was partially supported by grants from the Schlumberger Foundation, the BNP-Paribas Foundation and the European Union.

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Correspondence to Jean-Laurent Casanova.

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Supplementary Table 1

Missense mutations identified in the Human Gene Mutation Database. (XLS 57 kb)

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Vogt, G., Chapgier, A., Yang, K. et al. Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nat Genet 37, 692–700 (2005). https://doi.org/10.1038/ng1581

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