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Nat Genet. 2005 Jul;37(7):692-700. Epub 2005 May 29.

Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations.

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1
Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes INSERM U550, Necker Medical School, 156 rue de Vaugirard, 75015 Paris, France.

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 IFNgammaR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNgamma. 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 ( approximately 1.4%) in 77 genes ( approximately 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.

PMID:
15924140
DOI:
10.1038/ng1581
[Indexed for MEDLINE]
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