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¹ Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France
² University Paris René Descartes, Necker Medical School, 75015 Paris, France
³ Study Center of Primary Immunodeficiencies, APHP, and ⁴ Pediatric Immunology-Hematology Unit, Necker Hospital, 75015 Paris, France
⁵ Laboratory of Normal and Pathological Development of the Immune System, U768, INSERM, Necker-Enfants Malades Hospital, 75015 Paris, France
⁶ Trafic, Signaling and Delivery Laboratory, UMR144 Curie Centre National de la Recherche Scientifique, Institut Curie, 75005 Paris, France
⁷ Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143
⁸ Department of Pediatrics, Hotel Dieu de France Hospital, 90262 Beirut, Lebanon

CORRESPONDENCE Guillaume Vogt: vogt{at}necker.fr OR Jean-Laurent Casanova: casanova{at}necker.fr

Germline mutations may cause human disease by various mechanisms. Missense and other in-frame mutations may be deleterious because the mutant proteins are not correctly targeted, do not function correctly, or both. We studied a child with mycobacterial disease caused by homozygosity for a novel in-frame microinsertion in IFNGR2. In cells transfected with the mutant allele, most of the interferon receptor 2 (IFN-R2) protein was retained within the cell, and that expressed on the cell surface had an abnormally high molecular weight (MW). The misfolding mutation was not gain-of-glycosylation, as it created no new N-glycosylation site. The mutant IFNGR2 allele was null, as the patient's cells did not respond to IFN-. Based on the well-established relationship between protein N-glycosylation and protein quality control processes, we tested 29 compounds affecting maturation by N-glycosylation in the secretory pathway. Remarkably, up to 13 of these compounds reduced the MW of surface-expressed mutant IFN-R2 molecules and restored cellular responsiveness to IFN-. Modifiers of N-glycosylation may therefore complement human cells carrying in-frame and misfolding, but not necessarily gain-of-glycosylation, mutations in genes encoding proteins subject to trafficking via the secretory pathway. Some of these compounds are available for clinical use, paving the way for clinical trials of chemical complementation for various human genetic traits.

© 2008 Vogt et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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• Kong, X.-F., Vogt, G., Chapgier, A., Lamaze, C., Bustamante, J., Prando, C., Fortin, A., Puel, A., Feinberg, J., Zhang, X.-X., Gonnord, P., Pihkala-Saarinen, U. M., Arola, M., Moilanen, P., Abel, L., Korppi, M., Boisson-Dupuis, S., Casanova, J.-L. (2009). A novel form of cell type-specific partial IFN-{gamma}R1 deficiency caused by a germ line mutation of the IFNGR1 initiation codon. Hum Mol Genet 0: ddp507v2-ddp507 [Abstract] [Full Text]  
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