title: Complementation of a pathogenic IFNGR2 misfolding mutation with modifiers of N-glycosylation.
abstract: 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 gamma receptor 2 (IFN-gamma 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-gamma. 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-gamma R2 molecules and restored cellular responsiveness to IFN-gamma. 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.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France. vogt@necker.fr
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vogt
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Ariane
authors.initials: A
authors.lastname: Chapgier
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Stephanie
authors.initials: S
authors.lastname: Boisson Dupuis
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Nizar
authors.initials: N
authors.lastname: Mahlaoui
authors.forename: Laure
authors.initials: L
authors.lastname: Gineau
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.forename: Christophe
authors.initials: C
authors.lastname: Lamaze
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: Claudia Djambas
authors.initials: CD
authors.lastname: Khayat
authors.forename: Raymond
authors.initials: R
authors.lastname: Mikhael
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002675:Child, Preschool; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D005260:Female; D005816:Genetic Complementation Test; D006031:Glycosylation; D006720:Homozygote; D006801:Humans; D008297:Male; D016254:Mutagenesis, Insertional; D009154:Mutation; D015270:Mycobacterium avium-intracellulare Infection / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D010641:Phenotype; D017510:Protein Folding; D017471:Receptors, Interferon / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics*; D017384:Sequence Deletion; D014162:Transfection
chemical_list: C086185:IFNGR2 protein, human; D017471:Receptors, Interferon; D004247:DNA