title: 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 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.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes INSERM U550, Necker Medical School, 156 rue de Vaugirard, 75015 Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vogt
authors.forename: Ariane
authors.initials: A
authors.lastname: Chapgier
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Nadia
authors.initials: N
authors.lastname: Chuzhanova
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcais
authors.forename: Orchidée
authors.initials: O
authors.lastname: Filipe-Santos
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Ludovic
authors.initials: L
authors.lastname: de Beaucoudrey
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al-Mohsen
authors.forename: Sami
authors.initials: S
authors.lastname: Al-Hajjar
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al-Ghonaium
authors.forename: Parisa
authors.initials: P
authors.lastname: Adimi
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mirsaeidi
authors.forename: Soheila
authors.initials: S
authors.lastname: Khalilzadeh
authors.forename: Sergio
authors.initials: S
authors.lastname: Rosenzweig
authors.forename: Oscar
authors.initials: O
authors.lastname: de la Calle Martin
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bauer
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Dieter
authors.initials: D
authors.lastname: Furthner
authors.forename: Carolin
authors.initials: C
authors.lastname: Engelhorn
authors.forename: Bernd
authors.initials: B
authors.lastname: Belohradsky
authors.forename: Davood
authors.initials: D
authors.lastname: Mansouri
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Claire
authors.initials: C
authors.lastname: Soudais
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001500:BCG Vaccine / Q000009:adverse effects / Q000494:pharmacology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D020125:Mutation, Missense; D009164:Mycobacterium Infections / Q000235:genetics / Q000378:metabolism; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics*; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001500:BCG Vaccine; C086185:IFNGR2 protein, human; D017471:Receptors, Interferon; D014415:Tunicamycin; D018664:Interleukin-12