Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations.
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.
Vogt
Guillaume
G
Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes INSERM U550, Necker Medical School, 156 rue de Vaugirard, 75015 Paris, France.
Chapgier
Ariane
A
Yang
Kun
K
Chuzhanova
Nadia
N
Feinberg
Jacqueline
J
Fieschi
Claire
C
Boisson-Dupuis
Stéphanie
S
Alcais
Alexandre
A
Filipe-Santos
Orchidée
O
Bustamante
Jacinta
J
de Beaucoudrey
Ludovic
L
Al-Mohsen
Ibrahim
I
Al-Hajjar
Sami
S
Al-Ghonaium
Abdulaziz
A
Adimi
Parisa
P
Mirsaeidi
Mehdi
M
Khalilzadeh
Soheila
S
Rosenzweig
Sergio
S
de la Calle Martin
Oscar
O
Bauer
Thomas R
TR
Puck
Jennifer M
JM
Ochs
Hans D
HD
Furthner
Dieter
D
Engelhorn
Carolin
C
Belohradsky
Bernd
B
Mansouri
Davood
D
Holland
Steven M
SM
Schreiber
Robert D
RD
Abel
Laurent
L
Cooper
David N
DN
Soudais
Claire
C
Casanova
Jean-Laurent
JL
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
D000900:Anti-Bacterial Agents; D001500:BCG Vaccine; C086185:IFNGR2 protein, human; D017471:Receptors, Interferon; D014415:Tunicamycin; D018664:Interleukin-12