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Nature Genetics  37, 692 - 700 (2005)
Published online: 29 May 2005; | doi:10.1038/ng1581

Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations

Guillaume Vogt1, Ariane Chapgier1, Kun Yang1, 2, Nadia Chuzhanova3, 4, Jacqueline Feinberg1, Claire Fieschi1, 5, Stéphanie Boisson-Dupuis1, Alexandre Alcais1, Orchidée Filipe-Santos1, Jacinta Bustamante1, Ludovic de Beaucoudrey1, Ibrahim Al-Mohsen6, Sami Al-Hajjar6, Abdulaziz Al-Ghonaium6, Parisa Adimi7, Mehdi Mirsaeidi7, Soheila Khalilzadeh7, Sergio Rosenzweig8, 17, Oscar de la Calle Martin9, Thomas R Bauer10, Jennifer M Puck11, Hans D Ochs12, Dieter Furthner13, Carolin Engelhorn14, Bernd Belohradsky14, Davood Mansouri7, Steven M Holland8, Robert D Schreiber15, Laurent Abel1, David N Cooper4, Claire Soudais1 & Jean-Laurent Casanova1, 2, 16

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.

2  French-Chinese Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China.

3  Biostatistics and Bioinformatics Unit. Cardiff University, Cardiff CF14 4XN, UK.

4  Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK.

5  Department of Immunopathology, Saint Louis Hospital, 75010 Paris, France.

6  Pediatric Infectious Diseases and Immunology Units, Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

7  National Research Institute of Tuberculosis and Lung Diseases, Shaheed Beheshti University of Medical Sciences, Dar-Abad, 19556 Tehran, Iran.

8  Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

9  Service of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

10  National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

11  National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

12  Department of Pediatrics, University of Washington, Seattle, Washington 98109, USA.

13  Department of Pediatrics, Klinikum Wels, 4600 Wels, Austria.

14  Department of Pediatrics, Hospital for Sick Children, 80337 München, Germany.

15  Department of Pathology and Immunology, Washington University, Saint Louis, Missouri 63110, USA.

16  Pediatric Immunology & Hematology Unit, Necker Hospital, 75015 Paris, France.

17  Present address: Servicio de Inmunologia, Hospital Garrahan, Buenos Aires, Argentina.

Correspondence should be addressed to Jean-Laurent Casanova
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 IFNbold gammaR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNbold gamma. 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 (approx1.4%) in 77 genes (approx13.3%). 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.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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