Human Molecular Genetics Advance Access published online on November 17, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi409
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1 Department of Infectious Diseases, Leiden University Medical Center, C5-38 Albinusdreef 2, 2333 ZA Leiden, The Netherlands
* To whom correspondence should be addressed. Patients with mutations in IL12RB1, the gene encoding IL-12R
Received September 8, 2005
Revised October 26, 2005
Accepted October 26, 2005
Article
Molecular complementation of IL-12R
Esther van de Vosse 1 *,
Roelof A. de Paus 2,
Jaap T. van Dissel 2,
and
Tom H.M. Ottenhoff 3
1 deficiency reveals functional differences between IL-12R1 alleles including partial IL-12R1 deficiency
2 Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
3 Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Esther van de Vosse, E-mail: E.van_de_Vosse{at}LUMC.nl
Abstract 
1, suffer from combined IL-12R/IL-23R deficiency and are unusually susceptible to nontuberculous mycobacteria and salmonellae. The functional effects of amino acid changes in IL-12R1, however have not been determined at the molecular level. Molecular complementation studies are essential to demonstrate how structural amino acid changes affect IL-12R1 function, and whether functionally different IL-12R1 alleles can be distinguished. Thirteen different IL-12R1 alleles, including 11 amino acid substitutions and the two major haplotypes (214Q-365M-378G and 214R-365T-378R), were retrovirally transduced in IL-12R1 deficient human T-cells. We provide functional evidence that L77P, R173P, C186S, R213W and Y367C are deleterious mutations leading to non-functional proteins. Conversely, S74R, R156H, H438Y, A525T and G594E are fully functional IL-12R1 variants. The C198R mutation leads to a partially functional IL-12R1, representing the first molecularly proven partial IL-12R1 deficiency. Interleukin-12 (IL-12) induced not only Interferon-
(IFN-) but also IL-10 in all responder but not in null-mutant alleles, with intermediate levels in C198R. The QMG allele was found to be a higher IL-12 responder allele compared to the RTR allele. These results have implications for understanding IL-12R/IL-23R structure-function and the role of IL-12R/IL-23R in human disease.
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