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Human Molecular Genetics Advance Access originally published online on November 17, 2005
Human Molecular Genetics 2005 14(24):3847-3855; doi:10.1093/hmg/ddi409
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Molecular complementation of IL-12Rß1 deficiency reveals functional differences between IL-12Rß1 alleles including partial IL-12Rß1 deficiency

Esther van de Vosse1,*, Roelof A. de Paus1, Jaap T. van Dissel1,{dagger} and Tom H.M. Ottenhoff2,{dagger}

1Department of Infectious Diseases and 2Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, C5-38, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

* To whom correspondence should be addressed. Tel: +31 715261784/2613; Fax: +31 715266758; Email: e.van_de_vosse{at}lumc.nl

Received September 8, 2005; Accepted October 26, 2005

Patients with mutations in IL12RB1, the gene encoding IL-12Rß1, 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-12Rß1, however, have not been determined at the molecular level. Molecular complementation studies are essential to demonstrate how structural amino acid changes affect IL-12Rß1 function, and whether functionally different IL-12Rß1 alleles can be distinguished. Thirteen different IL-12Rß1 alleles, including 11 amino acid substitutions and the two major haplotypes (214Q-365M-378G and 214R-365T-378R), were retrovirally transduced in IL-12Rß1 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-12Rß1 variants. The C198R mutation leads to a partially functional IL-12Rß1, representing the first molecularly proven partial IL-12Rß1 deficiency. Interleukin-12 (IL-12) induced not only Interferon-{gamma} 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 with 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.

{dagger} Shared senior authorship.


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