Journal Article

Molecular complementation of IL-12Rβ1 deficiency reveals functional differences between IL-12Rβ1 alleles including partial IL-12Rβ1 deficiency

Esther van de Vosse, Roelof A. de Paus, Jaap T. van Dissel and Tom H.M. Ottenhoff

in Human Molecular Genetics

Volume 14, issue 24, pages 3847-3855
Published in print December 2005 | ISSN: 0964-6906
Published online November 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi409
Molecular complementation of IL-12Rβ1 deficiency reveals functional differences between IL-12Rβ1 alleles including partial IL-12Rβ1 deficiency

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Patients with mutations in IL12RB1, the gene encoding IL-12Rβ1, 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-12Rβ1, however, have not been determined at the molecular level. Molecular complementation studies are essential to demonstrate how structural amino acid changes affect IL-12Rβ1 function, and whether functionally different IL-12Rβ1 alleles can be distinguished. Thirteen different IL-12Rβ1 alleles, including 11 amino acid substitutions and the two major haplotypes (214Q-365M-378G and 214R-365T-378R), were retrovirally transduced in IL-12Rβ1 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-12Rβ1 variants. The C198R mutation leads to a partially functional IL-12Rβ1, representing the first molecularly proven partial IL-12Rβ1 deficiency. Interleukin-12 (IL-12) induced not only Interferon-γ 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.

Journal Article.  5413 words.  Illustrated.

Subjects: Genetics and Genomics

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