Missense mutation of the interleukin-12 receptor β1 chain-encoding gene is associated with impaired immunity against mycobacterium avium complex infection

Abstract

Interleukin-12 (IL-12) plays an important role in the production of interferon gamma (IFN-γ) and is essential for protection against intracellular pathogens such as Mycobacterium and Salmonella. A 31-year-old man had disseminated Mycobacterium avium complex (MAC) infection. The production of IFN-γ by peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA-PBMCs) was found severely impaired (40.7 pg/mL compared with 833 ± 289 pg/mL for the patient's and healthy subjects' (n = 3) PHA-PBMCs, respectively), and the patient's PHA-PBMCs completely lacked surface IL-12 receptor β1 (IL-12Rβ1) chain. The IL-12Rβ1 gene transcript in his PHA-PBMCs had an R213W substitution in each allele. Family history showed that both parents were heterozygotes in the R213W substitution. Transfection of a human embryonal kidney cell line 293 (HEKC293) with wild-type IL-12Rβ1wt gene led to cell surface IL-12Rβ1 expression; however, no expression was seen in HEKC293 transfected with the mutated IL-12Rβ1R213W gene. The IL-12Rβ1 gene transcript, but no IL-12Rβ1 protein, was detected in PHA-PBMCs and T cells, suggesting a post-translational event(s), most likely a shortened turnover of the protein. The R213W substitution was not detected in the cells of 32 healthy persons or of 25 patients with tuberculosis or MAC infection. Six amino acid substitutions (Q214R, M365T, G378R, H438Y, A525T, and G594E) were identified, but the incidences of such substitutions were not significantly different between the groups. The Q214R substitution is reportedly linked to IL-12Rβ1 deficiency; however, the study showed that 19 and 10 of 57 Japanese and 6 and 4 of 33 healthy white persons were heterozygous and homozygous for Arg-214, respectively, suggesting that the Q214R substitution represents a polymorphism and is not related to IL-12Rβ1 deficiency but that the R213W substitution is responsible for IL-12Rβ1 deficiency. © 2001 by The American Society of Hematology.