Alternative titles; symbols
HGNC Approved Gene Symbol: IL12RB1
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:18,058,995-18,098,816 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.11 | Immunodeficiency 30 | 614891 | Autosomal recessive | 3 |
IL12RB1 is a receptor chain that combines with IL12RB2 (601642) to form the receptor for IL12 (see IL12A, 161560). Alternatively, IL12RB1 can combine with IL23R (607562) to form the receptor for IL23 (see IL23A, 605580) (review by van de Vosse et al., 2013).
IL12 is a heterodimeric cytokine consisting of 2 subunits encoded by the genes IL12A and IL12B (161561). Chua et al. (1994) screened an expression lymphoblast cDNA library by using a monoclonal antibody that precipitated a complex of IL12 and its binding proteins and identified IL12RB1. The cDNA encodes a 662-amino acid type I transmembrane protein that is a member of the hemopoietin receptor superfamily and is most like the IL6 signal transducer, gp130 (IL6ST; 600694).
In their review, van de Vosse et al. (2013) stated that 2 mature mRNAs of about 2.1 kb are transcribed in equal amounts from IL12RB1. These mRNAs differ through alternative splicing of the last 13 bp of exon 16 and encode full-length isoforms of 662 and 660 amino acids that differ only in the last few amino acids. Both isoforms contain a 24-amino acid N-terminal signal peptide, followed by a large extracellular domain, a 31-amino acid transmembrane domain, and a short cytoplasmic domain containing box-1 and box-2 cytokine receptor motifs. The extracellular domain consists of 5 fibronectin (FN1; 135600) type III repeats, the first 2 of which form the cytokine-binding region and contain specific cytokine receptor family signature motifs. Van de Vosse et al. (2013) noted that a truncated IL12RB1 variant encoding a 381-amino acid isoform lacking the transmembrane and intracellular domains, as well as several minor splice variants, have also been reported.
Fieschi et al. (2003) stated that the IL12RB1 gene contains 17 coding exons.
Van de Vosse et al. (2013) stated that the IL12RB1 gene contains 17 exons and spans about 28 kb. The last exon is noncoding. In addition, a truncated IL12RB1 splice variant uses a cryptic exon in intron 9.
By fluorescence in situ hybridization, Yamamoto et al. (1997) mapped the IL12RB1 gene to chromosome 19p13.1.
Chua et al. (1994) expressed IL12RB1 in COS cells and observed low-affinity binding to IL12. An antibody raised against the protein was shown to inhibit IL12-induced proliferation of stimulated lymphocytes. Chua et al. (1994) speculated that another high-affinity IL12R component also exists and that the 2 proteins may be needed to produce a high-affinity receptor for IL12.
Presky et al. (1996) used expression cloning techniques to identify an additional beta-type IL12 receptor protein. They designated this receptor IL12R-beta-2 (IL12RB2; 601642) and referred to the previously identified IL12R-beta as beta-1. The beta-2 gene likewise bound IL12 with low affinity, but when coexpressed with beta-1 it conferred high-affinity binding and high IL12 responsiveness.
Robinson et al. (2010) demonstrated that, after infection of mice with Mycobacterium tuberculosis, Il12rb1 was spliced in lung dendritic cells (DCs) to form a variant mRNA encoding a protein that lacks a transmembrane domain and has an altered C-terminal sequence, which they termed Il12rb1-delta-TM. The variant was also induced under similar conditions in human DCs. Reconstitution of Il12rb1 -/- DCs with Il12rb1 or Il12rb1-delta-TM showed that the variant augmented Il12rb1-dependent DC migration and activation of M. tuberculosis-specific T cells. Robinson et al. (2010) proposed that IL12RB1-delta-TM acts as a novel positive regulator of IL12RB1-dependent DC function and of the immune response to M. tuberculosis.
Altare et al. (1998) found impairment of mycobacterial immunity in human IL12RB1 deficiency (IMD30; 614891), and de Jong et al. (1998) found severe mycobacterial and Salmonella infections in patients with this deficiency. In humans, deficiency of interferon-gamma receptor (IFNGR1; 107470) leads to a predisposition to mycobacterial infections (see IMD27A, 209950) and impairs the formation of mature granulomas. Altare et al. (1998) found deficiency of interleukin-12 receptor in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be secreted by activated natural killer and T cells. Thus, IL12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL12-independent IFN-gamma secretion.
Interleukin-12 promotes cell-mediated immunity to intracellular pathogens by inducing type 1 helper T cell responses and interferon-gamma production. IL12 binds to high-affinity beta-1/beta-2 heterodimeric IL12 receptor complexes on T cells and natural killer cells. De Jong et al. (1998) found 3 unrelated individuals with severe, idiopathic mycobacterial and Salmonella infections associated with lack of IL12RB1 expression. Their cells were deficient in IL12R signaling and IFN-gamma production, and their remaining T cell responses were independent of endogenous IL12. IL12RB1 sequence analysis demonstrated genetic mutations that resulted in premature stop codons in the extracellular domain. Defects in the IFNGR1 gene have been demonstrated in familial disseminated atypical mycobacterial infections (209950).
In a review of immunodeficiencies caused by defects in phagocytes, Lekstrom-Himes and Gallin (2000) discussed the defects of signaling resulting from mutations in the interferon-gamma receptor genes IFNGR1 (107470) and IFNGR2 (147569). They noted that IL12RB1 is in the same signaling pathway, and, like mutations in either chain of the interferon-gamma receptor, is associated with susceptibility to disseminated infection by atypical mycobacterial infection.
Altare et al. (2001) showed by flow cytometric, EMSA, and ELISA analyses that T cells from patients with the arg213-to-trp mutation (601604.0004) had no detectable cell surface IL12RB1 and did not translocate STAT4 (600558) to the nucleus or produce gamma-interferon (IFNG; 147570) in response to IL12. Transformation of the patients' cells with wildtype IL12RB1 restored these functions.
Akahoshi et al. (2003) found 3 common missense variants in the IL12RB1 gene, gln214 to arg (Q134R), met365 to thr (M365T), and gly378 to arg (G378R), each caused by a SNP. These SNPs were in almost perfect linkage disequilibrium and 2 common haplotypes of IL12RB1 were found: Q214-M365-G378 and R214-T365-R378. In a case-control association study of tuberculosis, Akahoshi et al. (2003) found that the R214-T365-R378 allele was overrepresented in patients with tuberculosis, and homozygosity for this allele was significantly associated with tuberculosis (OR = 2.45). In healthy individuals, homozygotes for this allele had lower levels of IL12-induced signaling. The authors suggested that this genetic variation may predispose individuals to tuberculosis infection by diminishing receptor responsiveness to IL12 and to IL23 (subunit p40 of IL12), leading to partial dysfunction of interferon-gamma-mediated immunity.
By SSCP and sequence analysis of the IL12RB1 gene in 120 unrelated probands, including 100 with atypical mycobacteriosis, Fieschi et al. (2003) identified 41 patients in 29 kindreds from 17 countries in Africa, America, Europe, and Asia with complete IL12RB1 surface expression deficiency. The patients were homozygous or compound heterozygous for 4 nonsense mutations, 4 splice site mutations, 6 missense mutations, 1 small insertion, 2 large deletions, and 4 deletion/insertions, for a total of 21 mutant alleles. None of the mutations were found in 50 unrelated healthy individuals from corresponding ethnic groups. Opportunistic childhood infections with weakly virulent Salmonella and Mycobacteria were observed in 34 patients, but 3 patients had clinical tuberculosis, including 1 with salmonellosis. Salmonellosis, but not the mycobacterial infections, was recurrent. BCG vaccination and disease protected against environmental mycobacteriosis but not against salmonellosis. BCG disease occurred in only 9 of 27 inoculated children. Fatality before age 8 occurred in 5 patients, 3 due to M. avium in non-BCG-vaccinated children and 2 due to disseminated BCG; the remaining patients were alive and well. Fieschi et al. (2003) proposed that IL12RB1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis and that the diagnosis should be pursued in healthy sibs of probands and in selected cases of tuberculosis. They concluded that the overall prognosis is good due to broad resistance to infection, low clinical penetrance, and the favorable outcome of the infections. Fieschi et al. (2003) noted the unexpected finding that IL12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella, possibly reflecting the difference in the natural course of infection in humans as opposed to the courses of experimental infections in animal models.
Fieschi et al. (2004) suggested that IL12RB1 deficiency is the most frequent genetic defect responsible for the syndrome of mendelian susceptibility to mycobacterial disease, with 54 patients from 16 countries having been reported to that time. They noted that 53 of these patients lacked IL12RB1 at the surface of all cells examined, which resulted from mutations that either interrupt the open reading frame or disrupt protein folding and stability They described the exceptional patient, who had a large in-frame deletion of 12,165 bp of the IL12RB1 gene (601604.0004), which resulted in cell surface expression of nonfunctional IL12RB1.
Van de Vosse et al. (2005) transduced 13 different IL12RB1 alleles, including 11 amino acid substitutions and the 2 major haplotypes, 214Q-365M-378G and 214R-365T-378R, into IL12RB1-deficient human T cells. Several missense mutations, including R213W (601604.0004), were shown to lead to nonfunctional proteins. The C198R mutation (601604.0007) led to a partially functional IL12RB1, representing the first molecularly proven partial IL12RB1 deficiency. Interleukin-12 (IL12) induced not only interferon-gamma (147570) but also IL10 (124092) in all responder but not in null mutant alleles, with intermediate levels in C198R. The QMG allele was found to be a higher IL12 responder allele compared with the RTR allele. Van de Vosse et al. (2005) showed several other reported missense alleles to be functional variants.
Takahashi et al. (2005) sequenced the IL12RB1 gene and identified 48 SNPs in 24 Japanese individuals. In a case-control study with 382 Japanese patients with atopic dermatitis (ATOD; 603165) and 658 healthy Japanese controls, they identified 2 promoter polymorphisms -111A/T (rs393548) and -2C/T (rs436857) that were significantly associated with an increased risk of ATOD under a recessive model (corrected p = 0.0035, OR, 2.46; corrected p = 0.006, OR, 2.60, respectively). The -111T-allele frequency in an independent of 304 Japanese patients with childhood asthma was also much higher than that in the control group. In addition, the -111T/T genotype was progressively more common in ATOD with high total serum IgE levels in an IgE-level-dependent manner. Deletion analysis of the IL12RB1 promoter suggested that the -265 to -104 region (that contains the -111A/T polymorphic site) harbored an important regulatory element. Furthermore, the -111A/T substitution appeared to cause decreased gene transcriptional activity, such that cells from -111A/A individuals exhibited higher IL12RB1 mRNA levels than those from -111T allele carriers. Takahashi et al. (2005) suggested that, in individuals with the -111T/T genotype, reduced IL12RB1 expression may lead to increased Th2 cytokine production in skin, and contribute to the development of ATOD and other subsequent allergic diseases.
By flow cytometric analysis following mitogen activation of IL17 (603149)-expressing blood T cells from healthy controls or patients with particular genetic traits affecting various cytokine signaling pathways, de Beaucoudrey et al. (2008) found that there was considerable interindividual variability in IL17 expression in controls and most patient groups. However, dominant-negative mutations in STAT3 (102582) in patients with autosomal dominant hyper-IgE recurrent infection syndrome (147060) and, to a lesser extent, null mutations in IL12B or IL12RB1 in patients with mendelian susceptibility to mycobacterial disease impaired development of IL17-producing T cells.
Van de Vosse et al. (2013) reviewed the molecular genetics of all IL12RB1 mutations and variants and introduced an IL12RB1 variation database.
De Jong et al. (1998) demonstrated homozygosity for a gln32-to-ter (Q32X) nonsense mutation of the IL12RB1 gene in a 26-year-old Dutch woman who developed a severe Salmonella paratyphi sepsis (IMD30; 614891) at the age of 3 years. This was complicated by abdominal abscesses. She presented at the age of 22 years with a Mycobacterium avium sepsis with extensive mediastinal lymphadenopathy.
De Jong et al. (1998) found homozygosity for a gln376-to-ter (Q376X) nonsense mutation in the IL12RB1 gene in a 19-year-old Dutch woman who presented with recurrent systemic M. avium intracellular infections (IMD30; 614891) at ages 4, 13, and 17 years and with severe systemic Salmonella type B infections at age 4, 7, and 14 years.
In a 3-year-old Turkish girl with consanguineous parents, de Jong et al. (1998) demonstrated deletion of nucleotides 409-549 from the IL12RB1 gene. This deletion led to a frameshift that introduced a premature stop codon at nucleotide positions 570 to 572 (TGA) in the extracellular domain of the IL12RB1 gene. Both parents were heterozygous for the deletion. It was suspected that the deletion resulted from a splice mutation that led to the skipping of 1 exon, but 1 of the flanking introns could not be amplified. This patient had developed progressive M. bovis BCG infection (IMD30; 614891) after vaccination at the age of 1 year, followed by severe and nearly fatal S. typhimurium sepsis at the age of 2 years. From histologic examination, the BCG lesion of this patient contained well-organized granulomatous infiltrates.
In a 14-year-old Moroccan boy and his 25-year-old sister, Altare et al. (2001) identified homozygosity for a C-to-T transition at nucleotide 637 in exon 7 of the IL12RB1 gene, leading to an arg213-to-trp (R213W) substitution. The patients' parents were heterozygous first cousins. The boy had a history of disseminated BCG (IMD30; 614891) after vaccination at birth, then S. typhimurium adenitis at age 4 years and S. typhimurium septicemia at age 7 years. All infections responded well to antibacterial therapy. The sister had no untoward responses and was transiently tuberculin skin test positive after each of 3 BCG vaccinations. She developed abdominal tuberculosis at age 18 and responded well to surgery and antimycobacterial therapy. Altare et al. (2001) concluded that IL12RB1 deficiency should be considered in patients with severe tuberculosis, even in the absence of complications from BCG vaccination or of atypical mycobacteriosis.
In a 6-year-old boy born to first-cousin parents of Bedouin origin living in Israel, who was previously reported by Fieschi et al. (2003), Fieschi et al. (2004) identified an in-frame deletion of 12,165 bp in the IL12RB1 gene as the cause of disseminated Salmonella enteritidis disease (IMD30; 614891). Between the ages of 1 and 3 years, the patient suffered 8 recurrences of systemic Salmonella infection, with the same serovar implicated on each occasion. The detailed clinical and bacteriologic features of these infections were reported by Staretz-Haham et al. (2003). The deletion encompassed exons 8-13 and was associated with cell surface expression of nonfunctional IL12RB1. The 6 deleted exons encode the proximal NH2-terminal half of the extracellular domain downstream from the cytokine-binding domain. Fieschi et al. (2004) found that 5 of 6 monoclonal anti-IL12RB1 antibodies recognized the internally truncated chain on the cell surface. Nonetheless, IL12 (see 165160) and IL23 (see 605580) did not bind normally to the patient's IL12RB1-containing respective heterodimeric receptors. As a result, signal transducer and activator of transcription-4 (STAT4; 600558) was not phosphorylated and production of interferon-gamma (147570) was not induced in the patient's cells upon stimulation with even high doses of IL12 or IL23. The functional defect was completely rescued by retrovirus-mediated IL12RB1 gene transfer. Fieschi et al. (2004) concluded that the detection of IL12RB1 on the cell surface does not exclude the possibility of complete IL12RB1 deficiency in patients with mycobacteriosis or salmonellosis.
Ozbek et al. (2005) reported an 11-year-old Turkish girl with IL12RB1 deficiency and severe abdominal tuberculosis (IMD30; 614891). The patient had a homozygous splice site mutation (1021+1G-C) in the IL12RB1 gene that led to skipping of exon 9. She was the fourth child of healthy, consanguineous parents. Like her parents and sibs, she had had no adverse effect from BCG vaccination, and there was no family history of mycobacterial disease or other intracellular infectious diseases. The patient had residual expression of IL12RB1 mRNA, but did not show augmented production of IFNG (147570) in response to antigen plus IL12 (see 161561). Her drug-resistant tuberculosis was treated with a range of antimicrobials for a prolonged period, and she appeared to be responding well at the time of the report.
Lichtenauer-Kaligis et al. (2003) reported a male patient from a consanguineous Turkish family who presented with localized BCG adenitis (IMD30; 614891) in the left axilla and shoulder within 2 months following BCG vaccination in the neonatal period. He responded well to conventional antituberculosis chemotherapy, and the lesions healed without major scar formation. Following appendectomy at 2.5 years of age he developed skin lesions in the gluteal and inguinal areas from which M. bovis BCG was cultured. The lesions recurred several times over a period of several years and each time responded to treatment with antimycobacterial antibiotics. There was no history of Salmonella infections. A consistent low response to IL12 was found in peripheral blood mononuclear cells from the patient, which could be further augmented by IL18 (600953). While no cell surface IL12RB1 expression was detected in permeabilized cells, normal levels of intracellular IL12RB1 were observed. The patient carried a homozygous 656T-C transition that resulted in a cys-to-arg substitution at codon 198 (C198R). Each parent, who had experienced no adverse effects from BCG vaccination, was heterozygous for the mutation. No intermediate phenotype, e.g., responsiveness to IL12, was found in heterozygous parent cells. Lichtenauer-Kaligis et al. (2003) concluded that this patient represented partial deficiency of IL12RB1.
Van de Vosse et al. (2005) confirmed that the C198R mutation generates a partially functional protein.
In a 33-year-old Iranian with complete autosomal recessive IL12RB1 deficiency (IMD30; 614891) who succumbed to disseminated multidrug (isoniazid and rifampin)-resistant tuberculosis (TB), Tabarsi et al. (2011) identified a homozygous 3-bp deletion in exon 10 of the IL12RB1 gene that was not found in 100 controls. The mutation resulted in a deletion of thr355 (T355del). The patient had a history of uncomplicated BCG vaccination, normal chest and abdominal radiography, normal immune function, no smoking history, and negative HIV serology and PCR. Two courses of standard anti-TB treatment had not been curative, and sputum tests were persistently positive for acid-fast bacilli (AFB), confirmed by PCR to be M. tuberculosis. Blood cells failed to produce IFNG (147570) in response to IL12 (see 161560), but they produced IL12 in response to BCG and IFNG. In response to second-line anti-TB treatment, the patient regained weight during the first 6 months, then developed profuse diarrhea after 8 months of treatment with no detectable pathogens. Colonoscopy and histologic analysis revealed diffuse polypoid ulcers and histiocytes filled with AFB. Tabarsi et al. (2011) concluded that genetic defects in the IL12-IFNG circuit must be considered in adults with disseminated TB, as some of these patients may benefit from IFNG therapy as an adjunct to antimicrobial treatment.
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