IL-12Rβ1 deficiency: mutation update and description of the IL12RB1 variation database

Abstract

IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rβ1 and molecular genetics of human IL12RB1.

Keywords: IL-12Rβ1 deficiency; IL12RB1; Mendelian susceptibility to mycobacterial disease.

Figure 1

(A) Schematic representation of the mature IL-12Rβ1 isoforms 1 and 2. The full-length IL-12Rβ1 receptor chain, isoform 1, contains a large extracellular segment comprised of five Fibronectin type III repeat regions (FNIII). The first two FNIII repeat regions together form the cytokine-binding region (CBR) that also contains the cytokine receptor signature (WSxWS motif and two Cys-Cys pairs). The other three FNIII repeat regions are required for proper dimerization. The extracellular domain is followed by a single transmembrane domain (TM). The intracellular part contains the box 1 and box 2 cytokine receptor motifs required for JAK-associated signal transduction. Isoform 2 contains the cytokine-binding region (CBR) and one more FNIII domain followed by a stretch of 41 aa with no similarity to known domains. (B) Schematic representation of signal transduction via the IL-12 and IL-23 receptors.

Figure 2

Genomic structure, encoded protein domains and mutation distribution in the IL12RB1 gene. Numbers and positions of total (A) and unique (B) variants are shown, as well as mutation distribution ratio as determined by dividing the number of unique mutations per exon by the exon length (C). FN III = Fibronectin type III repeat regions, TM = transmembrane domain. The coding region of the transcript is indicated in light grey. The last 13 bp of exon 16 (indicated in dark grey) are subject to alternative splicing (50:50 distribution). Note: mutations in splice sites and genomic deletions grouped under (first) affected exon.