IL12RB1 – Mendelian Susceptibility to Mycobacterial Disease due to Complete IL-12Rβ1 Deficiency

Autosomal recessive loss-of-function variants in IL12RB1 abrogate IL-12 and IL-23 receptor signaling, leading to Mendelian susceptibility to mycobacterial disease (MSMD). Patients present with severe infections by poorly pathogenic mycobacteria and Salmonella, often with mucocutaneous candidiasis.

Biallelic IL12RB1 mutations have been identified in 213 patients (PMID:29995221) across 164 unrelated kindreds (PMID:29995221), consistent with autosomal recessive inheritance. The variant spectrum includes 46% nonsense, frameshift, and splice-site mutations, as well as missense substitutions and large Alu-mediated copy number variations.

Segregation of IL12RB1 alleles has been demonstrated in multiple affected relatives, with 164 additional family members harboring biallelic variants and exhibiting clinical MSMD phenotypes (PMID:23864330). A representative pathogenic allele is c.592T>C (p.Cys198Arg), which disrupts the extracellular cytokine-binding domain and abolishes receptor function.

Functional assays including retroviral complementation of patient T cells confirm loss of IL-12Rβ1–dependent STAT4 phosphorylation and interferon-γ production, fully rescued by wild-type IL12RB1 (PMID:15178580, PMID:16293671). Structural modeling further delineates critical domain interfaces disrupted by missense variants.

A dedicated IL12RB1 variation database catalogs 70 morbid alleles, 66% causing premature termination or frameshifts, underscoring haploinsufficiency as the primary mechanism (PMID:23864330). Additionally, Alu-driven copy number variations in five families emphasize the need for CNV analysis in diagnostic workflows (PMID:29995221).

Integration of genetic and functional data provides definitive evidence for IL12RB1 as an autosomal recessive MSMD gene, supporting clinical genetic testing, targeted interferon-γ therapy, and family counseling. Key Take-home: IL12RB1 mutation analysis is essential for definitive diagnosis and management of MSMD.

References

• Blood • 2004 • A novel form of complete IL-12/IL-23 receptor beta1 deficiency with cell surface-expressed nonfunctional receptors PMID:15178580
• Human molecular genetics • 2005 • Molecular complementation of IL-12Rbeta1 deficiency reveals functional differences between IL-12Rbeta1 alleles including partial IL-12Rbeta1 deficiency PMID:16293671
• Human mutation • 2013 • IL-12Rβ1 deficiency: mutation update and description of the IL12RB1 variation database PMID:23864330
• Journal of clinical immunology • 2018 • A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency PMID:29995221

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