Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• The interleukin (IL)-12/interferon (IFN)-γ axis is crucial for controlling mycobacterial infections.
• Defects in this pathway lead to increased susceptibility to mycobacterial diseases.

Observation:

• A female Pakistani patient from a consanguineous marriage presented with severe bacille Calmette-Guérin (BCG) infection and recurrent tuberculosis.
• Enzyme-linked immunosorbent assay (ELISA), flow cytometry, and Sanger sequencing were used for investigation.

Findings:

• The patient exhibited significantly reduced IFNγ production from peripheral blood mononuclear cells (PBMCs).
• Flow cytometry showed no IL-12 receptor beta 1 (IL-12Rβ1) surface expression on activated T lymphocytes.
• A novel nonsense mutation (c.199G>T/p.E67*) in the IL-12Rβ1 gene was identified, leading to a truncated, likely inactive protein.
• Impaired STAT4 phosphorylation was observed in the patient's lymphocytes upon IL-12 stimulation.

Implications:

• This study expands the known genetic variations associated with IL-12Rβ1 deficiency.
• The findings underscore the importance of newborn screening for primary immunodeficiencies in regions with mandatory BCG vaccination.
• Early diagnosis and intervention can improve treatment outcomes and quality of life for affected individuals.