Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis
The interleukin (IL)-12/interferon(IFN)γ axis plays an important role in the control of mycobacterial diseases as demonstrated by the increased susceptibility to mycobacterial species in patients with an inborn error of the IL-12-dependent IFNγ immunity. Here, we report a novel mutation in the IL-12Rβ1 gene in a female Pakistani patient who was born in a consanguineous marriage and developed severe bacille Calmette–Guérin (BCG) infection and recurrent tuberculosis. After reviewing the patient’s clinical records, she was investigated for IL-12/IFNγ defects using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and DNA genetic Sanger sequencing. Quantification of secretory cytokines from the patient’s peripheral blood mononuclear cells (PBMCs) revealed significantly reduced IFNγ production. Flow cytometric analysis revealed no surface expression of IL-12Rβ1 on PHA-activated T lymphocytes. In addition, IL-12-induced impaired STAT4 phosphorylation in the patient’s lymphocytes when compared with those from five healthy controls. The genetic analysis of IL-12Rβ1 gene identified a novel nonsense mutation c.199G>T/p.E67* within exon 3, which encodes part of the cytokine-binding region (CBR). In silico analysis indicates that this novel nonsense mutation generates a truncated protein with an apparent inactivating effect. Our data expand the genetic spectrum of IL-12Rβ1 deficiency. Moreover, our findings highlight the need for developing newborn screening for patients with primary immunodeficiency associated with mycobacterial infections in areas where BCG vaccination is mandatory in order to improve the treatment of patients, and consequently their quality of life.
KeywordsIL-12Rβ1 Novel mutation IFNγ Tuberculosis
Severe combined immunodeficiency
NF-kappa B essential modulator
Mendelian susceptibility to mycobacterial disease
Fibronectin type-III domain
Compliance with ethical standards
The patient and healthy controls (all from Pakistan; mean age, 20 years old) provided written consent to participate in the study, and their blood sample was collected according to the institutional guidelines for functional and molecular characterization. The study was approved by the ethics committee of Kohat University of Science and Technology, Kohat, Pakistan.
Conflict of interest
The authors declare that they have no conflict of interest.
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