Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis

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  • Noor ul Akbar, Kohat University of Science and Technology (KUST)
  • ,
  • Shahid Niaz Khan, Kohat University of Science and Technology (KUST)
  • ,
  • Muhammad Usman Amin, Abasyn University
  • ,
  • Muhammad Ishfaq, Islamia College University
  • ,
  • Otavio Cabral-Marques, University of Freiburg
  • ,
  • Lena F. Schimke, University of Freiburg
  • ,
  • Asif Iqbal, University of Chicago, Chicago, Illinois.
  • ,
  • Ikram Ullah, International Islamic University Islamabad
  • ,
  • Mubashir Hussain, Kohat University of Science and Technology (KUST)
  • ,
  • Ijaz Ali, COMSATS University Islamabad
  • ,
  • Nasar Khan
  • Nadia El Khawanky, University of Freiburg, South Australian Health And Medical Research Institute
  • ,
  • Hazir Rahman, Abdul Wali Khan University Mardan
  • ,
  • Taj Ali Khan, Department of Microbiology, Kohat University of Science and Technology (KUST)

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.

Original languageEnglish
JournalImmunologic Research
Pages (from-to)408-415
Number of pages8
Publication statusPublished - Oct 2019

    Research areas

  • IFNγ, IL-12Rβ1, Novel mutation, Tuberculosis

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