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Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis

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Abstract

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.

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Abbreviations

TB:

Tuberculosis

IL:

Interleukin

IFN:

Interferon

BCG:

Bacille Calmette–Guérin

CBR:

Cytokine-binding region

NTM:

Non-tuberculous mycobacteria

TYK:

Tyrosine-protein kinase

JAK:

Janus kinase

PIDs:

Primary immunodeficiencies

SCID:

Severe combined immunodeficiency

G6PD:

Glucose-6-phosphate dehydrogenase

NEMO:

NF-kappa B essential modulator

MSMD:

Mendelian susceptibility to mycobacterial disease

FNIII:

Fibronectin type-III domain

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Author information

Authors and Affiliations

  1. Department of Zoology, Kohat University of Science and Technology, Kohat, Pakistan

    Noor ul Akbar & Shahid Niaz Khan

  2. Department of Pharmacy, Abasyn University, Peshawar, KPK, Pakistan

    Muhammad Usman Amin

  3. Centre for Omic Sciences, Islamia College University, Peshawar, Pakistan

    Muhammad Ishfaq

  4. Center for Chronic Immunodeficiency (CCI), Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany

    Otavio Cabral-Marques & Lena F Schimke

  5. Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA

    Asif Iqbal

  6. Suliman Bin Aba-Alkhail Center for Interdisciplinary Research in Basic Sciences (SA-CIRBS), International Islamic University, Islamabad, Pakistan

    Ikram Ullah

  7. Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan

    Mubashir Hussain & Taj Ali Khan

  8. Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan

    Ijaz Ali

  9. Interdisciplinary Nanoscience Center, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus, Denmark

    Nasar Khan

  10. Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Freiburg, Germany

    Nadia El Khawanky

  11. Precision Medicine Theme, The South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia

    Nadia El Khawanky

  12. Department of Microbiology, Faculty of Health Sciences, Abdul Wali Khan University Mardan (AWKUM), Mardan, KPK, Pakistan

    Hazir Rahman

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  1. Noor ul Akbar
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Corresponding author

Correspondence to Taj Ali Khan.

Ethics declarations

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.

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The authors declare that they have no conflict of interest.

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ul Akbar, N., Khan, S.N., Amin, M.U. et al. Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis. Immunol Res 67, 408–415 (2019). https://doi.org/10.1007/s12026-019-09094-8

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