Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis

  • Noor ul Akbar
  • Shahid Niaz Khan
  • Muhammad Usman Amin
  • Muhammad Ishfaq
  • Otavio Cabral-Marques
  • Lena F Schimke
  • Asif Iqbal
  • Ikram Ullah
  • Mubashir Hussain
  • Ijaz Ali
  • Nasar Khan
  • Nadia El Khawanky
  • Hazir Rahman
  • Taj Ali KhanEmail author
Original Article


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.


IL-12Rβ1 Novel mutation IFNγ Tuberculosis 









Bacille Calmette–Guérin


Cytokine-binding region


Non-tuberculous mycobacteria


Tyrosine-protein kinase


Janus kinase


Primary immunodeficiencies


Severe combined immunodeficiency


Glucose-6-phosphate dehydrogenase


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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Noor ul Akbar
    • 1
  • Shahid Niaz Khan
    • 1
  • Muhammad Usman Amin
    • 2
  • Muhammad Ishfaq
    • 3
  • Otavio Cabral-Marques
    • 4
  • Lena F Schimke
    • 4
  • Asif Iqbal
    • 5
  • Ikram Ullah
    • 6
  • Mubashir Hussain
    • 7
  • Ijaz Ali
    • 8
  • Nasar Khan
    • 9
  • Nadia El Khawanky
    • 10
    • 11
  • Hazir Rahman
    • 12
  • Taj Ali Khan
    • 7
    Email author
  1. 1.Department of ZoologyKohat University of Science and TechnologyKohatPakistan
  2. 2.Department of PharmacyAbasyn UniversityPeshawarPakistan
  3. 3.Centre for Omic SciencesIslamia College UniversityPeshawarPakistan
  4. 4.Center for Chronic Immunodeficiency (CCI), Medical Center – University of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburg im BreisgauGermany
  5. 5.Department of PharmacologyUniversity of Illinois at ChicagoChicagoUSA
  6. 6.Suliman Bin Aba-Alkhail Center for Interdisciplinary Research in Basic Sciences (SA-CIRBS)International Islamic UniversityIslamabadPakistan
  7. 7.Department of MicrobiologyKohat University of Science and TechnologyKohatPakistan
  8. 8.Department of BiosciencesCOMSATS University IslamabadIslamabadPakistan
  9. 9.Interdisciplinary Nanoscience CenterAarhus UniversityAarhusDenmark
  10. 10.Department of Hematology, Oncology and Stem Cell TransplantationFreiburg University Medical CenterFreiburgGermany
  11. 11.Precision Medicine ThemeThe South Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
  12. 12.Department of Microbiology, Faculty of Health SciencesAbdul Wali Khan University Mardan (AWKUM)MardanPakistan

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