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Pathog Dis. 2019 Apr 1;77(3). pii: ftz030. doi: 10.1093/femspd/ftz030.

Characterization of two novel mutations in IL-12R signaling in MSMD patients.

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Department of Immunology, School of Medicine, Iran University of Medical Sciences Tehran, Iran.
Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
Department of biology, School of basic sciences, University of Sistan and Balouchestan, Zahedan, Iran.
Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.


Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare syndrome with infections-among other complications-after Bacillus Calmette-Guerin (BCG) vaccination in children. We focused on the IL-12/IFN-γ pathway to identify new mutations in our patients. This study included 20 patients by vulnerability to mycobacteria and clinical manifestations of severe, recurrent infections. Blood samples were activated with BCG, BCG + IL-12 and BCG + IFN-γ. Cytokine levels were analyzed by ELISA. Measurements of IL-12Rβ1 and IL-12Rβ2 on the surface of peripheral blood mononuclear cells were performed by flow cytometry. To detect genetic defects, next-generation sequencing was performed by Thermo Fisher immunodeficiency panel. Flow cytometry analysis of 20 patients indicated reduction in IL-12R (β1/β2) expression in seven patients who showed incomplete production of IFN-γ by ELISA. In the patient with reduced IL-12 production, IFN-γR and IL-12R (β1/β2) expression levels were normal. Mutation analysis showed three previously reported mutations, two novel mutations in IL-12 R (β1/β2), and one previously reported mutation in IL-12.


Disseminated BCG infection; IFN-γR; IL-12R β1; IL-12R β2; MSMD


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