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Mutual alteration of NOD2-associated Blau syndrome and IFNγR1 deficiency

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Abstract

Blau syndrome (BS) is an auto-inflammatory granulomatous disease that possibly involves abnormal response to interferon gamma (IFNγ) due to exaggerated nucleotide-binding oligomerization domain containing 2 (NOD2) activity. Mendelian susceptibility to mycobacterial diseases (MSMD) is an infectious granulomatous disease that is caused by impaired production of or response to IFNγ. We report a mother and daughter who are both heterozygous for NOD2c.2264C˃T variant and dominant-negative IFNGR1818del4 mutation. The 17-year-old patient displayed an altered form of BS and milder form of MSMD, whereas the 44-year-old mother was completely asymptomatic. This experiment of nature supports the notion that IFNγ is an important driver of at least some BS manifestations and that elucidation of its involvement in the disease immunopathogenesis may identify novel therapeutic targets.

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Funding

This work was supported by grants GAUK 460218 and 954218 issued by the Charles University in Prague, Czech Republic, and AZV NV18-05-00162 from the Ministry of Health of the Czech Republic.

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Author notes

  1. Zuzana Parackova and Marketa Bloomfield contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 15006, Prague 5, Czech Republic

    Zuzana Parackova, Marketa Bloomfield, Petra Vrabcova, Irena Zentsova, Adam Klocperk, Tomas Milota & Anna Sediva

  2. Department of Pediatrics, 1st Faculty of Medicine Charles University and Thomayer’s Hospital, Prague, Czech Republic

    Marketa Bloomfield

  3. CLIP - Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

    Michael Svaton & Eva Fronkova

  4. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France

    Jean-Laurent Casanova & Jacinta Bustamante

  5. Imagine Institute, Paris Descartes University, Paris, France

    Jean-Laurent Casanova & Jacinta Bustamante

  6. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Jean-Laurent Casanova & Jacinta Bustamante

  7. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  8. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France

    Jean-Laurent Casanova

  9. Study Center for Primary Immunodeficiencies, AP-HP, Necker Children Hospital, Paris, France

    Jacinta Bustamante

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  1. Zuzana Parackova
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Contributions

ZP designed the study, performed the experiments, analyzed and interpreted the results, co-wrote the manuscript, and supervised all work. MB treated the patient, interpreted the results, and co-wrote the manuscript. PV, IZ, MR, and AK performed the experiments and analyzed the data. TM provided clinical information. EF and MS performed genetic analysis. JB and JLC revised the manuscript and contributed to the discussion. AS treated the patient and supervised the manuscript preparation. All authors contributed to manuscript revision, read and approved the submitted version.

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Correspondence to Zuzana Parackova.

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The authors declare that they have no conflicts of interest.

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This study was carried out in accordance with the recommendation of the Ethical Committee of the 2nd Faculty of Medicine, Charles University, in Prague and University Hospital in Motol, Czech Republic. The protocol was approved by the Ethical Committee and all subjects gave informed consent in accordance with the Declaration of Helsinki.

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Summary

A kindred harboring NOD2c.2264C˃T and IFNGR1818del4 mutations is reported, manifesting as combined phenotype of altered Blau syndrome and mitigated partial IFNγR1 deficiency.

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Parackova, Z., Bloomfield, M., Vrabcova, P. et al. Mutual alteration of NOD2-associated Blau syndrome and IFNγR1 deficiency. J Clin Immunol 40, 165–178 (2020). https://doi.org/10.1007/s10875-019-00720-6

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