Mutual alteration of NOD2-associated Blau syndrome and IFNγR1 deficiency

  • Zuzana ParackovaEmail author
  • Marketa Bloomfield
  • Petra Vrabcova
  • Irena Zentsova
  • Adam Klocperk
  • Tomas Milota
  • Michael Svaton
  • Jean-Laurent Casanova
  • Jacinta Bustamante
  • Eva Fronkova
  • Anna Sediva


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.


NOD2 IFNγR1 IFNγ WES MSMD Blau syndrome methotrexate 


Author contribution

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.

Funding information

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics statement

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.

Supplementary material

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Supplementary Figure 1

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High resolution image (TIF 3003 kb)


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Copyright information

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

Authors and Affiliations

  • Zuzana Parackova
    • 1
    Email author
  • Marketa Bloomfield
    • 1
    • 2
  • Petra Vrabcova
    • 1
  • Irena Zentsova
    • 1
  • Adam Klocperk
    • 1
  • Tomas Milota
    • 1
  • Michael Svaton
    • 3
  • Jean-Laurent Casanova
    • 4
    • 5
    • 6
    • 7
    • 8
  • Jacinta Bustamante
    • 4
    • 5
    • 6
    • 9
  • Eva Fronkova
    • 3
  • Anna Sediva
    • 1
  1. 1.Department of Immunology, 2nd Faculty of MedicineCharles University and Motol University HospitalPrague 5Czech Republic
  2. 2.Department of Pediatrics1st Faculty of Medicine Charles University and Thomayer’s HospitalPragueCzech Republic
  3. 3.CLIP - Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic
  4. 4.Laboratory of Human Genetics of Infectious Diseases, Necker BranchINSERM U1163, Necker Hospital for Sick ChildrenParisFrance
  5. 5.Imagine InstituteParis Descartes UniversityParisFrance
  6. 6.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller UniversityNew YorkUSA
  7. 7.Howard Hughes Medical InstituteNew YorkUSA
  8. 8.Pediatric Hematology-Immunology UnitNecker Hospital for Sick Children, AP-HPParisFrance
  9. 9.Study Center for Primary ImmunodeficienciesAP-HP, Necker Children HospitalParisFrance

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