Mutual alteration of NOD2-associated Blau syndrome and IFNγR1 deficiency
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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.
KeywordsNOD2 IFNγR1 IFNγ WES MSMD Blau syndrome methotrexate
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.
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.
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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