2. Academic Validation
  3. Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease

Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease

  • Proc Natl Acad Sci U S A. 2021 Apr 13;118(15):e2102804118. doi: 10.1073/pnas.2102804118.
Tom Le Voyer 1 2,  Anna-Lena Neehus 1 2,  Rui Yang 3,  Masato Ogishi 3,  Jérémie Rosain 1 2,  Fayhan Alroqi 4 5,  Maha Alshalan 6,  Sophie Blumental 7,  Fatima Al Ali 8,  Taushif Khan 8,  Manar Ata 8,  Laurence Rozen 9,  Anne Demulder 9,  Paul Bastard 1 2,  Conor Gruber 10 11 12,  Manon Roynard 1 2,  Yoann Seeleuthener 1 2,  Franck Rapaport 3,  Benedetta Bigio 3,  Maya Chrabieh 1 2,  Danielle Sng 13,  Laureline Berteloot 14,  Nathalie Boddaert 2 14,  Flore Rozenberg 15,  Saleh Al-Muhsen 16,  Aida Bertoli-Avella 17,  Laurent Abel 1 2 3,  Dusan Bogunovic 9 10 11,  Nico Marr 8 18,  Davood Mansouri 19 20,  Fuad Al Mutairi 5 6,  Vivien Béziat 1 2 3,  Dominique Weil 21,  Seyed Alireza Mahdaviani 19,  Alina Ferster 22,  Shen-Ying Zhang 1 2 3,  Bruno Reversade 13,  Stéphanie Boisson-Dupuis 1 2 3,  Jean-Laurent Casanova 23 2 3 24,  Jacinta Bustamante 23 2 3 25
Affiliations

Affiliations

  • 1 Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, 75015 Paris, France.
  • 2 Imagine Institute, University of Paris, 75015 Paris, France.
  • 3 St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065.
  • 4 Immunology Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia.
  • 5 King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia.
  • 6 Genetics & Precision Medicine Department, King Abdullah Specialized Children's Hospital, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia.
  • 7 Paediatric Infectious Diseases Unit, Queen Fabiola Children's University Hospital, 1020 Brussels, Belgium.
  • 8 Research Branch, Sidra Medicine, Doha, Qatar.
  • 9 Laboratory of Hematology LHUB-ULB, Free University of Brussels ULB, 1020 Brussels, Belgium.
  • 10 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 11 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 12 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 13 Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore, Agency for Science, Technology and Research, 138648 Singapore.
  • 14 Pediatric Radiology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, 75015 Paris, France.
  • 15 Virology Laboratory, Cochin Hospital, University of Paris, 75014 Paris, France.
  • 16 Immunology Research Laboratory, College of Medicine, King Saud University, Riyadh 114362, Saudi Arabia.
  • 17 Department of Genomic Research, CENTOGENE GmbH, 18055 Rostock, Germany.
  • 18 College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
  • 19 Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19569-44413, Iran.
  • 20 Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19569-44413, Iran.
  • 21 Laboratory of Biology of Development, Institute of Biology Paris Seine (IBPS), CNRS, Sorbonne University, 75005, Paris, France.
  • 22 Hemato-oncology Unit, Queen Fabiola Children's University Hospital, Brussels 1020, Belgium.
  • 23 Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, 75015 Paris, France; [email protected] [email protected].
  • 24 HHMI, New York, NY 10065.
  • 25 Study Center of Immunodeficiencies, Necker Hospital for Sick Children, 75015 Paris, France.
PMID: 33876776 DOI: 10.1073/pnas.2102804118
Abstract

Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.

Keywords

ZNFX1; inborn error of immunity; inflammation; monocytosis; mycobacteria.

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