Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
Image credit: Shutterstock/Dmitry Naumov.
Contributed by Jean-Laurent Casanova, March 5, 2021 (sent for review February 11, 2021; reviewed by Marcel A. Behr and Anne Sophie Korganow)
Significance
Mendelian susceptibility to mycobacterial disease (MSMD) is defined by selective vulnerability to weakly virulent mycobacteria. The 32 known inborn errors of IFN-γ immunity account for MSMD in about half of the patients, and for a smaller proportion of cases of tuberculosis (TB). We report homozygous ZNFX1 variants in two families in which the index cases had MSMD or TB with intermittent monocytosis. Upon overexpression, the two variants encode truncated proteins. We show that human ZNFX1 is localized in ribonucleoprotein granules called stress granules. The patients’ production of and response to IFN-γ are apparently intact, and the patients have not experienced severe viral illnesses. Inherited deficiency of stress granule-associated ZNFX1 is a genetic etiology of MSMD or TB with intermittent monocytosis.
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.
Footnotes
↵1A.-L.N., R.Y., and M.O. contributed equally to this work.
↵2F.A.M., V.B., D.W., S.A.M., A.F., S.-Y.Z., B.R., and S.B.-D. contributed equally to this work.
↵3J.-L.C. and J.B. contributed equally to this work.
- ↵4To whom correspondence may be addressed. Email: jean-laurent.casanova{at}rockefeller.edu or jacinta.bustamante{at}inserm.fr.
Author contributions: T.L.V., J.-L.C., and J.B. designed research; T.L.V., A.-L.N., R.Y., J.R., M.O., M. Alshalan, F.A.A., T.K., M. Ata, C.G., D.B., N.M., F.A.M., V.B., and S.B.-D. performed research; M.R., M.C., S.-Y.Z., and S.B.-D. contributed new reagents/analytic tools; M. Alshalan, F.A.A., T.K., M. Ata, P.B., Y.S., F. Rapaport, B.B., L.B., N.B., L.A., N.M., F.A.M., D.W., and S.-Y.Z. analyzed data; T.L.V., J.-L.C., and J.B. wrote the paper; T.L.V., S.B.-D., and J.B. recorded the clinical data and created the figures; F.A., S.B., D.S., S.A.-M., A.B.-A., D.M., F.A.M., S.A.M., A.F., and B.R. provided samples and performed clinical diagnosis and follow-up of the kindreds; L.R. and A.D. recorded the clinical data; and F. Rozenberg performed viral serological analyses.
Reviewers: M.A.B., McGill International TB Centre; and A.S.K., Strasbourg University Hospital.
The authors declare no competing interest.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2102804118/-/DCSupplemental.
Data Availability
All study data are included in the article and SI Appendix.
Published under the PNAS license.
References
Log in using your username and password
Log in through your institution
You may be able to gain access using your login credentials for your institution. Contact your library if you do not have a username and password.
If your organization uses OpenAthens, you can log in using your OpenAthens username and password. To check if your institution is supported, please see this list. Contact your library for more details.
Purchase access
You may purchase access to this article. This will require you to create an account if you don't already have one.
Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease
Article Classifications
- Biological Sciences
- Genetics
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Recent experiments and simulations are starting to answer some fundamental questions about how life came to be.
Image credit: Shutterstock/Radoslaw Lecyk.
Archaeologists have long tried to define the transition between the two time periods.
Image credit: Ceri Shipton.
Adam Mastroianni and Daniel Gilbert explore why conversations almost never end when people want them to.
A study finds that giant pandas roll in horse manure to increase their cold tolerance.
Image credit: Fuwen Wei.