Discovery of a new genetic disease predisposing to mycobacterial infections

MSMD, or mendelian susceptibility to mycobacterial diseases, is a group of rare diseases resulting in susceptibility to severe infections with usually low virulence mycobacteria. To date, 32 genetic defects in 17 genes, inborn errors of interferon gamma (IFN-γ)-related immunity, have been identified as possibly causing MSMD. Jacinta Bustamante's group, in the laboratory of Jean-Laurent Casanova, is dedicated to the research and elucidation of its genetic and immunological causes. Today, the team has discovered a new genetic defect that causes MSMD: mutations in the ZNFX1 gene, which was previously poorly understood and unidentified for this disease.

Published on 09.04.2021

Research Acceleration

A common thread in severe mycobacterial infections: interferon-gamma-related genetic defects

Although mycobacteria present in our environment or the live bacille Calmette et Guérin (BCG) vaccine do not generally cause disease, some people sometimes develop severe infections that can lead to death.

For 25 years, the laboratory of Prof. Jean-Laurent Casanova and Dr. Laurent Abel, at Institut Imagine (Université de Paris/AP-HP/Inserm) on the site of the Hôpital Necker-Enfants malades AP-HP, and at the Rockefeller University in New York, has been interested in understanding why people exposed to an infectious agent will or will not develop more or less severe forms of infection. 

Within the laboratory, Dr. Jacinta Bustamante's group studies genetic defects that render certain immune mechanisms ineffective against mycobacterial infections.

In the course of its work, the laboratory has demonstrated that these severe reactions to mycobacterial infections are due to insufficient production of IFN-γ by lymphoid cells, and/or altered responses of myeloid cells to this cytokine. To date, 32 genetic defects in 17 genes, all have in common that they alter the production and/or response to IFN-γ, a key player in our immune response to fight these infections. Very recently, the laboratory had for example demonstrated the role of the transcription factor T-bet (TBX21) in the innate immune response and the consequences when it is mutated, and discovered the first mutation affecting the IFNG gene coding for the key cytokine of antimycobacterial immunity. (links to dedicated website articles).

A new genetic disease and a new gene identified

Tom Le Voyer, an internist and science thesis student in Jacinta Bustamante's group, studied four patients from two unrelated families, whose members had mycobacterial disease, with BCG infection and disseminated tuberculosis (severe form), and intermittent elevation of their monocyte counts. None of them had a previously known innate IFN-γ error.

Mutations in the ZNFX1 gene were found in these patients, resulting in a defect in the expression of the ZNFX1 protein, which is expressed in myeloid cells called monocytes. The team also showed a link between the protein and ribonucleoprotein granules, called stress granules, which play a role in protecting the body from stress, transcribing messenger RNA and carrying out specific biological and immune processes.

This study shows that inherited deficiency of the stress granule-associated protein ZNFX1 plays an important role in monocyte homeostasis and protective immunity against mycobacteria. This is a new genetic etiology of MSMD and tuberculosis involving intermittent monocytosis. The team will continue to develop its research on this protein, its involvement in mycobacterial infections, particularly tuberculosis, and its interaction with messenger RNA.



* Jacinta Bustamante* is a senior lecturer at Université de Paris, a researcher in the team "Human genetics of infectious diseases: monogenic predisposition" (Inserm/Institute Imagine) directed by Jean-Laurent Casanova and a biologist at the Center for the Study of Immune Deficiencies (CEDI) - DMU Medical Biology, Genomic Medicine and Physiology, at the Necker-Enfants Malades Hospital AP-HP Centre.

**Jean-Laurent Casanova is Professor at Université de Paris/Necker-Enfants Malades AP-HP Centre and at the Rockefeller University in New York, and also Director of an Inserm research laboratory at Institut Imagine and the Howard Hughes Medical Institute in New York.

***Laurent Abel is co-founder of the Laboratory of Human Genetics of Infectious Diseases, an international Inserm laboratory organized in two branches, one at the Rockefeller in New York and the other at Institut Imagine.