New genetic disorder that causes susceptibility to opportunistic infections revealed in new study

An international consortium, has discovered a new genetic disorder that causes immunodeficiency and profound susceptibility to opportunistic infections including a life-threatening fungal pneumonia.

The error in this case of in-born error of immunity or IEI is a mutation in the gene for the protein IRF4, a transcription factor that is pivotal for the development and function of B and T white blood cells, as well as other immune cells.

In the current study, the consortium identified seven patients from six unrelated families across four continents with profound combination immunodeficiency who experienced recurrent and serious infections, including pneumonia caused by the fungus Pneumocystis jirovecii. Each patient had the same mutation in the DNA-binding domain of IRF4.

Extensive phenotyping of patients’ blood cells revealed immune cell abnormalities associated with the disease, including impaired maturation of antibody-producing B cells, and reduced T-cell production of infection-fighting cytokines.

Two knock-in mouse models, in which the mutation was inserted into the mouse genome, exhibited a severe defect in antibody production consistent with the combined immune deficiency observed in the patients. The researchers also discovered the mutation had a “multimorphic” effect detrimental to the activation and differentiation of immune cells.

While the mutant IRF4 binds to DNA with a higher affinity than the native form of the protein (in a hypermorphic way), its transcriptional activity in common, canonical genes is reduced (hypomorphic), and it binds to other DNA sites (in a neomorphic way), altering the protein’s normal gene expression profile.

Reference:

Rubén Martínez-Barricarte et al,A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency,Science Immunology,doi 10.1126/sciimmunol.ade7953