3D virus cells attacking a DNA strand
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An international collaboration co-led by Vanderbilt University Medical Center has uncovered a new genetic disorder that leaves patients vulnerable to opportunistic infections. The research could lead to genetic diagnosis and treatments for this condition, and guide the search for so-called “multimorphic” genetic variants linked to other diseases.

There are more than 400 known genetic conditions that weaken the immune system, often called primary immunodeficiencies. These diseases can make patients more prone to infectious diseases and cancer in some cases.

Despite advances in DNA sequencing and a huge increase in the discovery of genetic mutations underlying primary immunodeficiencies, many patients lack a genetic diagnosis that can help them to access the right treatment. In addition, the complexity of these conditions and low number of patients available for study make it tough to unpick the biological mechanisms of primary immunodeficiencies.

In a study recently published in Science Immunology, researchers around the world teamed up to characterize a new type of immunodeficiency encountered in seven patients. Since infancy, these patients had been suffering from recurrent opportunistic infections including the life-threatening fungal pneumonia Pneumocystis jirovecii

When their genome was sequenced, all patients in the study had the same variant in a gene encoding a protein called interferon regulatory factor 4 (IRF4). This protein is a transcription factor that controls the expression of other genes, especially those essential for immune cells to develop and mature.

According to the study results, the patients’ immune B cells were unable to mature properly and produce antibodies to fight off infections. Additionally, the patients’ T cells were unable to produce enough cytokines such as interleukin-2, which are critical for immunity. When the team reproduced the same mutation in mouse models of disease, the mice showed similar impairments in producing antibodies to the patients.

With the help of a deep learning tool, the group established that the mutated IRF4 protein undergoes a mixture of changes compared to the healthy form of the protein. For example, the mutated protein binds more strongly to DNA when regulating gene expression, making the mutation “hypermorphic.” At the same, the mutated protein is less able to promote the genes that the healthy IRF4 does, making the change “hypomorphic,” and instead activates other genes—a type of change known as “neomorphic.” Because it has all these differences at once, the mutation’s effect is multimorphic, and leads to the immunodeficiency symptoms.

The authors wrote that they are not aware of any human diseases caused by the multimorphic combination of hypermorphic, hypomorphic, and neomorphic activity as displayed by this mutated IRF4 protein. They suggested that the condition be called multimorphic IRF4 combined immunodeficiency.

“Our findings will provide the basis for genetic diagnosis and preventive treatment for these groups of patients,” said Rubén Martínez-Barricarte, immunogeneticist at Vanderbilt University Medical Center, and one of the leaders of the research.

For several years, the protein IRF4 has been in the crosshairs of the international collaboration behind the study, named the IRF4 International Consortium. Dysfunction of this protein is linked to a very wide range of diseases, including immunodeficiencies and a range of cancers such as lymphoma, lung adenocarcinoma and myeloma.

The IRF4 International Consortium began when Martínez-Barricarte collaborated with colleagues in Mexico to study the genetics of a young patient with multimorphic IRF4 combined immunodeficiency. They discovered the mutation, which arose de novo in the child’s development and was not inherited from his parents. They then teamed up with seven other groups that were studying the same mutation independently, and formed the consortium.

IRF4 might not be the only transcription factor to produce multimorphic mutations, said the authors. There could be many multimorphic gene variants in disease waiting to be discovered.

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