Mutated Transcription Factor Defies Current Understandings of Genetic Mutation

A digital representation of the human genome at the American Museum of Natural History in New York City on Aug. 15, 2001. Each color represents one the four chemical compenents of DNA. Mario Tama/Getty Images

An international team of scientists has identified a novel and extremely rare genetic mutation with unprecedented capabilities that may change the world’s understanding of immune deficiencies.

The mutation has been named T95R and causes a host of changes to the transcription factor IRF4—a protein that is crucial for the development and function of the immune system. Transcription factors are proteins that bind to regions of DNA and regulate gene production.

“The mutation in question is different from others,” said a member of the international team, Associate Prof. Anselm Enders from the Australian National University (ANU), in a university release.

“It doesn’t just enhance or reduce the ability of the protein to bind to DNA, it also allows the transcription factor to connect with other regions that were previously incompatible,” Enders said.

“A mutation will normally cause just one of those responses. For one mutation to do all three is very rare,” Enders said.

However, another member of the team and the Chief of Immunology Service at the National Institutes of Health, Dr Sergio D. Rosenzweig noted in an email to The Epoch Times that the terms compatible or incompatible don’t correctly apply to this situation.

Research technicians prepare DNA samples to be sequenced in the production lab of the New York Genome Center in New York City, on Sept. 19, 2013. Andrew Burton/Getty Images

Unique Capabilities of Mutation

Dr. Rosenzweig said that, like other transcription factors, the transcription factor IRF4 binds to specific areas on the DNA. He said that IRF4 binds to canonical consensus sequences, where they up-regulate or down-regulate the production (transcription) of particular genes, all together called the transcriptome.

Dr Rosenzweig said that the uncovered mutation makes IRF4 not only bind more strongly to its specific binding areas on the DNA, but also makes it bind to thousands of non-specific areas (noncanonical consensus sequences). He said that the mutation completely disrupted the transcriptome landscape in these patients.

Dr Rosenzweig said that the name multimorphic was invented for this novel disease mechanism. He said that this was because, in comparison to the common (wild type) IRF4, the uncovered IRF4 T95R mutation simultaneously acts by different mechanisms of action.

A medical employee uses a microscope at a microbiology laboratory in Bucharest, Romania, on April 12, 2018. Daniel Mihailescu/AFP/Getty Images

Dangers of Mutation

The mutation was first noticed in Germany when colleagues and long-term collaborators observed a hospital patient that was experiencing recurrent infections and sequenced their DNA.

The unknown and bizarre T95R mutation was revealed in the sequencing, and through collaboration, international colleagues realized that they had all found patients with very similar clinical presentations.

The mutation has been identified in seven hospital patients around the world who are from six unrelated families and don’t share an age or gender group. Prof. Enders said that all of the patients demonstrated a high susceptibility to infections and were subsequently experiencing similar symptoms.

“In fact, they all had infections with one particular pathogen, one that is harmless for most people but causes severe lung infection for those with serious immunodeficiency,” he said.

The researchers believe that if the mutation can cause a host of changes in IRF4 it’s likely to occur in other transcription factors.

“By understanding how mutations of this nature work, we can better understand the mechanisms of disease,” Enders said.

A lab technician works in the Emergency Department at Providence St. Mary Medical Center in Apple Valley, Calif., on March 11, 2022. Mario Tama/Getty Images

Mutations Impact on T and B Cells

The transcription factor IRF4 is crucial for the development of the immune system, especially for T and B cells.

“T cells and B cells are part of the “adaptive” immune system (the other part is the “innate” immune system),” said Dr. Rosenzweig.

“The adaptive immune system learns and adjusts to respond to particular triggers as infections and vaccines.”

“While the T cells are in charge of coordinating (e.g., T helper) or execute the work (e.g., effector), B cells produce antibodies that tag or kill the triggers of the immune response,” he said.

An example of IRF4’s role in the development of T-cells, is its essentialness in the function of certain memory T-cells that give a strengthened protective response against previously encountered antigens. And for B-cells, IRF4 controls important events during their development, such as germinal centre reactions and plasma cell differentiation, which are key components of the adaptive immune system.

A nurse uses a wireless electronic tablet to order medicines from the pharmacy at The Queen Elizabeth Hospital in Birmingham. Christopher Furlong/Getty Images

Treatments for Patients with Mutation

Dr. Rosenzweig said that treatments for patients with multimorphic IRF4 combined immunodeficiency could be divided into prophylactic or symptomatic of the complications, and curative of the disease.

He recommended that patients with this condition receive immunoglobulin replacement therapy and anti-infectious drugs such as trimethoprim-sulfamethoxazole as prophylactic medications. These medications are used because these patients have very low immunoglobulins and increased susceptibility to particular infectious diseases such as Pneumocystis jirovecci.

He also said that when infections break through, patients are treated with specific anti-infectious agents against the microbes that they have been infected with.

“As for curing multimorphic IRF4 combined immunodeficiency, bone marrow transplantation has been curative in two of the patients we reported in our work,” he said.