Scientists trace teenage boy’s ITP to mutation in ELF4 gene: Report
They showed that it disrupts activity of several types of immune cells
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A mutation in the gene ELF4 likely set the stage for a teenage boy to develop immune thrombocytopenia (ITP), according to a new report.
The scientists, led by researchers in Turkey, showed that this genetic mutation disrupts the activity of several types of immune cells, a finding they said probably contributed to his autoimmune disease.
“This case expands the clinical spectrum of [health disorders linked to ELF4 mutations] and underscores the relevance of evaluating ELF4 mutations in patients with unexplained cytopenias [blood cell disorders],” the scientists wrote.
The study, “A novel ELF4 gene variant disrupts T and NK cell function in a patient with immune thrombocytopenia (ITP),” was published in Inflammation Research.
ELF4 gene provides instructions to make protein of the same name
ITP is an autoimmune disorder in which the immune system erroneously attacks and destroys platelets, cell fragments that normally help blood to clot. As with most autoimmune diseases, the underlying causes of ITP are not fully understood. Genetic mutations are generally thought not to cause ITP outright, but genetic variations can alter immune cell activity, setting the stage for the disease to develop.
The gene ELF4 (E74-like ETS family transcription factor 4) provides instructions to make a protein, also called ELF4, that is known to help regulate the activity of certain immune cells, particularly T-cells and natural killer (NK) cells. Both T-cells and NK cells normally play vital roles in protecting the body against infections and cancers, but in autoimmune disorders such as ITP, these cells may also participate in the abnormal immune attack that drives the disease.
There have been previous reports of people with mutations in the ELF4 gene who develop immune disorders. But less than two dozen such cases have been reported, so much is still unknown about how mutations in this gene may dysregulate the activity of immune cells.
Boy’s mutation caused the protein to have a different amino acid
In this study, researchers described the case of a 14-year-old boy who had been diagnosed with ITP at age 10. He had tried a range of ITP treatments, including intravenous immunoglobulin and corticosteroids, Nplate (romiplostim), rituximab, and Promacta (eltrombopag), but none had effectively increased his platelet count. As of the latest follow-up, the boy was taking Promacta, and although he had persistently low platelet levels, he was not experiencing any bleeding-related symptoms.
The boy also had a history of ulcers (sores) on his mouth and lips, which led clinicians to suspect he might be experiencing inflammatory dysregulation beyond ITP itself. Based on this hypothesis, genetic sequencing tests were performed to identify mutations that might have contributed to his condition.
These tests revealed the boy had a mutation in the ELF4 gene. The ELF4 protein, like all proteins, is composed of building blocks called amino acids that are strung together in a long chain. The 608th position of the ELF4 protein normally contains a specific amino acid called glycine. But this boy’s mutation caused the protein to have a different amino acid, arginine.
Based on the specific biochemical properties of glycine and arginine, the researchers said that this substitution “can alter protein stability and regulatory interactions.”
The team then conducted detailed analyses of the boy’s immune cells. Among other alterations, they found abnormal growth and division of T-cell populations upon stimulation, which was consistent with impaired ELF4-dependent regulation of effector T-cells that destroy threats, helping eliminate infection and disease. In addition, NK cells showed signs of defective maturation and function.
Altogether, these data suggest that the boy’s ELF4 mutation likely disrupted the function of his immune cells, setting the stage for ITP to develop. The researchers noted that this boy also did not have a history of recurrent severe infections or digestive system problems, as documented in other patients carrying mutations in this gene. As such, they said this case expands the known spectrum of diseases possibly linked to ELF4 mutations.
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