Researchers identify link between BRF2 gene mutations and rare diseases

A patient and his family, who had suffered from unexplained immunodeficiency, developmental disorders, and lymphoma for 16 years, have finally found the genetic cause.

This breakthrough was made possible by a Korean research team that newly discovered the link between mutations in the BRF2 gene—essential for maintaining cellular homeostasis—and rare diseases, elucidating the underlying pathogenesis for the first time worldwide.

On Tuesday, Seoul National University Hospital (SNUH) announced that a joint research team analyzed genomic and cellular data from patients with undiagnosed rare diseases and their families. They identified that BRF2 mutations could be the cause of rare immune deficiency and developmental disorders.

The joint research team was led by Professors Chae Jong-hee and Lee Seung-bok of the Department of Clinical Genomics at SNUH, student Kwon Hae-yoon of the Seoul National University College of Medicine, and Professor Kim Keun-pil and Dr. Yoon Seo-bin of the Department of Life Sciences at Chung-Ang University.

BRF2 is a gene essential for cell survival and homeostasis. It forms a complex with other genes to induce the production of selenocysteine tRNA (SeCys-tRNA), a necessary component for protein synthesis. Proteins synthesized using SeCys tRNA play a crucial role in protecting cells from damage caused by reactive oxygen species and maintaining redox balance.

However, research on BRF2-related diseases has been scarce, and the possibility of treating this mutation has never been explored.

The research team performed whole-exome sequencing on a pediatric patient exhibiting complex symptoms, including congenital immune deficiency, multisystem malformations, intellectual disability, and lymphoma, along with their family. Analysis revealed that an autosomal recessive mutation—each parent passing down a different variant—was the cause. Subsequent 3D structural analysis and single-cell RNA sequencing elucidated the impact of the mutation on cellular function.

The results showed the BRF2 mutation disrupted gene complex formation, reducing SeCys tRNA, which is essential for protein synthesis. This led to a significant reduction in the expression of antioxidant proteins (such as GPX4 and GPX1) that protect cells from reactive oxygen species within specific blood cell populations, making the cells vulnerable to oxidative stress.

Furthermore, under oxidative stress conditions, the expression of the BRF2 gene itself was suppressed, reducing SeCys tRNA production and creating a vicious cycle of increased vulnerability. The researchers explained that these changes cause cascading problems affecting immune function, development, and genomic stability.

Additionally, through further experiments, the team found that supplementing damaged cells with antioxidants (selenium) significantly restored GPX4 protein expression. This result demonstrates the potential for pharmacological improvement in BRF2-related diseases.

“This study demonstrates the importance and value of research into undiagnosed rare diseases,” Professor Chae said. “It is highly significant that, after prolonged exploration by physicians and life scientists alongside patients and their families, we identified a target substance that could lead to treatment, offering a small clue toward overcoming rare diseases.”

Professor Kim remarked, “We plan to continue our efforts to enable this patient and their family to determine treatment directions through clinical research. Furthermore, we will continue research to identify the causes of rare diseases and establish treatment platforms.”