[Hinews] In a major advance for rare disease research, a patient who endured unexplained immunodeficiency, developmental disorders, and lymphoma for 16 years has finally received a genetic diagnosis. A collaborative team from Seoul National University Hospital and Chung-Ang University has, for the first time, established that mutations in the BRF2 gene can directly cause such conditions, while also uncovering the underlying disease mechanisms—a world first.

The study was jointly led by Professor Jong-Hee Chae's team at Seoul National University Hospital and Professor Keun Pil Kim's team at Chung-Ang University. Researchers performed whole exome sequencing on a pediatric patient with an undiagnosed rare disease and the patient’s family, identifying a recessive BRF2 mutation as the cause. They followed this with three-dimensional protein structure analysis and single-cell RNA sequencing to precisely track the mutation's impact on cellular function.

BRF2 is a gene involved in the synthesis of selenoproteins essential for cell survival, forming part of a complex that produces SeCys tRNA, which is critical for protein production. The identified BRF2 mutation disrupts this complex formation, leading to reduced SeCys tRNA levels and diminished expression of antioxidant selenoproteins such as GPX4 and GPX1. As a result, cells become vulnerable to oxidative stress, with widespread effects on immune and developmental processes.

From left: Professor Jong-Hee Chae, Seoul National University Hospital; Professor Keun Pil Kim, Chung-Ang University; Dr. Seobin Yoon, Chung-Ang University; Professor Seungbok Lee, Seoul National University Hospital; and Haeyoon Kwon, student, Seoul National University College of Medicine. (Photo courtesy of Seoul National University Hospital)
From left: Professor Jong-Hee Chae, Seoul National University Hospital; Professor Keun Pil Kim, Chung-Ang University; Dr. Seobin Yoon, Chung-Ang University; Professor Seungbok Lee, Seoul National University Hospital; and Haeyoon Kwon, student, Seoul National University College of Medicine. (Photo courtesy of Seoul National University Hospital)

The team also discovered that under oxidative stress, BRF2 gene expression itself is suppressed, further reducing SeCys tRNA production and creating a vicious cycle. This cascade contributes to broader cellular dysfunction and provides key insights into the fundamental pathophysiology of the disease.

In damaged cells, supplementing with the antioxidant selenium restored GPX4 protein expression, a finding that suggests potential therapeutic avenues for BRF2-related disorders.

Professor Jong-Hee Chae of Seoul National University Hospital described the work as "a study that offers real clues to a patient with a rare disease that was difficult even to diagnose," adding that it was "the result of long-term efforts by the patient, their family, and the research team." Professor Keun Pil Kim of Chung-Ang University noted plans to expand research into gene-based therapies.

The research received support from the Lee Kun-hee Pediatric Cancer and Rare Disease Conquest Project and the National Research Foundation of Korea, and was published in the latest issue of the international journal Molecular Therapy.

키워드

#서울대병원#희귀질환#BRF2유전자변이
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