2. Academic Validation
  3. GJB2 c.109G > A mutation activating IFI27-mediated mitochondrial apoptosis pathway leading to hereditary non-syndromic hearing loss

GJB2 c.109G > A mutation activating IFI27-mediated mitochondrial apoptosis pathway leading to hereditary non-syndromic hearing loss

  • Sci Rep. 2026 Jan 26;16(1):6240. doi: 10.1038/s41598-026-37393-2.
Yao Chen # 1,  Peiran Zhao # 1,  Qingying Lin 1,  Yinglin Zeng 1,  Xiaolong Qiu 1,  Ting Huang 1,  Jianping Tang 2 3,  Liangpu Xu 4 5
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China.
  • 2 Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China. [email protected].
  • 3 Fujian Provincial Maternal and Child Health Hospital, No. 18, Daoshan Road, Gulou District, Fuzhou City, Fujian Province, China. [email protected].
  • 4 Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China. [email protected].
  • 5 Fujian Provincial Maternal and Child Health Hospital, No. 18, Daoshan Road, Gulou District, Fuzhou City, Fujian Province, China. [email protected].
  • # Contributed equally.
PMID: 41588186 DOI: 10.1038/s41598-026-37393-2
Abstract

Non-syndromic hereditary deafness is a congenital condition that severely impairs the lives of affected children. GJB2 mutations are a common cause of this condition, but their underlying mechanism remains unclear. This study investigates the effects of GJB2 mutations on ear structure and function, as well as the underlying cellular mechanisms, and provides directions for potential therapies. We generated zebrafish models carrying the GJB2 c.109G > A mutation and performed knockdown experiments. Using microscopy, we monitored zebrafish development, inner ear structure changes, hair cell staining, and behavior in response to sound to assess ear function. Transcriptome analysis was then performed to was then conducted to elucidate the mechanism by which GJB2 influences non-syndromic hereditary deafness. Finally, we evaluate the impact of gene regulation was then conducted to elucidate. GJB2 c.109G > A mutation and knockdown led to delayed zebrafish growth, altered ear structure, hair cell Apoptosis, and impair hearing. Transcriptome analysis showed that GJB2 activated mitochondrial cytochrome C protein and upregulated apoptosis-related genes Bax, Caspase3, and Caspase9, which was corroborated by qPCR and Western blot validation. Furthermore, in vitro intervention targeting the downstream gene IFI27 reduced cellular Reactive Oxygen Species (ROS) and Apoptosis levels compared with GJB2 mutation alone. This findings suggests that IFI27 can be a therapeutic target for GJB2-mutated non-syndromic hereditary deafness. Collectively, GJB2 may regulates non-syndromic hereditary deafness by activating IFI27-mediated mitochondrial Apoptosis pathways, providing a theoretical basis for future treatments.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-37393-2.

Keywords

GJB2 c.109G > A; IFI27; Mitochondrial apoptosis pathway; Non-syndromic hearing loss; Zebrafish.

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