PUBLICATION
Identification and Functional Characterization of a Novel PRPS1 Variant in X-Linked Nonsyndromic Hearing Loss: Insights From Zebrafish and Cellular Models
- Authors
- Wan, Y., Li, J., Guo, Y., Guo, F., Zhao, Y., Li, Y., Yang, X., Chen, H., Xie, S., Wang, M., Guan, G., Zhu, Y., Li, X.
- ID
- ZDB-PUB-250718-8
- Date
- 2025
- Source
- Human Mutation 2025: 66905886690588 (Journal)
- Registered Authors
- Keywords
- PRPS1, X-linked nonsyndromic hearing loss, exome sequencing, novel variant, oxidative stress
- MeSH Terms
-
- Superoxide Dismutase/genetics
- Superoxide Dismutase/metabolism
- Genetic Diseases, X-Linked*/genetics
- Zebrafish/genetics
- Exome Sequencing
- Mitochondria/metabolism
- Reactive Oxygen Species/metabolism
- Deafness*/genetics
- Pedigree
- Disease Models, Animal
- Humans
- Female
- Animals
- Zebrafish Proteins*/genetics
- Mutation, Missense
- Hair Cells, Auditory/metabolism
- Male
- Animals, Genetically Modified
- PubMed
- 40677922 Full text @ Hum. Mutat.
Citation
Wan, Y., Li, J., Guo, Y., Guo, F., Zhao, Y., Li, Y., Yang, X., Chen, H., Xie, S., Wang, M., Guan, G., Zhu, Y., Li, X. (2025) Identification and Functional Characterization of a Novel PRPS1 Variant in X-Linked Nonsyndromic Hearing Loss: Insights From Zebrafish and Cellular Models. Human Mutation. 2025:66905886690588.
Abstract
Purpose: The study was aimed at identifying the pathogenic gene responsible for X-linked nonsyndromic hearing loss (NSHL) in a five-generation Chinese family and at elucidating the gene's function both in vivo using a zebrafish model and in vitro using PRPS1 knockdown HEI-OC1 cells. Methods: Exome sequencing (ES) and Sanger sequencing were used to identify the pathogenic variants. A transgenic zebrafish model overexpressing the novel PRPS1 variant (c.494G>A: p.Cys165Tyr) was constructed, and PRPS1 was knocked down in HEI-OC1 cells using siRNA to explore the underlying mechanisms. Hair cell development and behavior were assessed in zebrafish, and mitochondrial function and cell viability were analyzed in HEI-OC1 cells. Results: A novel missense variant (c.494G>A: p.Cys165Tyr) in the PRPS1 gene was identified as the pathogenic variant causing progressive X-linked deafness-1 (DFNX1). The variant led to hair cell death in zebrafish, with disrupted swimming behavior. In HEI-OC1 cells, PRPS1 knockdown resulted in downregulation of the nicotinamide adenine dinucleotide (NAD+)/sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) pathway, increased reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and apoptosis, which were partially rescued by pretreatment with nicotinamide mononucleotide (NMN), a precursor of NAD+. Conclusion: The study reports a novel PRPS1 variant contributing to the variant spectrum of PRPS1 and highlights the role of PRPS1 deficiency in increasing oxidative stress-induced hair cell apoptosis via the NAD+/SIRT3/SOD2 pathway. These findings provide new insights into the molecular mechanisms of PRPS1-related hearing loss and potential therapeutic targets.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping