Identification and Functional Characterization of a Novel PRPS1 Variant in X‐Linked Nonsyndromic Hearing Loss: Insights From Zebrafish and Cellular Models

作者：Yining Wan, Jinqiu Li, Yingyuan Guo, Fang Guo, Ying Zhao, Yue Li, Xia Yang, Huidan Chen, Shimin Xie, Mingyong Wang, Guofang Guan, Yilong Zhu, Xiao Li · 发表于：Human Mutation · 年份：2025 · DOI：10.1155/humu/6690588 · 被引用次数：1 · 研究领域：RNA regulation and disease、Sirtuins and Resveratrol in Medicine、Calcium signaling and nucleotide metabolism

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 ...