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

文献类型： 外文期刊

第一作者： Wan, Yining

作者： Wan, Yining;Li, Jinqiu;Guo, Yingyuan;Guo, Fang;Zhao, Ying;Guan, Guofang;Li, Yue;Yang, Xia;Chen, Huidan;Xie, Shimin;Zhu, Yilong;Wang, Mingyong;Li, Xiao

作者机构：

关键词： exome sequencing; novel variant; oxidative stress; PRPS1; X-linked nonsyndromic hearing loss

期刊名称：HUMAN MUTATION （ 影响因子：3.7； 五年影响因子：4.0 ）

ISSN： 1059-7794

年卷期： 2025 年 2025 卷 1 期

页码：

收录情况： SCI

摘要： 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.

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