Generation and Auditory Phenotypic Characterization of Prps1 p.Ala87Thr Mouse Knock-In Model for Human DFNX1 Deafness.

Variants in the phosphoribosylpyrophosphate synthetase (PRPS1) gene have been shown to cause X-linked nonsyndromic hearing loss (HL) (DFNX1) in humans. A c.259G>A transition in PRPS1, which leads to p.Ala87Thr, has been demonstrated to cause HL. The aim of this study was to generate a transgenic knock-in (KI) mouse with the Prps1 missense variant p.Ala87Thr and to study its impact on the auditory phenotype. Compared to wild-type (WT) control, transgenic Prps1 KI mice started to exhibit HL at 32 kHz at 4-12 weeks of age, with HL extending to 8 and 16 kHz by 48 weeks of age. A significant decrease in the number of hair cells and spiral ganglion neuron (SGN) counts was observed at 48 weeks of age in transgenic KI mice. These traits may be associated with the Bak-dependent mitochondrial apoptosis program, which is triggered by oxidative stress and has been identified as a key mechanism of age-related HL in C57BL/6J mice. Enzymatic assay showed a significant reduction in Prps1 enzymatic activity in KI compared to WT animals. The Prps1 p.Ala87Thr KI mouse model will serve as a valuable tool for developing therapeutic strategies to mitigate HL associated with PRPS1 variants.