A New Mouse Model for Usher Syndrome Crossing Kunming Mice with CBA/J Mice.

Background: Previously, we discovered a strain of Kunming mice, referred to as the KM ^ush/ush strain, that exhibited notably abnormal electroretinogram (ERG) readings and elevated thresholds for auditory brainstem responses (ABRs), which resembled the characteristics of Usher Syndrome (USH). We successfully identified the pathogenic genes, Pde6b and Adgrv1, after KM ^ush/ush crossbred with CBA/CaJ mice, referred to as CBA-1 ^ush/ush , CBA-2 ^ush/ush or CBA-2 ^ush/ush . In this investigation, we crossbred KM ^ush/ush and CBA/J mice to establish novel recombinant inbred lines and analysed their phenotypic and genotypic characteristics.
Methods: ERG readings, ABR testing, fundus morphology, histological examination of the retina and inner ear, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, western blotting, DNA sequence analysis and behavioural experiments were performed to assess the phenotypes and genotypes of the progeny lines.
Results: No obvious waveforms in the ERG were detected in F1 hybrid mice while normal ABR results were recorded. The F2 hybrids, which were called J1 ^ush/ush or J2 ^ush/ush , exhibited segregated hearing-loss phenotypes. J1 ^ush/ush mice had a retinitis pigmentosa (RP) phenotype with elevated ABR thresholds, whereas J2 ^ush/ush mice exhibited only the RP phenotype. Interestingly, J1 ^ush/ush mice showed significantly higher ABR thresholds than wild-type mice at 28 days post born (P28), and RT-qPCR and DNA-sequencing analysis showed that Adgrv1 gene expression was significantly altered in J1 ^ush/ush mice, but histological analysis showed no significant structural changes in the organ of Corti or spiral ganglia. Further elevation of ABR-related hearing thresholds by P56 manifested only as a reduced density of spiral ganglion cells, which differed significantly from the previous pattern of cochlear alterations in CBA-2 ^ush/ush mice.
Conclusions: We successfully introduced the hearing-loss phenotype of inbred mice with USH into CBA/J mice, which provides a good animal model for future studies on the important physiological roles of the Adgrv1 gene in inner-ear structure and for therapeutic studies targeting Adgrv1-mutated USH.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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