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

Shaoheng Li; Yihong Jiang; Lei Zhang; Weiming Yan; Dongyu Wei; Min Zhang; Bin Zhu; Tao Chen; Xiaocheng Wang; Zuoming Zhang; Yuting Su

doi:10.1016/j.gene.2024.148562

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

Gene. 2024 May 15:922:148562. doi: 10.1016/j.gene.2024.148562. Online ahead of print.

Authors

Shaoheng Li¹, Yihong Jiang², Lei Zhang³, Weiming Yan⁴, Dongyu Wei², Min Zhang², Bin Zhu⁵, Tao Chen⁶, Xiaocheng Wang⁷, Zuoming Zhang⁸, Yuting Su⁹

Affiliations

¹ Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an 710032, China; Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Air Force Medical University, Xi'an 710032, China.
² Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an 710032, China.
³ Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an 710004, Shaanxi Province, China.
⁴ The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou 350000, China.
⁵ Outpatient Department, General Hospital of Xizang Military Region, Lhasa 850007, China.
⁶ Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an 710032, China; Department of Aviation Medicine, Xijing Hospital, Air Force Medical University, Xi'an 710032, China.
⁷ Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an 710032, China; Department of Aviation Medicine, Xijing Hospital, Air Force Medical University, Xi'an 710032, China. Electronic address: wxcnose@126.com.
⁸ Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an 710032, China. Electronic address: zhangzm@fmmu.edu.cn.
⁹ Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Air Force Medical University, Xi'an 710032, China; Department of Aviation Medicine, Xijing Hospital, Air Force Medical University, Xi'an 710032, China. Electronic address: sssusyt@163.com.

PMID: 38754567
DOI: 10.1016/j.gene.2024.148562

Abstract

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.

Keywords: Adgrv1; Auditory brainstem response; Electroretinogram; Inbred strain; Mutation; Usher Syndrome.