Background Leber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophies. In approximately 56% of Chinese probands, genetic defects can be detected in known LCA-causing genes. In this study, the objective was to identify pathogenic variants in two unsolved Chinese families with LCA.
Methods To identify the genetic defect, whole-exome sequencing (WES) and clinical analysis was performed in both probands with LCA as well as in 3011 in-house controls with other hereditary eye diseases. The expression profiles, as well as the phenotype analysis of knockdown zebrafish model and knockout mice model, were performed to investigate the function of USP45 in photoreceptors.
Results By analysing WES data based on allele frequencies of in-house controls, population allele frequencies and in silico prediction tools, two rare homozygous mutations in USP45 were identified in two unrelated families. Immunohistochemistry of USP45 in the human and zebrafish retinal sections revealed enriched expression in the inner segments of photoreceptors. The knockdown of usp45 transcript in zebrafish led to abnormal retinal development with effects on photoreceptors, which could be successfully rescued by wild-type usp45 mRNA. Moreover, targeted knockout of Usp45 in mice caused abnormal electroretinography responses, similar to that seen in patients with LCA.
Conclusions Our study implicates that biallelic mutations in USP45 are associated with the occurrence of LCA. Moreover, our results indicate that USP45 is indispensable to the maintenance of photoreceptor function.
- Leber congenital amaurosis
- autosomal recessive
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Contributors XX, SL and QZ recruited patients. ZY, WS, XX, SL, XJ and PW collected the clinical data. XX and QZ performed whole exome analysis. QZ and ZY performed the bioinformatic analysis and designed the study. ZY performed the expression analysis. JO, ZY and WS conducted zebrafish experiments. ZY conducted mice experiments. ZY, WS and QZ discussed the results and wrote the manuscript. All authors reviewed and approved the manuscript.
Funding This study was supported by grants from the Key Projects of Guangzhou (201607020013), the Science and Technology Planning Projects of Guangdong (2017B030314025) and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology. QZ is a recipient of National Science Fund for Distinguished Young Scholars.
Competing interests None declared.
Ethics approval This study was approved by the Institutional Review Board of the Zhongshan Ophthalmic Center.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.