Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis

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.

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.

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.

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.