PUBLICATION
Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis
- Authors
- Yi, Z., Ouyang, J., Sun, W., Xiao, X., Li, S., Jia, X., Wang, P., Zhang, Q.
- ID
- ZDB-PUB-181224-2
- Date
- 2018
- Source
- Journal of Medical Genetics 56(5): 325-331 (Journal)
- Registered Authors
- Keywords
- Leber congenital amaurosis, USP45, autosomal recessive, mutations
- MeSH Terms
-
- Alleles*
- Animals
- Computational Biology/methods
- Deubiquitinating Enzymes/genetics
- Deubiquitinating Enzymes/metabolism
- Disease Models, Animal
- Exome Sequencing
- Gene Knockdown Techniques
- Genetic Association Studies*
- Genetic Predisposition to Disease*
- Genotype
- Humans
- Leber Congenital Amaurosis/diagnosis
- Leber Congenital Amaurosis/genetics*
- Mice
- Mutation*
- Pedigree
- Sequence Analysis, DNA
- Ubiquitin-Specific Proteases/genetics*
- Ubiquitin-Specific Proteases/metabolism
- Zebrafish
- PubMed
- 30573563 Full text @ J. Med. Genet.
Citation
Yi, Z., Ouyang, J., Sun, W., Xiao, X., Li, S., Jia, X., Wang, P., Zhang, Q. (2018) Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis. Journal of Medical Genetics. 56(5):325-331.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping