PUBLICATION
Comparative exome sequencing reveals novel candidate genes for retinitis pigmentosa
- Authors
- Yi, Z., Ouyang, J., Sun, W., Li, S., Xiao, X., Zhang, Q.
- ID
- ZDB-PUB-200527-12
- Date
- 2020
- Source
- EBioMedicine 56: 102792 (Journal)
- Registered Authors
- Keywords
- DACT2, ENSA, Knockdown zebrafish, Knockout mice, Loss-of-function variant, Retinitis pigmentosa
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics*
- Animals
- Discoidin Domain Receptor 1/genetics
- Disease Models, Animal
- Down-Regulation
- Electroretinography
- Exome Sequencing/methods*
- Female
- Gene Expression Profiling
- Gene Knockdown Techniques
- Gene Knockout Techniques
- Genetic Association Studies
- Humans
- Intercellular Signaling Peptides and Proteins/genetics*
- Loss of Function Mutation*
- Male
- Mice
- Pedigree
- Retina/chemistry
- Retinitis Pigmentosa/genetics*
- Sequence Analysis, DNA
- Zebrafish
- PubMed
- 32454406 Full text @ EBioMedicine
Citation
Yi, Z., Ouyang, J., Sun, W., Li, S., Xiao, X., Zhang, Q. (2020) Comparative exome sequencing reveals novel candidate genes for retinitis pigmentosa. EBioMedicine. 56:102792.
Abstract
Background Retinitis pigmentosa (RP) is the most common form of inherited retinal degeneration, but genetic defects in nearly half of families remain unresolved. This study aims to identify novel genes associated with RP based on whole exome sequencing (WES) data from 552 probands with RP.
Methods Biallelic loss-of-function (LoF) variants were selected from the WES data of 552 probands with RP and compared with that of 4728 in-house controls and the gnomAD database. Expression analysis and knockout mice model or knockdown zebrafish model were performed to confirm the association of a few candidate genes with RP.
Findings Unique biallelic LoF variants in ENSA, DACT2, DDR1, and CCDC188 were identified in four probands with RP, but were absent in 4728 in-house controls and were extremely rare in the gnomAD database. The expression of ENSA was enriched in the rod outer segments of human retina, and significant reduced responses of rods and cones were detected in Ensa knockout mice compared to wild-type mice by electroretinogram. The DACT2 transcript showed the highest expression in human retina and knockdown of dact2 in zebrafish resulted in photoreceptor disc membrane disarrangement.
Interpretation This study suggests that ENSA is likely a novel gene for RP and DACT2 is a potentially candidate gene for RP. Further studies are expected to evaluate the association between mutations in the other two genes and RP. To our knowledge, mutations in these genes have not been reported to be associated with RP before.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping