Abstract
Purpose: UBAP1L is a newly discovered gene related to recessive inherited retinal degeneration (IRD) with an unknown pathogenic mechanism. This study aims to investigate whether biallelic pathogenic variants in UBAP1L contribute to the unsolved cases in Chinese IRD families and to explore the impact of the Ubap1l genetic defect in a mouse model. Methods: Next-generation sequencing was used to detect variants in families with unknown pathogenic variants. Biallelic variants in UBAP1L, evaluated through multistep bioinformatic analysis, comparison across multiple databases, and related phenotype analysis based on thoroughly reviewed clinical data, were confirmed by Sanger sequencing and cosegregation analysis. The expression profiles of UBAP1L in human and Ubap1l in mouse were demonstrated using quantitative RT-PCR and RNAscope. Phenotype and photoreceptor morphology were analyzed in the Ubap1l knockout mouse model. Results: Biallelic novel pathogenic variants in UBAP1L were exclusively detected in two unrelated families with retinitis pigmentosa (RP), including a homozygous c.[278C>A;280dup]/p.[(T93K;I94fs)] variant in one family and compound heterozygous variants (i.e., c.[278C>A;280dup]/p.[(T93K;I94fs)] and c.1051A>G/p.M351V) in the other family. Quantitative RT-PCR showed that UBAP1L was highly expressed in human and mouse retina. RNAscope analysis revealed that UBAP1L was specifically expressed in the outer nuclear and inner segments in the human and mouse retina. Notably, in the human retina, UBAP1L was more highly expressed in cones, with low but detectable expression in the RPE, whereas this expression pattern was not observed in the mouse retina. Ubap1l knockout mice exhibited mottled retinal degeneration, impaired photoreceptor function, and deformation of the rod outer segments. Conclusions: For the first time, biallelic pathogenic variants in UBAP1L were reported to explain the genetic defect among East Asian families with RP. The expression profile and precise localization of UBAP1L were demonstrated. A Ubap1l knockout mouse model replicating key hallmarks of IRD was established. These findings provide valuable insights into the essential role of UBAP1L in maintaining photoreceptor function and offer potential avenues for therapeutic development targeting IRD.