Identification of a novel gene defect UBAP1L underlying for autosomal recessive rod-cone and cone-rod dystrophy

Abstract

Purpose : To identify the missing gene defect underlying inherited retinal dystrophies (IRDs), namely rod-cone and cone-rod dystrophy in a large cohort.

Methods : Whole genome, targeted next-generation and Sanger sequencing was applied to a cohort of ~4000 IRDs cases. Expression analyses included Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium (RPE) cells and zebrafish. Variants’ pathogenicity was accessed using 3D-modeling and/or ROs.

Results : We identified a novel gene defect with three distinct pathogenic variants in UBAP1L in four independent autosomal recessive IRD cases from Tunisia. One case had a rod-cone dystrophy with early onset macular involvement while the three other cases had a diagnosis of cone-rod dystrophy. UBAP1L is expressed in the RPE and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin associated (SOUBA) domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the SOUBA domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein.

Conclusions : Biallelic UBAP1L variants represent a novel cause of IRDs with early onset macular involvement, most likely enriched in the North African population.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.