Variants in UBAP1L lead to autosomal recessive rod-cone and cone-rod dystrophy

• Published in: Genetics in medicine Vol. 26; no. 6; p. 101081
• Main Authors: Zeitz, Christina, Navarro, Julien, Azizzadeh Pormehr, Leila, Méjécase, Cécile, Neves, Luiza M., Letellier, Camille, Condroyer, Christel, Albadri, Shahad, Amprou, Andréa, Antonio, Aline, Ben-Yacoub, Tasnim, Wohlschlegel, Juliette, Andrieu, Camille, Serafini, Malo, Bianco, Lorenzo, Antropoli, Alessio, Nassisi, Marco, El Shamieh, Said, Chantot-Bastaraud, Sandra, Mohand-Saïd, Saddek, Smirnov, Vasily, Sahel, José-Alain, Del Bene, Filippo, Audo, Isabelle
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2024; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adult; Animals; Autosomal recessive rod-cone and cone-rod dystrophy; Biochemistry, Molecular Biology; Cone-Rod Dystrophies - genetics; Cone-Rod Dystrophies - pathology; Female; Genes, Recessive; Genetics; Genome sequencing; Genomics; Human genetics; Human health and pathology; Humans; Life Sciences; Male; Mutation - genetics; Novel gene defect; Pedigree; Phenotype; Populations and Evolution; Retina - metabolism; Retina - pathology; Retinal Cone Photoreceptor Cells - metabolism; Retinal Cone Photoreceptor Cells - pathology; Retinal organoids; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Retinal Rod Photoreceptor Cells - metabolism; Retinal Rod Photoreceptor Cells - pathology; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - pathology; Sensory Organs; Tunisia; Zebrafish; Zebrafish - genetics; Tunisia; Retinal organoids; Zebrafish; Autosomal recessive rod-cone and cone-rod dystrophy; Genome sequencing; Novel gene defect; genome sequencing; novel gene defect; UBAP1L; retinal pigment epithelium; zebrafish; retinal organoids; 3D-modelling; autosomal recessive rod-cone and cone-rod dystrophy
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1016/j.gim.2024.101081

Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent. Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants’ pathogenicity was accessed using 3D-modeling and/or ROs. Here, we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in 4 independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the retinal pigment epithelium 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 domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein. Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.