Biomaterial Database

Loss-of-function variants in UBAP1L cause autosomal recessive retinal degeneration. 2024

Ji Hoon Han, and Kim Rodenburg, and Tamar Hayman, and Giacomo Calzetti, and Karolina Kaminska, and Mathieu Quinodoz, and Molly Marra, and Sandrine Wallerich, and Gilad Allon, and Zoltán Z Nagy, and Krisztina Knézy, and Yumei Li, and Rui Chen, and Mirella Telles Salgueiro Barboni, and Paul Yang, and Mark E Pennesi, and L Ingeborgh van den Born, and Balázs Varsányi, and Viktória Szabó, and Dror Sharon, and Eyal Banin, and Tamar Ben-Yosef, and Susanne Roosing, and Robert K Koenekoop, and Carlo Rivolta

Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland.

OBJECTIVE Inherited retinal diseases (IRDs) are a group of monogenic conditions that can lead to progressive blindness. Their missing heritability is still considerable, due in part to the presence of disease genes that await molecular identification. The purpose of this work was to identify novel genetic associations with IRDs. METHODS Patients underwent a comprehensive ophthalmological evaluation using standard-of-care tests, such as detailed retinal imaging (macular optical coherence tomography and short-wavelength fundus autofluorescence) and electrophysiological testing. Exome and genome sequencing, as well as computer-assisted data analysis were used for genotyping and detection of DNA variants. A minigene-driven splicing assay was performed to validate the deleterious effects of 1 of such variants. RESULTS We identified 8 unrelated families from Hungary, the United States, Israel, and The Netherlands with members presenting with a form of autosomal recessive and nonsyndromic retinal degeneration, predominantly described as rod-cone dystrophy but also including cases of cone/cone-rod dystrophy. Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later. Myopia greater than 5 diopters was present in 5 of 7 cases with available refractive data, and retinal detachment was reported in 2 cases. All ascertained patients carried biallelic loss-of-function variants in UBAP1L (HGNC: 40028), a gene with unknown function and with homologies to UBAP1, encoding a protein involved in ubiquitin metabolism. One of these pathogenic variants, the intronic NM_001163692.2:c.910-7G>A substitution, was identified in 5 unrelated families. Minigene-driven splicing assays in HEK293T cells confirmed that this DNA change is responsible for the creation of a new acceptor splice site, resulting in aberrant splicing. CONCLUSIONS We identified UBAP1L as a novel IRD gene. Although its function is currently unknown, UBAP1L is almost exclusively expressed in photoreceptors and the retinal pigment epithelium, hence possibly explaining the link between pathogenic variants in this gene and an ocular phenotype.