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

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

doi:10.1016/j.gim.2024.101106

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

Genet Med. 2024 Feb 28:101106. doi: 10.1016/j.gim.2024.101106. Online ahead of print.

Authors

Ji Hoon Han¹, Kim Rodenburg², Tamar Hayman³, Giacomo Calzetti¹, Karolina Kaminska¹, Mathieu Quinodoz⁴, Molly Marra⁵, Sandrine Wallerich¹, Gilad Allon⁶, Zoltán Z Nagy⁷, Krisztina Knézy⁷, Yumei Li⁸, Rui Chen⁸, Mirella Telles Salgueiro Barboni⁷, Paul Yang⁵, Mark E Pennesi⁵, L Ingeborgh van den Born⁹, Balázs Varsányi⁷, Viktória Szabó⁷, Dror Sharon³, Eyal Banin³, Tamar Ben-Yosef¹⁰, Susanne Roosing², Robert K Koenekoop¹¹, Carlo Rivolta¹²

Affiliations

¹ Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland.
² Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁴ Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom.
⁵ Casey Eye Institute, Oregon Health and Science University, Portland, OR.
⁶ Department of Ophthalmology, Meir Medical Center, Kfar Saba, Israel.
⁷ Department of Ophthalmology, Semmelweis University, Budapest, Hungary.
⁸ Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
⁹ The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
¹⁰ Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
¹¹ Departments of Pediatric Surgery, Human Genetics and Ophthalmology, Montreal Children's Hospital, McGill University and McGill University Health Center Research Institute, Montreal, QC, Canada.
¹² Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom. Electronic address: carlo.rivolta@iob.ch.

PMID: 38420906
DOI: 10.1016/j.gim.2024.101106

Abstract

Purpose: 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.

Conclusion: 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.

Keywords: Cone-rod dystrophy; Inherited retinal diseases; Rod-cone dystrophy; UBAP1L; Ubiquitin-associated protein 1-like.