Language
English
Publication Date
6-1-2024
Journal
Genetics in Medicine
DOI
10.1016/j.gim.2024.101106
PMID
38420906
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
Adolescent, Adult, Child, Female, Humans, Male, Middle Aged, Young Adult, Cone-Rod Dystrophies, Genes, Recessive, Genetic Predisposition to Disease, Hungary, Loss of Function Mutation, Pedigree, Retinal Degeneration, Adaptor Proteins, Signal Transducing, Cone-rod dystrophy, Inherited retinal diseases, Rod-cone dystrophy, UBAP1L, Ubiquitin-associated protein 1-like
Published Open-Access
yes
Recommended Citation
Han, Ji Hoon; Rodenburg, Kim; Hayman, Tamar; et al., "Loss-of-Function Variants in UBAP1L Cause Autosomal Recessive Retinal Degeneration" (2024). Faculty and Staff Publications. 4363.
https://digitalcommons.library.tmc.edu/baylor_docs/4363