TY - JOUR
T1 - Loss-of-function variants in UBAP1L cause autosomal recessive retinal degeneration
AU - Han, Ji Hoon
AU - Rodenburg, Kim
AU - Hayman, Tamar
AU - Calzetti, Giacomo
AU - Kaminska, Karolina
AU - Quinodoz, Mathieu
AU - Marra, Molly
AU - Wallerich, Sandrine
AU - Allon, Gilad
AU - Nagy, Zoltán Z.
AU - Knézy, Krisztina
AU - Li, Yumei
AU - Chen, Rui
AU - Barboni, Mirella Telles Salgueiro
AU - Yang, Paul
AU - Pennesi, Mark E.
AU - van den Born, L. Ingeborgh
AU - Varsányi, Balázs
AU - Szabó, Viktória
AU - Sharon, Dror
AU - Banin, Eyal
AU - Ben-Yosef, Tamar
AU - Roosing, Susanne
AU - Koenekoop, Robert K.
AU - Rivolta, Carlo
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
KW - Cone-rod dystrophy
KW - Inherited retinal diseases
KW - Rod-cone dystrophy
KW - UBAP1L
KW - Ubiquitin-associated protein 1-like
UR - http://www.scopus.com/inward/record.url?scp=85189673701&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2024.101106
DO - 10.1016/j.gim.2024.101106
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C2 - 38420906
AN - SCOPUS:85189673701
SN - 1098-3600
VL - 26
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 6
M1 - 101106
ER -