Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Genet Med. 2024 Jun;26(6):101106. doi: 10.1016/j.gim.2024.101106. Epub 2024 Feb 28.
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.
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.
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.
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.
遗传性视网膜疾病（IRDs）是一组单基因疾病，可导致进行性失明。由于部分疾病基因有待分子鉴定，其遗传缺失仍然相当大。本工作的目的是确定与 IRD 相关的新的遗传关联。
患者接受了全面的眼科评估，包括标准护理测试，如详细的视网膜成像（黄斑光学相干断层扫描和短波长眼底自发荧光）和电生理测试。外显子组和基因组测序以及计算机辅助数据分析用于基因分型和检测 DNA 变异。进行了迷你基因驱动的剪接分析实验，以验证其中一种变异的有害影响。
我们从匈牙利、美国、以色列和荷兰确定了 8 个无血缘关系的家族，其成员表现为常染色体隐性和非综合征性视网膜变性，主要描述为杆锥营养不良，但也包括锥/锥杆营养不良的病例。发病年龄差异很大，一些患者在 40 多岁或更晚出现首发症状。在 7 例有可获得的屈光数据的病例中，有 5 例存在大于 5 屈光度的近视，有 2 例报告了视网膜脱离。所有确诊的患者均携带UBAP1L（HGNC：40028）的双等位基因功能丧失变异，该基因功能未知，与编码参与泛素代谢的蛋白质的 UBAP1 同源。在 5 个无血缘关系的家族中发现了其中一个致病性变异，即内含子 NM_001163692.2:c.910-7G>A 替换。在 HEK293T 细胞中的迷你基因驱动的剪接分析实验证实，这种 DNA 变化导致了新的接受剪接位点的产生，从而导致异常剪接。
我们确定 UBAP1L 为一种新的 IRD 基因。尽管其功能目前尚不清楚，但 UBAP1L 几乎仅在光感受器和视网膜色素上皮中表达，因此可能解释了该基因中的致病变异与眼部表型之间的联系。
