UBAP1L 变异导致常染色体隐性杆-锥-杆营养不良症

IF 6.6 1区 医学 Q1 GENETICS & HEREDITY
Christina Zeitz , Julien Navarro , Leila Azizzadeh Pormehr , Cécile Méjécase , Luiza M. Neves , Camille Letellier , Christel Condroyer , Shahad Albadri , Andréa Amprou , Aline Antonio , Tasnim Ben-Yacoub , Juliette Wohlschlegel , Camille Andrieu , Malo Serafini , Lorenzo Bianco , Alessio Antropoli , Marco Nassisi , Said El Shamieh , Sandra Chantot-Bastaraud , Saddek Mohand-Saïd , Isabelle Audo
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引用次数: 0

摘要

目的 影响视杆细胞和视锥细胞的进行性遗传性视网膜变性(IRDs)在临床和基因上具有异质性,可导致失明,但治疗方法有限。主要基因缺陷已在欧洲和亚洲血统的受试者中发现,只有少数报道涉及北非血统。在人源视网膜器官组织(ROs)、视网膜色素上皮(RPE)细胞和斑马鱼上进行了表达分析,包括芯片-序列数据库分析。结果在突尼斯的四例独立常染色体隐性 IRD 病例中,我们发现了 UBAP1L 中存在三种不同致病变体的新型基因缺陷。UBAP1L 在 RPE 和视网膜中表达,特别是在视杆细胞和视锥细胞中,与表型一致。它编码泛素相关蛋白 1-like,含有一个重叠泛素相关(SOUBA)结构域,预计能与泛素相互作用。硅学和体外研究(包括三维建模和 ROs)显示,SOUBA 结构域被截断,因此泛素结合很可能在本文确定的所有变体中继发废止。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Variants in UBAP1L lead to autosomal recessive rod-cone and cone-rod dystrophy

Purpose

Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent.

Methods

Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants’ pathogenicity was accessed using 3D-modeling and/or ROs.

Results

Here, we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in 4 independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the retinal pigment epithelium and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin-associated domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein.

Conclusion

Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.

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来源期刊
Genetics in Medicine
Genetics in Medicine 医学-遗传学
CiteScore
15.20
自引率
6.80%
发文量
857
审稿时长
1.3 weeks
期刊介绍: Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health. GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.
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