RLIM 特异性活性报告确定了 Tonne-Kalscheuer 综合征的变异致病性。

IF 3.3 Q2 GENETICS & HEREDITY HGG Advances Pub Date : 2024-10-31 DOI:10.1016/j.xhgg.2024.100378
Venkateshwarlu Bandi, Martin Rennie, Intisar Koch, Polly Gill, Oscar D Pacheco, Aaron D Berg, Hong Cui, D Isum Ward, Francisco Bustos
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引用次数: 0

摘要

Tonne-Kalscheuer 综合征(TOKAS,OMIM # 300978)是一种 X 连锁隐性遗传病,会给患者带来智力障碍、发育迟缓和多种先天畸形等严重后果。TOKAS 与编码 RING 型 E3 泛素连接酶的 RLIM 基因的半杂合子变异有关。目前报道的意义不明的 RLIM 变异持续增加,因此迫切需要开发能筛选这些变异并通过实验确定其致病性和疾病关联性的检测方法。在此,我们设计了基于流式细胞术的 RLIM 特异性报告物,以测量 TOKAS 中的 RLIM 活性。本文介绍了 RLIM 特异性报告物的设计和使用,以确定 TOKAS RLIM 基因变体的致病性。我们的数据表明,基于底物 REX1 的全长或脱粒区的 RLIM 特异性流式细胞术报告可测量细胞中的 RLIM 活性。此外,我们还描述了 TOKAS 变体 RLIM p.Asn581Lys,并通过报告分析确定它破坏了 RLIM 的催化活性。这些数据揭示了 p.Asn581Lys 变体是如何损害 RLIM 功能的,并提出了致病机制。RLIM特异性报告基因的使用将大大加快对TOKAS中意义不确定的变异和疾病关联的解析。
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RLIM-specific activity reporters define variant pathogenicity in Tonne-Kalscheuer syndrome.

Tonne-Kalscheuer syndrome (TOKAS; MIM: 300978) is an X-linked recessive disorder with devastating consequences for patients, such as intellectual disability, developmental delay, and multiple congenital abnormalities. TOKAS is associated with hemizygous variants in the RLIM gene, which encodes a RING-type E3 ubiquitin ligase. The current sustained increase in reported RLIM variants of uncertain significance creates an urgent need to develop assays that can screen these variants and experimentally determine their pathogenicity and disease association. Here, we engineered flow cytometry-based RLIM-specific reporters to measure RLIM activity in TOKAS. This paper describes the design and use of RLIM-specific reporters to determine the pathogenicity of a TOKAS RLIM gene variant. Our data demonstrate that RLIM-specific flow cytometry reporters based on either the full length or a degron region of the substrate REX1 measure RLIM activity in cells. Further, we describe the TOKAS variant RLIM p.Asn581Lys and, using reporter assays, determine that it disrupts RLIM catalytic activity. These data reveal how the p.Asn581Lys variant impairs RLIM function and suggests pathogenic mechanisms. The use of RLIM-specific reporters will greatly accelerate the resolution of variants of uncertain significance and disease association in TOKAS.

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来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
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