TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease.
TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease.
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DOI：
10.1016/j.preteyeres.2020.100883
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发表时间：
2021-03
影响因子：
17.8
通讯作者：
Davidson AE
中科院分区：
文献类型：
--
作者：
Fautsch MP;Wieben ED;Baratz KH;Bhattacharyya N;Sadan AN;Hafford-Tear NJ;Tuft SJ;Davidson AE
Fuchs角膜内皮营养不良（FECD）是老年人遗传性视力丧失的常见原因。自从首次描述FECD和位于转录因子4（TCF 4）基因内的常见多态性之间的关联以来，遗传和分子研究表明内含子CTG三核苷酸重复序列（CTG 18.1）扩增是大多数FECD患者的致病变异。到目前为止，已经提出了几个非相互排斥的机制，驱动和/或加剧疾病的发作。这些机制包括（i）TCF 4失调;（ii）来自含TCF 4重复序列的RNA的毒性功能获得;（iii）来自重复序列相关非AUG依赖性（RAN）翻译的毒性功能获得;以及（iv）CTG 18.1的体细胞不稳定性。然而，这些提出的机制在疾病发病机制中的相对贡献目前尚不清楚。在这篇综述中，我们总结了疾病发病机制中涉及重复扩增的研究，定义了FECD和CTG18.1扩增之间的表型-基因型相关性，并提供了可用于研究FECD作为三核苷酸重复扩增疾病的研究工具的更新。此外，正在进行的开发新型CTG18.1扩增介导的FECD治疗方法的国际研究工作也得到了强调，我们对该领域尚未解决的关键问题提供了前瞻性的观点。FECD是一种常见的年龄相关性角膜营养不良。大多数病例与CTG重复扩增（CTG18.1）相关。FECD是人类最常见的三核苷酸重复扩增疾病。证据支持病理生理学的多种分子机制。新的CTG18.1靶向疗法正在开发中。
Fuchs endothelial corneal dystrophy (FECD) is a common cause for heritable visual loss in the elderly. Since the first description of an association between FECD and common polymorphisms situated within the transcription factor 4 (TCF4) gene, genetic and molecular studies have implicated an intronic CTG trinucleotide repeat (CTG18.1) expansion as a causal variant in the majority of FECD patients. To date, several non-mutually exclusive mechanisms have been proposed that drive and/or exacerbate the onset of disease. These mechanisms include (i) TCF4 dysregulation; (ii) toxic gain-of-function from TCF4 repeat-containing RNA; (iii) toxic gain-of-function from repeat-associated non-AUG dependent (RAN) translation; and (iv) somatic instability of CTG18.1. However, the relative contribution of these proposed mechanisms in disease pathogenesis is currently unknown. In this review, we summarise research implicating the repeat expansion in disease pathogenesis, define the phenotype-genotype correlations between FECD and CTG18.1 expansion, and provide an update on research tools that are available to study FECD as a trinucleotide repeat expansion disease. Furthermore, ongoing international research efforts to develop novel CTG18.1 expansion-mediated FECD therapeutics are highlighted and we provide a forward-thinking perspective on key unanswered questions that remain in the field. FECD is a common, age-related corneal dystrophy. The majority of cases are associated with expansion of a CTG repeat (CTG18.1). FECD is the most common trinucleotide repeat expansion disease in humans. Evidence supports multiple molecular mechanisms underlying the pathophysiology. Novel CTG18.1-targeted therapeutics are in development.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
4.8
作者：
Bayly, R;Chuen, L;LeBrun, DP
通讯作者：
LeBrun, DP
影响因子：
9.8
作者：
Bidichandani, SI;Ashizawa, T;Patel, PI
通讯作者：
Patel, PI
影响因子：
3.4
作者：
Braz SO;Acquaire J;Gourdon G;Gomes-Pereira M
通讯作者：
Gomes-Pereira M
DOI：
10.1073/pnas.1901484116
发表时间：
2019-04-16
影响因子：
11.1
作者：
Angelbello, Alicia J.;Rzuczek, Suzanne G.;Disney, Matthew D.
通讯作者：
Disney, Matthew D.