转甲状腺素突变:对淀粉样蛋白生成和疾病的影响。

IF 6.6 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY
Zaida L Almeida, Daniela C Vaz, Rui M M Brito
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引用次数: 0

摘要

转甲状腺素(TTR)是一种存在于血浆、脑脊液和眼睛中的同型四聚体蛋白,在几种发病率和死亡率很高的淀粉样变性疾病的发病过程中起着关键作用。野生型 TTR 及其天然淀粉样变体的蛋白聚集和纤维形成分别是 ATTRwt 和 ATTRv 淀粉样变性病的特征。可溶性淀粉样蛋白聚集体的形成以及不溶性淀粉样蛋白纤维和沉积物在多个组织中的积累可导致器官功能障碍和细胞死亡。ATTR 最常见的表现是多发性神经病和心肌病。不过,也可能出现腕管综合征、脑外膜和眼淀粉样变性等临床表现。本综述提供了迄今已知的所有 TTR 单氨基酸突变的最新清单。在约 220 个单点突变中,93% 被认为是致病性的。天冬氨酸是突变频率最高的残基,而色氨酸则是高度保守的残基。"本手稿还回顾了为 TTR 淀粉样纤维形成而提出的蛋白质聚集模型,以及将原生 TTR 转化为易聚集分子物种的瞬时构象状态。最后,文章汇编了目前用于研究和药物开发的各种体外 TTR 聚集方案。总之,本文回顾并讨论了 TTR 诱变和淀粉样蛋白生成及其对疾病发生的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Transthyretin mutagenesis: impact on amyloidogenesis and disease.

Transthyretin (TTR), a homotetrameric protein found in plasma, cerebrospinal fluid, and the eye, plays a pivotal role in the onset of several amyloid diseases with high morbidity and mortality. Protein aggregation and fibril formation by wild-type TTR and its natural more amyloidogenic variants are hallmarks of ATTRwt and ATTRv amyloidosis, respectively. The formation of soluble amyloid aggregates and the accumulation of insoluble amyloid fibrils and deposits in multiple tissues can lead to organ dysfunction and cell death. The most frequent manifestations of ATTR are polyneuropathies and cardiomyopathies. However, clinical manifestations such as carpal tunnel syndrome, leptomeningeal, and ocular amyloidosis, among several others may also occur. This review provides an up-to-date listing of all single amino-acid mutations in TTR known to date. Of approximately 220 single-point mutations, 93% are considered pathogenic. Aspartic acid is the residue mutated with the highest frequency, whereas tryptophan is highly conserved. "Hot spot" mutation regions are mainly assigned to β-strands B, C, and D. This manuscript also reviews the protein aggregation models that have been proposed for TTR amyloid fibril formation and the transient conformational states that convert native TTR into aggregation-prone molecular species. Finally, it compiles the various in vitro TTR aggregation protocols currently in use for research and drug development purposes. In short, this article reviews and discusses TTR mutagenesis and amyloidogenesis, and their implications in disease onset.

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来源期刊
CiteScore
20.00
自引率
0.00%
发文量
25
审稿时长
>12 weeks
期刊介绍: Critical Reviews in Clinical Laboratory Sciences publishes comprehensive and high quality review articles in all areas of clinical laboratory science, including clinical biochemistry, hematology, microbiology, pathology, transfusion medicine, genetics, immunology and molecular diagnostics. The reviews critically evaluate the status of current issues in the selected areas, with a focus on clinical laboratory diagnostics and latest advances. The adjective “critical” implies a balanced synthesis of results and conclusions that are frequently contradictory and controversial.
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