复合T60I和V122I取代在ATTRv淀粉样变性中的加性不稳定效应。

IF 5.2 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tatiana Prokaeva, Elena S Klimtchuk, Polina Feschenko, Brian Spencer, Haili Cui, Eric J Burks, Roshanak Aslebagh, Khaja Muneeruddin, Scott A Shaffer, Elizabeth Varghese, John L Berk, Lawreen H Connors
{"title":"复合T60I和V122I取代在ATTRv淀粉样变性中的加性不稳定效应。","authors":"Tatiana Prokaeva,&nbsp;Elena S Klimtchuk,&nbsp;Polina Feschenko,&nbsp;Brian Spencer,&nbsp;Haili Cui,&nbsp;Eric J Burks,&nbsp;Roshanak Aslebagh,&nbsp;Khaja Muneeruddin,&nbsp;Scott A Shaffer,&nbsp;Elizabeth Varghese,&nbsp;John L Berk,&nbsp;Lawreen H Connors","doi":"10.1080/13506129.2022.2135988","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The amyloidogenic transthyretin (TTR) variant, V122I, occurs in 4% of the African American population and frequently presents as a restricted cardiomyopathy. While heterozygosity for TTR V122I predominates, several compound heterozygous cases have been previously described. Herein, we detail features of ATTRv amyloidosis associated with novel compound heterozygous TTR mutation, T60I/V122I and provide evidence supporting the amyloidogenecity of T60I.</p><p><strong>Methods: </strong>A 63-year-old African American female presented with atrial fibrillation, congestive heart failure, autonomic and peripheral neuropathy. <i>In vitro</i> studies of TTR T60I and V122I were undertaken to compare the biophysical properties of the proteins.</p><p><strong>Results: </strong>Congophilic deposits in a rectal biopsy were immunohistochemically positive for TTR. Serum screening by isoelectric focussing revealed two TTR variants in the absence of wild-type protein. DNA sequencing identified compound heterozygous <i>TTR</i> gene mutations, c.239C > T and c.424G > A. Adipose amyloid deposits were composed of both T60I and V122I. While kinetic stabilities of T60I and V122I variants were similar, distinct thermodynamic stabilities and amyloid growth kinetics were observed.</p><p><strong>Conclusions: </strong>This report provides clinical and experimental results supporting the amyloidogenic nature of a novel TTR T60I variant. <i>In vitro</i> data indicate that the destabilising effect of individual T60I and V122I variants appears to be additive rather than synergistic.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"An additive destabilising effect of compound T60I and V122I substitutions in ATTRv amyloidosis.\",\"authors\":\"Tatiana Prokaeva,&nbsp;Elena S Klimtchuk,&nbsp;Polina Feschenko,&nbsp;Brian Spencer,&nbsp;Haili Cui,&nbsp;Eric J Burks,&nbsp;Roshanak Aslebagh,&nbsp;Khaja Muneeruddin,&nbsp;Scott A Shaffer,&nbsp;Elizabeth Varghese,&nbsp;John L Berk,&nbsp;Lawreen H Connors\",\"doi\":\"10.1080/13506129.2022.2135988\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The amyloidogenic transthyretin (TTR) variant, V122I, occurs in 4% of the African American population and frequently presents as a restricted cardiomyopathy. While heterozygosity for TTR V122I predominates, several compound heterozygous cases have been previously described. Herein, we detail features of ATTRv amyloidosis associated with novel compound heterozygous TTR mutation, T60I/V122I and provide evidence supporting the amyloidogenecity of T60I.</p><p><strong>Methods: </strong>A 63-year-old African American female presented with atrial fibrillation, congestive heart failure, autonomic and peripheral neuropathy. <i>In vitro</i> studies of TTR T60I and V122I were undertaken to compare the biophysical properties of the proteins.</p><p><strong>Results: </strong>Congophilic deposits in a rectal biopsy were immunohistochemically positive for TTR. Serum screening by isoelectric focussing revealed two TTR variants in the absence of wild-type protein. DNA sequencing identified compound heterozygous <i>TTR</i> gene mutations, c.239C > T and c.424G > A. Adipose amyloid deposits were composed of both T60I and V122I. While kinetic stabilities of T60I and V122I variants were similar, distinct thermodynamic stabilities and amyloid growth kinetics were observed.</p><p><strong>Conclusions: </strong>This report provides clinical and experimental results supporting the amyloidogenic nature of a novel TTR T60I variant. <i>In vitro</i> data indicate that the destabilising effect of individual T60I and V122I variants appears to be additive rather than synergistic.</p>\",\"PeriodicalId\":50964,\"journal\":{\"name\":\"Amyloid-Journal of Protein Folding Disorders\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2023-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Amyloid-Journal of Protein Folding Disorders\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/13506129.2022.2135988\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Amyloid-Journal of Protein Folding Disorders","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/13506129.2022.2135988","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:淀粉样蛋白促甲状腺素(TTR)变异体V122I发生在4%的非裔美国人群中,经常表现为限制性心肌病。虽然TTR V122I的杂合性占主导地位,但先前已经描述了几种复合杂合病例。在此,我们详细介绍了与新型复合杂合TTR突变T60I/V122I相关的ATTRv淀粉样变性的特征,并提供了支持T60I淀粉样变性的证据。方法:一名63岁的非裔美国女性,表现为心房颤动、充血性心力衰竭、自主神经和周围神经病变。对TTR T60I和V122I进行了体外研究,比较了它们的生物物理特性。结果:直肠活检中嗜血性沉积物呈TTR免疫组化阳性。在缺乏野生型蛋白的情况下,等电聚焦血清筛查显示两种TTR变体。DNA测序鉴定出复合杂合TTR基因突变,c.239C > T和c.424G > A。脂肪淀粉样蛋白沉积由T60I和V122I组成。虽然T60I和V122I变体的动力学稳定性相似,但观察到不同的热力学稳定性和淀粉样蛋白生长动力学。结论:本报告提供的临床和实验结果支持一种新的TTR T60I变异的淀粉样变性。体外数据表明,单个T60I和V122I变体的不稳定效应似乎是相加的,而不是协同的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
An additive destabilising effect of compound T60I and V122I substitutions in ATTRv amyloidosis.

Background: The amyloidogenic transthyretin (TTR) variant, V122I, occurs in 4% of the African American population and frequently presents as a restricted cardiomyopathy. While heterozygosity for TTR V122I predominates, several compound heterozygous cases have been previously described. Herein, we detail features of ATTRv amyloidosis associated with novel compound heterozygous TTR mutation, T60I/V122I and provide evidence supporting the amyloidogenecity of T60I.

Methods: A 63-year-old African American female presented with atrial fibrillation, congestive heart failure, autonomic and peripheral neuropathy. In vitro studies of TTR T60I and V122I were undertaken to compare the biophysical properties of the proteins.

Results: Congophilic deposits in a rectal biopsy were immunohistochemically positive for TTR. Serum screening by isoelectric focussing revealed two TTR variants in the absence of wild-type protein. DNA sequencing identified compound heterozygous TTR gene mutations, c.239C > T and c.424G > A. Adipose amyloid deposits were composed of both T60I and V122I. While kinetic stabilities of T60I and V122I variants were similar, distinct thermodynamic stabilities and amyloid growth kinetics were observed.

Conclusions: This report provides clinical and experimental results supporting the amyloidogenic nature of a novel TTR T60I variant. In vitro data indicate that the destabilising effect of individual T60I and V122I variants appears to be additive rather than synergistic.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Amyloid-Journal of Protein Folding Disorders
Amyloid-Journal of Protein Folding Disorders 生物-生化与分子生物学
CiteScore
10.60
自引率
10.90%
发文量
48
审稿时长
6-12 weeks
期刊介绍: Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are: etiology, pathogenesis, histopathology, chemical structure, nature of fibrillogenesis; whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders. Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信