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Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations

Hereditary transthyretin cardiac amyloidosis (hATTR-CA) is a rare autosomal dominantly inherited disease caused by mutations in the transthyretin (TTR) gene. TTR mutations often cause the instability of transthyretin, production of misfolded proteins, and ultimately excessive deposition of insoluble...

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Autores principales: Ma, Qunchao, Wang, Mengdie, Huang, Yanan, Nie, Ying, Zhang, Xin, Yang, Dan Dan, Wang, Zhuo, Ding, Siyin, Qian, Ningjing, Liu, Yu, Pan, Xiaohong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909007/
https://www.ncbi.nlm.nih.gov/pubmed/36776255
http://dx.doi.org/10.3389/fcvm.2023.1091183
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author Ma, Qunchao
Wang, Mengdie
Huang, Yanan
Nie, Ying
Zhang, Xin
Yang, Dan Dan
Wang, Zhuo
Ding, Siyin
Qian, Ningjing
Liu, Yu
Pan, Xiaohong
author_facet Ma, Qunchao
Wang, Mengdie
Huang, Yanan
Nie, Ying
Zhang, Xin
Yang, Dan Dan
Wang, Zhuo
Ding, Siyin
Qian, Ningjing
Liu, Yu
Pan, Xiaohong
author_sort Ma, Qunchao
collection PubMed
description Hereditary transthyretin cardiac amyloidosis (hATTR-CA) is a rare autosomal dominantly inherited disease caused by mutations in the transthyretin (TTR) gene. TTR mutations often cause the instability of transthyretin, production of misfolded proteins, and ultimately excessive deposition of insoluble amyloid fibrils in the myocardium, thereby leading to cardiac dysfunction. Herein, we report a novel transthyretin D39Y mutation in a Chinese family. We characterized the kinetic and thermodynamic stabilities of D39Y mutant TTR, revealing that TTR D39Y mutant was less stable than WT TTR and more stable than amyloidogenic mutation TTR L55P. Meanwhile, the only FDA approved drug Tafamidis showed satisfactory inhibitory effect toward ATTR amyloid formation and strong binding affinity in test tube revealed by isothermal titration calorimetry. Finally, we measured the well-folded tetrameric TTR concentration in patient’s and his descents’ blood serum using a previously reported UPLC-based assay. Notably, the tetramer concentrations gradually increased from symptomatic D39Y gene carrier father, to asymptomatic D39Y gene carrier daughter, and further to wild type daughter, suggesting the decrease in functional tetrameric TTR concentration may serve as an indicator for disease age of onset in D39Y gene carriers. The study described a Chinese family with hATTR-CA due to the TTR variant D39Y with its destabilizing effect in both kinetic and thermodynamic stabilities.
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spelling pubmed-99090072023-02-10 Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations Ma, Qunchao Wang, Mengdie Huang, Yanan Nie, Ying Zhang, Xin Yang, Dan Dan Wang, Zhuo Ding, Siyin Qian, Ningjing Liu, Yu Pan, Xiaohong Front Cardiovasc Med Cardiovascular Medicine Hereditary transthyretin cardiac amyloidosis (hATTR-CA) is a rare autosomal dominantly inherited disease caused by mutations in the transthyretin (TTR) gene. TTR mutations often cause the instability of transthyretin, production of misfolded proteins, and ultimately excessive deposition of insoluble amyloid fibrils in the myocardium, thereby leading to cardiac dysfunction. Herein, we report a novel transthyretin D39Y mutation in a Chinese family. We characterized the kinetic and thermodynamic stabilities of D39Y mutant TTR, revealing that TTR D39Y mutant was less stable than WT TTR and more stable than amyloidogenic mutation TTR L55P. Meanwhile, the only FDA approved drug Tafamidis showed satisfactory inhibitory effect toward ATTR amyloid formation and strong binding affinity in test tube revealed by isothermal titration calorimetry. Finally, we measured the well-folded tetrameric TTR concentration in patient’s and his descents’ blood serum using a previously reported UPLC-based assay. Notably, the tetramer concentrations gradually increased from symptomatic D39Y gene carrier father, to asymptomatic D39Y gene carrier daughter, and further to wild type daughter, suggesting the decrease in functional tetrameric TTR concentration may serve as an indicator for disease age of onset in D39Y gene carriers. The study described a Chinese family with hATTR-CA due to the TTR variant D39Y with its destabilizing effect in both kinetic and thermodynamic stabilities. Frontiers Media S.A. 2023-01-26 /pmc/articles/PMC9909007/ /pubmed/36776255 http://dx.doi.org/10.3389/fcvm.2023.1091183 Text en Copyright © 2023 Ma, Wang, Huang, Nie, Zhang, Yang, Wang, Ding, Qian, Liu and Pan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Ma, Qunchao
Wang, Mengdie
Huang, Yanan
Nie, Ying
Zhang, Xin
Yang, Dan Dan
Wang, Zhuo
Ding, Siyin
Qian, Ningjing
Liu, Yu
Pan, Xiaohong
Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations
title Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations
title_full Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations
title_fullStr Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations
title_full_unstemmed Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations
title_short Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations
title_sort identification of a novel transthyretin mutation d39y in a cardiac amyloidosis patient and its biochemical characterizations
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909007/
https://www.ncbi.nlm.nih.gov/pubmed/36776255
http://dx.doi.org/10.3389/fcvm.2023.1091183
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