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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1091183/full |
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| author | Qunchao Ma Mengdie Wang Mengdie Wang Yanan Huang Ying Nie Xin Zhang Xin Zhang Dan Dan Yang Zhuo Wang Siyin Ding Ningjing Qian Yu Liu Xiaohong Pan |
| author_facet | Qunchao Ma Mengdie Wang Mengdie Wang Yanan Huang Ying Nie Xin Zhang Xin Zhang Dan Dan Yang Zhuo Wang Siyin Ding Ningjing Qian Yu Liu Xiaohong Pan |
| author_sort | Qunchao Ma |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T20:14:43Z |
| format | Article |
| id | doaj.art-a1855c3439b74441ada6ad7d0d5e22ab |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-10T20:14:43Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-a1855c3439b74441ada6ad7d0d5e22ab2023-01-26T06:09:32ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-01-011010.3389/fcvm.2023.10911831091183Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizationsQunchao Ma0Mengdie Wang1Mengdie Wang2Yanan Huang3Ying Nie4Xin Zhang5Xin Zhang6Dan Dan Yang7Zhuo Wang8Siyin Ding9Ningjing Qian10Yu Liu11Xiaohong Pan12Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaChinese Academy of Sciences (CAS) Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, ChinaDepartment of Chemistry, University of Chinese Academy of Sciences, Beijing, ChinaChinese Academy of Sciences (CAS) Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, ChinaInstrumentation and Service Center for Physical Sciences, Westlake University, Hangzhou, Zhejiang, ChinaSchool of Science, School of Life Sciences, Westlake University, Hangzhou, ChinaWestlake Laboratory of Life Sciences and Biomedicine, Institute of Natural Sciences, Westlake Institute for Advanced Study, Hangzhou, ChinaDepartment of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaChinese Academy of Sciences (CAS) Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, ChinaDepartment of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaHereditary 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.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1091183/fullcardiac amyloidosisnovel mutationstabilitytransthyretintetramer concentration |
| spellingShingle | Qunchao Ma Mengdie Wang Mengdie Wang Yanan Huang Ying Nie Xin Zhang Xin Zhang Dan Dan Yang Zhuo Wang Siyin Ding Ningjing Qian Yu Liu Xiaohong Pan Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations Frontiers in Cardiovascular Medicine cardiac amyloidosis novel mutation stability transthyretin tetramer concentration |
| 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 | cardiac amyloidosis novel mutation stability transthyretin tetramer concentration |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1091183/full |
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