Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation
Objects: This study was intended to find out more about the clinical characterizations of patients carrying transthyretin (TTR) E61K (p.Glu81Lys) gene mutation and the biochemical characterization of this mutant protein.Materials and methods: Five patients who had been diagnosed with hereditary tran...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.1003303/full |
| _version_ | 1828105982197104640 |
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| author | Xujun Chu Mengdie Wang Mengdie Wang Ran Tang Yanan Huang Jiaxi Yu Yunfeng Cao Yilei Zheng Zhiying Xie Jianwen Deng Zhi Wang Wei Ma Wenjing Song Yuan Wu He Lv Wei Zhang Zhaoxia Wang Yun Yuan Yu Liu Lingchao Meng |
| author_facet | Xujun Chu Mengdie Wang Mengdie Wang Ran Tang Yanan Huang Jiaxi Yu Yunfeng Cao Yilei Zheng Zhiying Xie Jianwen Deng Zhi Wang Wei Ma Wenjing Song Yuan Wu He Lv Wei Zhang Zhaoxia Wang Yun Yuan Yu Liu Lingchao Meng |
| author_sort | Xujun Chu |
| collection | DOAJ |
| description | Objects: This study was intended to find out more about the clinical characterizations of patients carrying transthyretin (TTR) E61K (p.Glu81Lys) gene mutation and the biochemical characterization of this mutant protein.Materials and methods: Five patients who had been diagnosed with hereditary transthyretin amyloidosis and two asymptomatic carriers carrying TTR E61K gene mutation were reported. Biochemical and biophysical tests were conducted to observe the thermodynamic and kinetic stability. Fibril formation tests measured by turbidity assay were performed to explore the pathogenicity of this mutation. Kinetic stabilizer responsiveness was measured to determine the inhibitory effect on protein aggregation.Results: The average age of onset for the five patients was 62 years, and the course of the disease ranged from 2 to 10 years. Cardiac disease was prominent in this group of patients. Nerve pathology revealed a mildly to moderately reduced myelinated fiber density and muscle pathology showed predominant neurogenic impairment accompanied by possible myogenic impairment. E61K-TTR was characterized as a kinetically destabilized protein compared to WT-TTR but its thermodynamic stability was not compromised. In addition, the subunit exchange of E61K with WT-TTR further destabilized the heterozygous tetramer. Meanwhile, the E61K:WT heterozygous tetramer exhibited a poor response to kinetic stabilizers in the fibril formation assay. Finally, the serum TTR tetramer concentration was low in E61K-TTR symptomatic patients and in one asymptomatic gene carrier. Vyndamax (Tafamidis) could increase the TTR tetramer concentration.Conclusions: Patients with E61K mutation tended to be late-onset. The concentration of TTR tetramer in the serum might serve as a biomarker to monitor disease progress, therapeutic window time, and therapeutic response to TTR kinetic stabilizer drugs. |
| first_indexed | 2024-04-11T10:10:16Z |
| format | Article |
| id | doaj.art-19be44965334423db88e2e8bef4466df |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-11T10:10:16Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-19be44965334423db88e2e8bef4466df2022-12-22T04:30:07ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-10-011510.3389/fnmol.2022.10033031003303Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutationXujun Chu0Mengdie Wang1Mengdie Wang2Ran Tang3Yanan Huang4Jiaxi Yu5Yunfeng Cao6Yilei Zheng7Zhiying Xie8Jianwen Deng9Zhi Wang10Wei Ma11Wenjing Song12Yuan Wu13He Lv14Wei Zhang15Zhaoxia Wang16Yun Yuan17Yu Liu18Lingchao Meng19Department of Neurology, Peking University First Hospital, Beijing, ChinaCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaDong’e County People’s Hospital, Liaocheng, ChinaCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaShanghai Institute for Biomedical and Pharmaceutical Technologies, NHC Key Laboratory of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai, ChinaDepartment of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Cardiology, Peking University First Hospital, Beijing, ChinaDepartment of Cardiology, Peking University First Hospital, Beijing, ChinaDepartment of Ophthalmology, Peking University First Hospital, Beijing, ChinaDepartment of Ophthalmology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaObjects: This study was intended to find out more about the clinical characterizations of patients carrying transthyretin (TTR) E61K (p.Glu81Lys) gene mutation and the biochemical characterization of this mutant protein.Materials and methods: Five patients who had been diagnosed with hereditary transthyretin amyloidosis and two asymptomatic carriers carrying TTR E61K gene mutation were reported. Biochemical and biophysical tests were conducted to observe the thermodynamic and kinetic stability. Fibril formation tests measured by turbidity assay were performed to explore the pathogenicity of this mutation. Kinetic stabilizer responsiveness was measured to determine the inhibitory effect on protein aggregation.Results: The average age of onset for the five patients was 62 years, and the course of the disease ranged from 2 to 10 years. Cardiac disease was prominent in this group of patients. Nerve pathology revealed a mildly to moderately reduced myelinated fiber density and muscle pathology showed predominant neurogenic impairment accompanied by possible myogenic impairment. E61K-TTR was characterized as a kinetically destabilized protein compared to WT-TTR but its thermodynamic stability was not compromised. In addition, the subunit exchange of E61K with WT-TTR further destabilized the heterozygous tetramer. Meanwhile, the E61K:WT heterozygous tetramer exhibited a poor response to kinetic stabilizers in the fibril formation assay. Finally, the serum TTR tetramer concentration was low in E61K-TTR symptomatic patients and in one asymptomatic gene carrier. Vyndamax (Tafamidis) could increase the TTR tetramer concentration.Conclusions: Patients with E61K mutation tended to be late-onset. The concentration of TTR tetramer in the serum might serve as a biomarker to monitor disease progress, therapeutic window time, and therapeutic response to TTR kinetic stabilizer drugs.https://www.frontiersin.org/articles/10.3389/fnmol.2022.1003303/fullE61K mutationkinetic stabilitythermodynamic stabilityTTR tetramerkinetic stabilizersATTRv amyloidosis |
| spellingShingle | Xujun Chu Mengdie Wang Mengdie Wang Ran Tang Yanan Huang Jiaxi Yu Yunfeng Cao Yilei Zheng Zhiying Xie Jianwen Deng Zhi Wang Wei Ma Wenjing Song Yuan Wu He Lv Wei Zhang Zhaoxia Wang Yun Yuan Yu Liu Lingchao Meng Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation Frontiers in Molecular Neuroscience E61K mutation kinetic stability thermodynamic stability TTR tetramer kinetic stabilizers ATTRv amyloidosis |
| title | Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation |
| title_full | Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation |
| title_fullStr | Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation |
| title_full_unstemmed | Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation |
| title_short | Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation |
| title_sort | clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by e61k mutation |
| topic | E61K mutation kinetic stability thermodynamic stability TTR tetramer kinetic stabilizers ATTRv amyloidosis |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.1003303/full |
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