Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation

Chu, Xujun; Wang, Mengdie; Tang, Ran; Huang, Yanan; Yu, Jiaxi; Cao, Yong; Zheng, Yilei; Xie, Zongwu; Deng, Jianwen; Wang, Zhi; Ma, Wei; Song, Wenjing; Yuan, Wei; Lv, He; Zhang, Wei; Wang, Zhaoxia; Yuan, Yun; Liu, Yu; Meng, Lingchao

doi:10.3389/fnmol.2022.1003303

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…4a-c). In addition, consistent with what was observed in other TTR muta-tions (e.g., E61K-TTR and T96R-TTR) [35,36], the G47V:WT-TTR heterozygous protein showed much poorer drug response to all three small molecule stabilizers compared to the G47V-TTR homozygous proteins (shown in Fig. 4d-f).…”

Section: G47v-ttr Responses Poorly To Small Molecule Kinetic Stabilizerssupporting

confidence: 88%

Characterization of Transthyretin Mutation G47V Associated with Hereditary Cardiac Amyloidosis

He,

Wang,

Sun

et al. 2024

Cardiology

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Introduction: Amyloidosis caused by TTR mutations (ATTRv) is a rare inherited and autosomal dominant disease. More than 150 mutants of TTR have been reported, whereas some of them remain to be investigated. Methods: A 52-year-old male presented with heart failure and clinically diagnosed ATTR cardiac amyloidosis (ATTR-CA) was recruited. Whole exome sequencing (WES) was performed. Biochemical and biophysical experiments characterized protein stability using urea-mediated tryptophan fluorescence. Drug response was analyzed by fibril formation assay. Finally, tetramer TTR concentration in patient’ serum sample was measured by ultra-performance liquid chromatography (UPLC). Results: For the proband, whole exome sequencing revealed a mutation (c.200G>T; p.Gly67Val and referred to as G47V) in TTR gene. Biochemical and biophysical kinetics study showed that the thermodynamic stability of G47V-TTR (Cm = 2.4 M) was significantly lower than that of WT-TTR (Cm = 3.4 M) and comparable to that of L55P-TTR (Cm = 2.3 M), an early age-of-onset mutation. G47V:WT-TTR heterozygous tetramers kinetic stability (t1/2 = 1.4 h) was further compromised compared to that of the homozygous G47V-TTR (t1/2 = 3.1 h). Among three small molecule stabilizers, AG10 exhibited the best inhibition of the fibrillation of G47V-TTR homozygous protein. Using a UPLC assay, nearly 40% of TTR in this patient was calculated to be non-tetrameric. Conclusion: In this work, we reported a patient presented early onset of clinically typical ATTR-CM due to G47V-TTR mutation. Our work not only for the first time characterized the biochemical properties of G47V-TTR mutation, but also provided hints for the pathogenicity of this mutation.

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Section: G47v-ttr Responses Poorly To Small Molecule Kinetic Stabilizerssupporting

confidence: 88%

Characterization of Transthyretin Mutation G47V Associated with Hereditary Cardiac Amyloidosis

He,

Wang,

Sun

et al. 2024

Cardiology

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“…We previously reported pedigrees of TTR carrying TTRE61K mutation 40 and cardiomyopathy, with m/and cardiomyopathy, with mean TTR concentration (3.63 μM) before oral Vyndamax (Tafamidis, 61 mg QD) and after taking the drug (5.19 μM). Unlike our previously reported cases of TTRE61K, 40 the TTR concentration did not increase significantly after 1 month of taking Tafamidis. The TTR concentration was monitored to increase after 6 months, but the concentration gradually decreased to 2.52 μM.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and biophysical properties of a rare TTRA81V mutation causing mild transthyretin amyloid cardiomyopathy

Sha,

Zhang,

Wang

et al. 2023

ESC Heart Failure

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AimsWe conducted a presentation on an 84‐year‐old male patient who has been diagnosed with TTRA81V (p. TTRA101V) hereditary transthyretin cardiac amyloidosis (hATTR‐CM). In order to establish its pathogenicity, we extensively investigated the biochemical and biophysical properties of the condition.Methods and resultsTransthyretin amyloid cardiomyopathy (ATTR‐CM) is an increasingly acknowledged progressive infiltrative cardiomyopathy that leads to heart failure and potentially fatal arrhythmias. Gaining a comprehensive understanding of the biochemical and biophysical characteristics of genetically mutated TTR proteins serves as the fundamental cornerstone for delivering precise medical care to individuals affected by ATTR. Laboratory assessments indicated a brain natriuretic peptide of 200.12 ng/L (normal range: 0–100 ng/L) and high‐sensitivity cardiac troponin I of 0.189 μg/L (normal range: 0–0.1 μg/L). Echocardiography identified left atrial enlargement, symmetrical left ventricular hypertrophy (16 mm septal and 16 mm posterior wall), and a left ventricular ejection fraction of 56%. Cardiac‐enhanced magnetic resonance imaging revealed subendocardial late gadolinium enhancement. Tc‐99m‐PYP nuclear scintigraphy confirmed grade 3 myocardial uptake, showing an increased heart‐to‐contralateral ratio (H/CL = 2.33). Genetic testing revealed a heterozygous missense mutation in the TTR gene (c.302C>T), resulting in an alanine‐to‐valine residue change (p. Ala81Val, following the first 20 residues of signal sequence nomenclature). Biochemical analysis of this variant displayed compromised kinetic stability in both the TTRA81V:WT (wild‐type) heterozygote protein (half‐life, t1/2 = 21 h) and the TTRA81V homozygote protein (t1/2 = 17.5 h). The kinetic stability fell between that of the TTRWT (t1/2 = 42 h) and the early‐onset TTRL55P mutation (t1/2 = 4.4 h), indicating the patient's late‐onset condition. Kinetic stabilizers (Tafamidis, Diflunisal, and AG10) all exhibited the capacity to inhibit TTRA81V acid‐ and mechanical force‐induced fibril formation, albeit less effectively than with TTRWT. Chromatographic assessment of the patient's serum TTR tetramers indicated a slightly lower concentration (3.0 μM) before oral administration of Tafamidis compared with the normal range (3.6–7.2 μM).ConclusionsWe identified a patient with hATTR‐CM who possesses a rare TTRA81V mutation solely associated with cardiac complications. The slightly reduced kinetic stability of this mutation indicates its late‐onset nature and contributes to the gradual progression of the disease.

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“…Interestingly, in patients carrying this variant, sural nerve biopsy showed no amyloid deposits, although significant loss of myelinated fibers was detected. Deposits were, however, present in muscle, salivary gland, and heart biopsies [52][53][54]. Additionally, some non-pathogenic variants (Thr119Met and Arg104His) can have a protective effect in compound heterozygotes carrying the Val30Met variant.…”

Section: Genotypementioning

confidence: 98%

Hereditary transthyretin amyloidosis: a myriad of factors that influence phenotypic variability

Carvalho,

Dias,

Coelho

et al. 2024

J Neurol

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Hereditary transthyretin-related amyloidosis (ATTRv amyloidosis) is a rare and progressively debilitating disease characterized by the deposition of transthyretin (TTR) amyloid fibrils in various organs and tissues, most commonly in the heart and peripheral nerves. This pathological deposition can lead to significant organ dysfunction and, ultimately, organ failure. ATTRv amyloidosis exhibits a broad range of clinical presentations, from purely neurological symptoms to purely cardiac manifestations, as well as mixed phenotypes which result from both neurological and cardiac implications. This wide phenotypical spectrum realistically challenges disease diagnosis and prognosis, especially in individuals without or with an unknown family history. Multiple factors are thought to contribute to this variability, including genetic, epigenetic, and even environmental influences. Understanding these factors is crucial, as they can significantly affect disease expression and progression. This review aims to summarize each of these contributing factors, to help elucidate the current knowledge on the phenotypical variability of ATTRv amyloidosis.

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Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation

Cited by 4 publications

References 47 publications

Characterization of Transthyretin Mutation G47V Associated with Hereditary Cardiac Amyloidosis

Characterization of Transthyretin Mutation G47V Associated with Hereditary Cardiac Amyloidosis

Biochemical and biophysical properties of a rare TTRA81V mutation causing mild transthyretin amyloid cardiomyopathy

Hereditary transthyretin amyloidosis: a myriad of factors that influence phenotypic variability

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