Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis · 2022
Biochemical and biophysical properties of an unreported T96R mutation causing transthyretin cardiac amyloidosis.
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Jiang Meng, Wang Mengdie, Tao Zhengyu, Chai Yezi, Liu Qiming, Lu Qifan, Wu Qizhen, Ying Xiaoying, Huang Yanan, Nie Ying, Tang Yuqi, Zhang Xin, Liu Yu, Pu Jun
Аннотация
OBJECTIVES: We presented an unreported T96R mutation induced transthyretin cardiac amyloidosis (ATTR). The biochemical and biophysical properties were explored to support its pathogenicity.
BACKGROUND: Understanding the biochemical and biophysical nature of genetically mutated transthyretin (TTR) proteins is key to provide precise medical cares for ATTR patients.
RESULTS: Genetic testing showed heterozygosity for the T96R pathogenic variant c.347C > G (ATTR p.T116R) after myocardial biopsy confirmed amyloid deposition. Biochemical characterizations revealed slight perturbation of its thermodynamic stability (Cm=3.7 M for T96R, 3.4 M for WT and 2.3 M for L55P (commonly studied TTR mutant)) and kinetic stability (t1/2=39.8 h for T96R, 42 h for WT and 4.4 h in L55P). Crosslinking experiment demonstrated heterozygous subunit exchange between wild-type and TTR T96R protein destabilized the tetramer. Inhibitory effect of tafamidis and diflunisal on TTR T96R fibril formation was slightly less effective compared to WT and L55P.
CONCLUSIONS: A novel T96R mutation was identified for TTR protein. Biochemical and biophysical analyses revealed slightly destabilized kinetic stability. T96R mutation destabilized heterozygous protein but not proteolytic degradation, explaining its pathogenicity. Inhibitory effect of small molecule drugs on T96R mutation was different, suggesting personalized treatment may be required.
BACKGROUND: Understanding the biochemical and biophysical nature of genetically mutated transthyretin (TTR) proteins is key to provide precise medical cares for ATTR patients.
RESULTS: Genetic testing showed heterozygosity for the T96R pathogenic variant c.347C > G (ATTR p.T116R) after myocardial biopsy confirmed amyloid deposition. Biochemical characterizations revealed slight perturbation of its thermodynamic stability (Cm=3.7 M for T96R, 3.4 M for WT and 2.3 M for L55P (commonly studied TTR mutant)) and kinetic stability (t1/2=39.8 h for T96R, 42 h for WT and 4.4 h in L55P). Crosslinking experiment demonstrated heterozygous subunit exchange between wild-type and TTR T96R protein destabilized the tetramer. Inhibitory effect of tafamidis and diflunisal on TTR T96R fibril formation was slightly less effective compared to WT and L55P.
CONCLUSIONS: A novel T96R mutation was identified for TTR protein. Biochemical and biophysical analyses revealed slightly destabilized kinetic stability. T96R mutation destabilized heterozygous protein but not proteolytic degradation, explaining its pathogenicity. Inhibitory effect of small molecule drugs on T96R mutation was different, suggesting personalized treatment may be required.