• Meng Jiang, Mengdie Wang, Zhengyu Tao, Yezi Chai, Qiming Liu, Qifan Lu, Qizhen Wu, Xiaoying Ying, Yanan Huang, Ying Nie, Yuqi Tang, Xin Zhang, Yu Liu, and Jun Pu.
• State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Coronary Heart Disease, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
• Amyloid. 2023 Jun 1; 30 (2): 188198188-198.

ObjectivesWe presented an unreported T96R mutation induced transthyretin cardiac amyloidosis (ATTR). The biochemical and biophysical properties were explored to support its pathogenicity.BackgroundUnderstanding the biochemical and biophysical nature of genetically mutated transthyretin (TTR) proteins is key to provide precise medical cares for ATTR patients.ResultsGenetic 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.ConclusionsA 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.

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