UNASSIGNED: Understanding the biochemical and biophysical nature of genetically mutated transthyretin (TTR) proteins is key to provide precise medical cares for ATTR patients.
UNASSIGNED: 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.
UNASSIGNED: 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.
未经批准:了解基因突变的转甲状腺素蛋白(TTR)蛋白的生化和生物物理性质是为ATTR患者提供精确医疗服务的关键。
UNASSIGNED:心肌活检证实淀粉样蛋白沉积后,遗传检测显示T96R致病变异c.348C>G(ATTRp.T116R)的杂合性。生化表征显示其热力学稳定性略有扰动(T96R的Cm=3.7M,WT为3.4M,L55P为2.3M(通常研究的TTR突变体))和动力学稳定性(T96R的t1/2=39.8h,WT为42小时,L55P为4.4小时)。交联实验证明野生型和TTRT96R蛋白之间的杂合亚基交换使四聚体不稳定。与WT和L55P相比,tafamidis和diflunnal对TTRT96R原纤维形成的抑制作用略低。
未经证实:针对TTR蛋白鉴定了一种新的T96R突变。生化和生物物理分析显示动力学稳定性略有不稳定。T96R突变使杂合蛋白不稳定,但没有蛋白水解降解,解释其致病性。小分子药物对T96R突变的抑制作用不同,建议可能需要个性化治疗。