Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA.
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
Amyloid. 2023 Jun;30(2):141-152. doi: 10.1080/13506129.2022.2135988. Epub 2022 Oct 26.
The amyloidogenic transthyretin (TTR) variant, V122I, occurs in 4% of the African American population and frequently presents as a restricted cardiomyopathy. While heterozygosity for TTR V122I predominates, several compound heterozygous cases have been previously described. Herein, we detail features of ATTRv amyloidosis associated with novel compound heterozygous TTR mutation, T60I/V122I and provide evidence supporting the amyloidogenecity of T60I.
A 63-year-old African American female presented with atrial fibrillation, congestive heart failure, autonomic and peripheral neuropathy. studies of TTR T60I and V122I were undertaken to compare the biophysical properties of the proteins.
Congophilic deposits in a rectal biopsy were immunohistochemically positive for TTR. Serum screening by isoelectric focussing revealed two TTR variants in the absence of wild-type protein. DNA sequencing identified compound heterozygous gene mutations, c.239C > T and c.424G > A. Adipose amyloid deposits were composed of both T60I and V122I. While kinetic stabilities of T60I and V122I variants were similar, distinct thermodynamic stabilities and amyloid growth kinetics were observed.
This report provides clinical and experimental results supporting the amyloidogenic nature of a novel TTR T60I variant. data indicate that the destabilising effect of individual T60I and V122I variants appears to be additive rather than synergistic.
载脂蛋白变异体 TTR（转甲状腺素蛋白）V122I 在 4%的非裔美国人中出现，常表现为限制性心肌病。虽然 TTR V122I 杂合子占优势，但以前已经描述了几个复合杂合子病例。在此，我们详细介绍了与新型 TTR 突变 T60I/V122I 相关的 ATTRv 淀粉样变性的特征，并提供了支持 T60I 淀粉样生成的证据。
一位 63 岁的非裔美国女性因心房颤动、充血性心力衰竭、自主神经和周围神经病变就诊。对 TTR T60I 和 V122I 进行了研究，以比较蛋白质的生物物理特性。
直肠活检中的嗜刚果纤维沉积免疫组织化学上 TTR 阳性。血清等电聚焦筛查显示在没有野生型蛋白的情况下存在两种 TTR 变体。DNA 测序确定了复合杂合基因突变 c.239C>T 和 c.424G>A。脂肪组织淀粉样沉积物由 T60I 和 V122I 组成。虽然 T60I 和 V122I 变体的动力学稳定性相似，但观察到明显的热力学稳定性和淀粉样蛋白生长动力学不同。
本报告提供了支持新型 TTR T60I 变体淀粉样生成特性的临床和实验结果。数据表明，单个 T60I 和 V122I 变体的不稳定效应似乎是累加的，而不是协同的。
