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首页> 外文期刊>Amyloid: the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis >Thermodynamic stability and denaturation kinetics of a benign natural transthyretin mutant identified in a Danish kindred.
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Thermodynamic stability and denaturation kinetics of a benign natural transthyretin mutant identified in a Danish kindred.

机译：丹麦亲属鉴定的良性天然运甲状腺素蛋白突变体的热力学稳定性和变性动力学。

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摘要

The disease phenotype of transthyretin (TTR) is dramatically influenced by single point mutations in the TTR gene. Herein, we report on a novel mutation D99N (Asp99Asn) in TTR found in a Danish kindred. None of the family members carrying this mutation have so far shown any clinical signs of amyloidosis. One carrier found compound heterozygous for TTR D99N and L111M (Leu111Met) associated with cardiac amyloid is asymptomatic (42 years). Disease severity can often be linked to both the kinetics of fibril formation and the degree of destabilisation of the native state. In this study, we show that the thermodynamic stability and rate of tetramer dissociation of the variant TTR D99N is unchanged or slightly more stable than wild type (WT) TTR. Furthermore, the in vitro fibrillation kinetics of the variant reveals an unchanged or slightly suppressed tendency to form fibrils compared to WT. Thus, the in vitro experiments support the lack of clinical symptoms observed so far for the TTR D99N carriers. In line with this, studies on kinetic stability and fibrillation kinetics reveal indistinguishable stability of TTR heterotetramers D99N/L111M compared to the heterotetramers WT/L111M. In conclusion, TTR D99N is predicted to be a non-pathogenic benign mutation with WT properties.
机译：甲状腺素转运蛋白（TTR）的疾病表型受TTR基因单点突变的影响很大。本文中，我们报道了丹麦亲戚发现的TTR中的新型突变D99N（Asp99Asn）。迄今为止，尚无携带这种突变的家庭成员显示出淀粉样变性的任何临床体征。发现与心脏淀粉样蛋白相关的TTR D99N和L111M（Leu111Met）的复合杂合子是无症状的（42岁）。疾病的严重程度通常与原纤维形成的动力学和天然状态的不稳定程度有关。在这项研究中，我们显示了变体TTR D99N的热力学稳定性和四聚体解离速率比野生型（WT）TTR不变或稍稳定。此外，与WT相比，该变体的体外原纤化动力学显示出形成原纤的趋势不变或略微被抑制。因此，体外实验支持迄今未观察到TTR D99N携带者的临床症状。与此相一致，对动力学稳定性和原纤化动力学的研究表明，与异四聚体WT / L111M相比，TTR异四聚体D99N / L111M的稳定性无可辩驳。总之，TTR D99N被预测为具有WT特性的非致病性良性突变。

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