Mutations in specific structural regions of immunoglobulin light chains are associated with free light chain levels in patients with AL amyloidosis.
Mutations in specific structural regions of immunoglobulin light chains are associated with free light chain levels in patients with AL amyloidosis.
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DOI：
10.1371/journal.pone.0005169
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Ramirez-Alvarado M
中科院分区：
文献类型：
--
作者：
Poshusta TL;Sikkink LA;Leung N;Clark RJ;Dispenzieri A;Ramirez-Alvarado M
淀粉样变性是蛋白质错误折叠疾病，其特征是淀粉样蛋白沉积，导致细胞死亡和组织变性。在免疫球蛋白轻链淀粉样变性 (AL) 中，每位患者都有独特的单克隆免疫球蛋白轻链 (LC)，可形成淀粉样蛋白沉积物。 AL LC 中的体细胞突变使这些蛋白质的热力学稳定性低于非淀粉样蛋白形成蛋白，导致错误折叠并最终形成淀粉样原纤维。我们假设非保守突变的位置而不是数量决定了轻链的淀粉样蛋白生成性。我们对 50 κ 和 91 λ AL 轻链的可变域进行了序列比对，并计算了每个二级结构元件的非保守突变数量占患者总数的比例，以识别积累非保守突变的区域。在 AL 患者中，循环免疫球蛋白游离轻链的水平差异很大，但即使水平非常低的患者也可能出现非常严重的淀粉样蛋白沉积。我们的结果表明，在特定的二级结构元件中，正常序列和AL序列之间的非保守突变数量存在显着差异。不同分泌轻链水平的患者的AL序列在非保守突变的位置上存在明显差异，这表明对于轻链水平极低且淀粉样蛋白沉积晚期的患者，非保守突变的位置而不是循环中游离轻链的量可能决定轻链的淀粉样变倾向。
The amyloidoses are protein misfolding diseases characterized by the deposition of amyloid that leads to cell death and tissue degeneration. In immunoglobulin light chain amyloidosis (AL), each patient has a unique monoclonal immunoglobulin light chain (LC) that forms amyloid deposits. Somatic mutations in AL LCs make these proteins less thermodynamically stable than their non-amyloidogenic counterparts, leading to misfolding and ultimately the formation of amyloid fibrils. We hypothesize that location rather than number of non-conservative mutations determines the amyloidogenicity of light chains. We performed sequence alignments on the variable domain of 50 κ and 91 λ AL light chains and calculated the number of non-conservative mutations over total number of patients for each secondary structure element in order to identify regions that accumulate non-conservative mutations. Among patients with AL, the levels of circulating immunoglobulin free light chain varies greatly, but even patients with very low levels can have very advanced amyloid deposition. Our results show that in specific secondary structure elements, there are significant differences in the number of non-conservative mutations between normal and AL sequences. AL sequences from patients with different levels of secreted light chain have distinct differences in the location of non-conservative mutations, suggesting that for patients with very low levels of light chains and advanced amyloid deposition, the location of non-conservative mutations rather than the amount of free light chain in circulation may determine the amyloidogenic propensity of light chains.
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影响因子：
4.8
作者：
Kim, YS;Wall, JS;Carpenter, JF
通讯作者：
Carpenter, JF
影响因子：
2.9
作者：
RADZICKA, A;PEDERSEN, L;WOLFENDEN, R
通讯作者：
WOLFENDEN, R
影响因子：
5.5
作者：
Sikkink, Laura A.;Ramirez-Alvarado, Marina
通讯作者：
Ramirez-Alvarado, Marina
DOI：
10.3109/13506120009146835
发表时间：
2000-09-01
期刊：
AMYLOID-INTERNATIONAL JOURNAL OF EXPERIMENTAL AND CLINICAL INVESTIGATION
影响因子：
--
作者：
Stevens, FJ
通讯作者：
Stevens, FJ
DOI：
10.1016/s0925-4439(99)00019-8
发表时间：
1999-05-31
影响因子：
6.2
作者：
Wally, J;Kica, G;Comenzo, RL
通讯作者：
Comenzo, RL