Antibody recognition of amyloidogenic transthyretin variants in serum of patients with familial amyloidotic polyneuropathy
Antibody recognition of amyloidogenic transthyretin variants in serum of patients with familial amyloidotic polyneuropathy
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DOI：
10.1007/s001090000163
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发表时间：
2001-01-01
影响因子：
4.7
通讯作者：
Saraiva, MJ
中科院分区：
文献类型：
--
作者：
Palha, JA;Moreira, P;Saraiva, MJ
家族性淀粉样多发性神经病（FAP）是一种迟发性遗传性疾病，其特征是淀粉样纤维沉积，FAP与甲状腺素运载蛋白（TTR）基因突变有关。一种单克隆抗体，MAb 39-44，与高分子量的TTR聚集体反应，但不与四聚体TTR最近已产生和表征。该抗体识别在分离的重组淀粉样蛋白突变体和离体淀粉样蛋白中表达的隐蔽表位。在目前的工作中，我们表明，这种淀粉样蛋白特异性抗体特异性识别在直接酶联免疫测定（ELISA）血浆TTR从携带者的各种突变与FAP，无论是在无症状的个人和患者。相反，它不与健康个体或非致病性突变携带者的血浆TTR反应。使用本研究中开发的ELISA，我们确定了三种不同的TTR突变的葡萄牙患者不明原因的神经病变，后来显示有淀粉样组织沉积。该抗体识别表达与FAP相关的淀粉样TTR变体共享的隐蔽表位的构象，而非致病性TTR分子中不存在。该抗体将有助于进一步鉴定和表征淀粉样蛋白生成级联反应的中间体。此外，在使用蛋白质和/或DNA分析进行精确的分子诊断之前，它也将用于筛查患有不明原因的神经病的患者中的淀粉样蛋白TTR突变。
Familial amyloidotic polyneuropathy (FAP) is a late-onset inherited disease characterized by the deposition of amyloid fibrils, FAP is associated with mutations on the transthyretin (TTR) gene. A monoclonal antibody, MAb 39-44, reacting with high molecular weight aggregates of TTR but not with tetrameric TTR has recently been generated and characterized. This antibody recognizes a cryptic epitope that is expressed in isolated recombinant amyloidogenic mutants and in ex vivo amyloid. In the present work we show that this amyloid-specific antibody specifically recognizes in a direct enzyme-linked immunoassay (ELISA) plasma TTR from carriers of various mutations associated with FAP, both in asymptomatic individuals and in patients. In contrast, it does not react with plasma TTR from healthy individuals or that from carriers of nonpathogenic mutations. Using the ELISA developed in this study we identified three different TTR mutations in Portuguese patients with neuropathy of unknown cause, later shown to have amyloid tissue deposition. This antibody recognizes conformations that express cryptic epitopes shared by amyloidogenic TTR variants associated with FAP, not present among nonpathogenic TTR molecules. This antibody will contribute to further identify and characterize intermediates of the amyloidogenic cascade. In addition, it will also be useful for screening amyloidogenic TTR mutations in patients with neuropathy of unknown cause, prior to precise molecular diagnosis using protein and/or DNA analysis.