AMYLOID FIBRIL PROTEIN IN FAMILIAL AMYLOIDOTIC POLYNEUROPATHY, PORTUGUESE TYPE - DEFINITION OF MOLECULAR ABNORMALITY IN TRANSTHYRETIN (PREALBUMIN)
AMYLOID FIBRIL PROTEIN IN FAMILIAL AMYLOIDOTIC POLYNEUROPATHY, PORTUGUESE TYPE - DEFINITION OF MOLECULAR ABNORMALITY IN TRANSTHYRETIN (PREALBUMIN)
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DOI：
10.1172/jci111390
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发表时间：
1984-01-01
影响因子：
15.9
通讯作者：
GOODMAN, DS
中科院分区：
文献类型：
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作者：
SARAIVA, MJM;BIRKEN, S;GOODMAN, DS
家族性淀粉样变性多神经病变患者的淀粉样纤维蛋白与转甲状腺素（TTR）有化学关系，TTR是血浆蛋白，通常称为前白蛋白。基因异常的TTR可能与本病有关。对2例死于家族性淀粉样变性的葡萄牙患者组织中分离的淀粉样纤维蛋白（AFp）和该疾病患者血清中分离的TTR进行了研究。通过与Sepharose连接的视黄醇结合蛋白亲和层析纯化的AFp与血浆TTR相似，形成稳定的四聚体结构，并且与甲状腺素和视黄醇结合蛋白的结合亲和力相似。结构研究包括：胰酶消化后反相高效液相色谱（HPLC）比较肽图谱；溴化氰[CNBr]的切割研究：和选定的胰蛋白酶和CNBr肽的氨基酸微序列分析。根据已知的TTR氨基酸序列，对比色氨酸图显示AFp与TTR相比存在一个异常的色氨酸（肽4，残基22-34）。这种异常肽含有一种蛋氨酸残基，不存在于正常的色氨酸4中。CNBr切割AFp产生2个额外的肽片段，分别通过HPLC分析和十二烷基硫酸钠凝胶电泳证实。序列分析表明，与TTR相比，AFp在第30位存在蛋氨酸对缬氨酸的替代。因此，纯化的淀粉样纤维蛋白包含一个TTR变体，在第30位有蛋氨酸为缬氨酸的替代。缬氨酸30可能密码子的一个核苷酸变化可以解释这种取代。变体TTR也存在于淀粉样变性患者血清中分离的TTR中，同时也存在较大（4- 6倍）的正常TTR。因此，在这些患者中，变体TTR与大量正常TTR一起在血浆中循环。变异的TTR可能代表了该疾病的特定生化原因，这种异常形式的TTR选择性地沉积在组织中，成为该疾病的淀粉样蛋白特征。
Amyloid fibril protein in patients with familial amyloidotic polyneuropathy is chemically related to transthyretin (TTR), the plasma protein that is usually referred to as prealbumin. A genetically abnormal TTR may be involved in this disease. Studies were conducted on amyloid fibril protein (AFp) isolated from tissues of 2 Portuguese patients who died with familial amyloidosis, and on TTR isolated from sera of patients with this disease. AFp, purified by affinity chromatography on retinol-binding protein linked to Sepharose, resembled plasma TTR in forming a stable tetrameric structure, and in its binding afinities for both thyroxine and retinol-binding protein. The structural studies included: comparative peptide mappings by reverse-phase high performance liquid chromatography (HPLC) after trypsin digestion; cyanogen bromide [CNBr] cleavage studies: and amino acid microsequence analysis of selected tryptic and CNBr peptides. On the basis of the known amino acid sequence of TTR, comparative tryptic peptide maps showed the presence of a single aberrant tryptic peptide (peptide 4, residues 22-34) in AFp as compared with TTR. This aberrant peptide contained a methionine residue, not present in normal tryptic peptide 4. CNBr cleavage of AFp produced 2 extra peptide fragments, which were demonstrated, respectively, by HPLC analysis and by sodium dodecyl sulfate-gel electrophoresis. Sequence analyses indicated the presence of a methionine-for-valine substitution at position 30 in AFp as compared with TTR. Thus, the purified amyloid fibril protein comprised a TTR variant with a methionine-for-valine substitution at position 30. A single nucleotide change in a possible codon for valine 30 could explain the substitution. The variant TTR was also present in the TTR isolated from the pooled sera of amyloidoses patients, together with larger (4- to 6-fold) amounts of the normal TTR. Thus, in these patients, the variant TTR was circulating in plasma, along with larger amounts of normal TTR. The variant TTR probably represents the specific biochemical cause of the disease, and this abnormal form of TTR selectively deposits in tissues as the amyloid characteristic of the disease.