Ghiso J, Haltia M, Prelli F, Novello J, Frangione B
Department of Pathology, New York University Medical Center, NY 10016.
Biochem J. 1990 Dec 15;272(3):827-30. doi: 10.1042/bj2720827.
Familial amyloidosis, Finnish type (FAF), is an inherited form of systemic amyloidosis clinically characterized by cranial neuropathy and lattice corneal dystrophy. We have demonstrated that the protein subunit isolated from amyloid fibrils shows considerable sequence identity with gelsolin, an actin-binding protein. We have purified the amyloid subunit from a second case and further analysed different fractions from the previous one. Sequence analysis shows that, in both cases, the amyloid subunit starts at position 173 of the mature molecule; it has a heterogeneous N-terminus and contains one amino acid substitution, namely asparagine for aspartic acid, at position 15 (gelsolin residue 187), that is due to a guanine-to-adenine transversion corresponding to nucleotide-654 of human plasma gelsolin cDNA. The substitution maps in a fragment with actin-binding activity and is located in a repetitive motif highly conserved among species. Thus FAF is the first human disease known to be caused by an internal abnormal degradation of a gelsolin variant. We designate this variant of gelsolin-associated amyloidosis 'Agel Asn-187'.
芬兰型家族性淀粉样变性（FAF）是一种遗传性全身性淀粉样变性，临床特征为颅神经病变和格子状角膜营养不良。我们已经证明，从淀粉样纤维中分离出的蛋白质亚基与凝溶胶蛋白（一种肌动蛋白结合蛋白）具有相当高的序列同一性。我们从第二例患者中纯化了淀粉样亚基，并对前一例患者的不同组分进行了进一步分析。序列分析表明，在这两例患者中，淀粉样亚基均从成熟分子的第173位开始；其N端具有异质性，并且在第15位（凝溶胶蛋白残基187）含有一个氨基酸替换，即天冬酰胺替换为天冬氨酸，这是由于对应于人血浆凝溶胶蛋白cDNA核苷酸654的鸟嘌呤到腺嘌呤的颠换所致。该替换位于具有肌动蛋白结合活性的片段中，并且位于物种间高度保守的重复基序中。因此，FAF是已知的首例由凝溶胶蛋白变体的内部异常降解引起的人类疾病。我们将这种与凝溶胶蛋白相关的淀粉样变性变体命名为“Agel Asn-187”。
