HUMAN LYSOZYME GENE-MUTATIONS CAUSE HEREDITARY SYSTEMIC AMYLOIDOSIS
HUMAN LYSOZYME GENE-MUTATIONS CAUSE HEREDITARY SYSTEMIC AMYLOIDOSIS
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DOI：
10.1038/362553a0
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发表时间：
1993-04-08
期刊：
影响因子：
64.8
通讯作者：
HSUAN, JJ
中科院分区：
文献类型：
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作者：
PEPYS, MB;HAWKINS, PN;HSUAN, JJ
遗传性非神经性系统性淀粉样变性（奥斯特塔格型）1是一种罕见的常染色体显性疾病，其中内脏中的淀粉样蛋白沉积通常在第五个十年内致命。在一些家庭中，它是由载脂蛋白AI基因突变引起的2，3，但在我们治疗的两个不相关的英国家庭中，淀粉样蛋白沉积物不含apoAI，尽管有报道称其中一个可能是这种情况4。溶菌酶是一种普遍存在的溶菌酶，存在于外部分泌物5以及多形细胞和巨噬细胞中，但其生理作用并不总是清楚的6。在这里，我们报告说，在这两个家庭，溶菌酶是淀粉样纤维蛋白。受影响的个体是溶菌酶基因中引起高度保守残基取代的点突变的杂合子，即一个家族中第56位的苏氨酸取代异亮氨酸，另一个家族中第67位的组氨酸取代天冬氨酸。来自一个个体的淀粉样原纤维由全长Thr-56变体溶菌酶分子组成。据我们所知，这是第一次报告自然发生的变种人溶菌酶和溶菌酶相关疾病。由于人类7和鸡蛋蛋白溶菌酶8的结构是已知的原子分辨率和它们的折叠和结构-功能关系已被详尽地分析，我们的观察应该提供一个强大的模型，了解淀粉样变性。
HEREDITARY non-neuropathic systemic amyloidosis (Ostertag-type)1 is a rare autosomal dominant disease in which amyloid deposition in the viscera is usually fatal by the fifth decade. In some families it is caused by mutations in the apolipoprotein AI gene2,3 but in two unrelated English families under our care the amyloid deposits did not contain apoAI, despite a report that this may have been the case in one of them4. Lysozyme is a ubiquitous bacteriolytic enzyme present in external secretions5 and in polymorphs and macrophages, but its physiological role is not always clear6. Here we report that in these two families, lysozyme is the amyloid fibril protein. Affected individuals are heterozygous for point mutations in the lysozyme gene that cause substitution of highly conserved residues, namely threonine for isoleucine at position 56 in one family, and histidine for aspartic acid at residue 67 in the other. Amyloid fibrils from one individual were composed of the full-length Thr-56 variant lysozyme molecule. To our knowledge, this is the first report of naturally occurring variants of human lysozyme and of lysozyme-associated disease. As the structures of human7 and hen egg-white lysozyme8 are known to atomic resolution and their folding and structure-function relationships have been exhaustively analysed, our observations should provide a powerful model for understanding amyloidogenesis.