A decamer duplication in the 3′ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred
A decamer duplication in the 3′ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred
复制标题
DOI：
10.1073/pnas.080076097
复制
发表时间：
2000-04-25
影响因子：
11.1
通讯作者：
Frangione, B
中科院分区：
文献类型：
--
作者：
Vidal, R;Révész, T;Frangione, B
常见的丹麦痴呆症（FDD），也称为遗传性眼耳脑病。是一种常染色体显性遗传疾病，其特征为白内障、耳聋、进行性共济失调和痴呆。神经病理学表现包括严重的广泛性脑淀粉样血管病、海马斑块和神经纤维缠结，类似于阿尔茨海默病。分离的柔脑膜淀粉样纤维的N-末端序列分析显示与ABri同源，ABri是由家族性英国痴呆中BRI基因终止密码子的点突变引起的肽。对丹麦家系BRI基因的分子遗传学分析显示了不同的缺陷，即在密码子265和266之间存在10-nt重复（795- 796 insTTTAATTTGT），在正常终止密码子267之前的一个密码子。十聚体重复突变在BRI序列中产生移码，产生比正常前体蛋白更大的前体蛋白，其中淀粉样蛋白亚基（称为ADan）包含最后34个C末端氨基酸。这种新产生的淀粉样蛋白生成肽与丹麦家族的遗传缺陷有关，强调了淀粉样蛋白形成作为神经变性和痴呆症致病因素的重要性。
Familiar Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica. is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia, Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia.