Rogaev E I, Sherrington R, Rogaeva E A, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T
Department of Medicine (Neurology), University of Toronto, Ontario, Canada.
Nature. 1995 Aug 31;376(6543):775-8. doi: 10.1038/376775a0.
We report the cloning of a novel gene (E5-1) encoded on chromosome 1 which has substantial nucleotide and amino-acid sequence similarity to the S182 gene on chromosome 14q24.3. Mutations, including three new missense mutations in the S182 gene, are associated with the AD3 subtype of early-onset familial Alzheimer's disease (AD). Both the E5-1 and the S182 proteins are predicted to be integral membrane proteins with seven membrane-spanning domains, and a large exposed loop between the sixth and seventh transmembrane domains. Analysis of the nucleotide sequence of the open reading frame (ORF) of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (50-70 years versus 30-60 years for AD3). These observations imply that the E5-1 gene on chromosome 1 and the S182 gene on chromosome 14q24.3 are members of a family of genes (presenilins) with related functions, and indicates that mutations in conserved residues of E5-1 could also play a role in the genesis of AD. Our results also indicate that still other AD susceptibility genes exist.
我们报告了一个位于1号染色体上的新基因（E5-1）的克隆情况，该基因与位于14q24.3染色体上的S182基因在核苷酸和氨基酸序列上有很大的相似性。包括S182基因中的三个新错义突变在内的突变与早发性家族性阿尔茨海默病（AD）的AD3亚型相关。E5-1和S182蛋白预计都是具有七个跨膜结构域的整合膜蛋白，在第六和第七个跨膜结构域之间有一个大的暴露环。对E5-1基因开放阅读框（ORF）的核苷酸序列分析导致在发病年龄比AD3亚型晚（AD3为30-60岁，该型为50-70岁）的家族性AD家系的患病成员中，在保守氨基酸残基处发现了两个错义替换。这些观察结果表明，1号染色体上的E5-1基因和14q24.3染色体上的S182基因是具有相关功能的基因家族（早老素）的成员，并表明E5-1保守残基中的突变也可能在AD的发生中起作用。我们的结果还表明存在其他AD易感基因。
