Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene

• Published in: Nature (London) Vol. 376; no. 6543; pp. 775 - 778
• Main Authors: Rogaev, E. I, Sherrington, R, Rogaeva, E. A, Levesque, G, Ikeda, M, Liang, Y, Chi, H, Lin, C, Holman, K, Tsuda, T, Mar, L, Sorbi, S, Nacmias, B, Piacentini, S, Amaducci, L, Chumakov, I, Cohen, D, Lannfelt, L, Fraser, P. E, Rommens, J. M, George-Hyslop, P. H. St
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 31.08.1995; Nature Publishing Group
• Subjects: Alzheimer Disease - classification; Alzheimer Disease - genetics; Alzheimer's disease; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Chromosomes, Human, Pair 1; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Deoxyribonucleic acid; DNA; Genes; Humans; Medical sciences; Medicin och hälsovetenskap; Membrane Proteins - genetics; Membrane Proteins - physiology; Molecular Sequence Data; Mutation; Neurology; Presenilin-1; Presenilin-2; Sequence Homology, Amino Acid; Genetic mapping; Human; Nervous system diseases; Membrane protein; Nucleotide sequence; Alzheimer disease; Homology; Cerebral disorder; Genetic disease; Gene; Central nervous system disease; Genetics; Multigene family; Degenerative disease; Mutation; Molecular cloning; A1-Chromosome
• ISSN: 0028-0836; 1476-4687
• 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.