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Nature 376, 775 - 778 (31 August 2002); doi:10.1038/376775a0

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

E. I. Rogaev*, R. Sherrington*, E. A. Rogaeva*, G. Levesque*, M. Ikeda*, Y. Liang*, H. Chi*, C. Lin*, K. Holman*, T. Tsuda*, L. Mar, S. Sorbi, B. Nacmias, S. Piacentini, L. Amaducci, I. Chumakov§, D. Cohen§, L. Lannfelt, P. E. Fraser*, J. M. Rommens & P. H. St George-Hyslop*

*Centre for Research into Neurodegenerative Diseases, Departments of Medicine (Neurology) and Medical Biophysics, University of Toronto, Toronto, and Division of Neurology, Department of Medicine, The Toronto Hospital, Toronto, Ontario M5S 1A8, Canada
Research Institute, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
Department of Neurology and Psychiatry, University of Florence,viale Morgagni 85, Florence, Italy
§Centre d'Etude Polymorphisme Humaine, 27 rue Juliette Dodu, 75010, Paris, France
Department of Clinical Neuroscience (Geriatric Medicine), Huddinge Hospital, Karolinska Institute, 14186 Huddinge, Sweden

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)1. 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.



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