title: Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP.
abstract: Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset (<65 years) Alzheimer's disease (AD). We performed a screening for mutations in the coding regions of presenilins, as well as exons 16 and 17 of the APP gene in a total of 231 patients from the Iberian peninsular with a clinical diagnosis of early-onset AD (mean age at onset of 52.9 years; range 31-64). We found three novel mutations in PSEN1, one novel mutation in PSEN2, and a novel mutation in the APP gene. Four previously described mutations in PSEN1 were also found. The same analysis was carried in 121 elderly healthy controls from the Iberian peninsular, and a set of 130 individuals from seven African populations belonging to the Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP), in order to determine the extent of normal variability in these genes. Interestingly, in the latter series, we found five new non-synonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD. In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rita Joao
authors.initials: RJ
authors.lastname: Guerreiro
authors.forename: Miquel
authors.initials: M
authors.lastname: Baquero
authors.forename: Rafael
authors.initials: R
authors.lastname: Blesa
authors.forename: Mercè
authors.initials: M
authors.lastname: Boada
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Brás
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Bullido
authors.forename: Ana
authors.initials: A
authors.lastname: Calado
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: Carla
authors.initials: C
authors.lastname: Ferreira
authors.forename: Ana
authors.initials: A
authors.lastname: Frank
authors.forename: Teresa
authors.initials: T
authors.lastname: Gómez-Isla
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.forename: Alvaro
authors.initials: A
authors.lastname: Machado
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez-Lage
authors.forename: José
authors.initials: J
authors.lastname: Masdeu
authors.forename: Laura
authors.initials: L
authors.lastname: Molina-Porcel
authors.forename: José L
authors.initials: JL
authors.lastname: Molinuevo
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.forename: Jordi
authors.initials: J
authors.lastname: Pérez-Tur
authors.forename: Rute
authors.initials: R
authors.lastname: Relvas
authors.forename: Catarina Resende
authors.initials: CR
authors.lastname: Oliveira
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Ribeiro
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Alfredo
authors.initials: A
authors.lastname: Sa
authors.forename: Lluís
authors.initials: L
authors.lastname: Samaranch
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Valle
authors.forename: Isabel
authors.initials: I
authors.lastname: Santana
authors.forename: Lluís
authors.initials: L
authors.lastname: Tàrraga
authors.forename: Fernando
authors.initials: F
authors.lastname: Valdivieso
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
mesh_terms: D000328:Adult; D000349:Africa; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011174:Portugal; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics*; D013030:Spain
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053766:Presenilin-2