Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP.
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.
Guerreiro
Rita Joao
RJ
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Baquero
Miquel
M
Blesa
Rafael
R
Boada
Mercè
M
Brás
Jose Miguel
JM
Bullido
Maria J
MJ
Calado
Ana
A
Crook
Richard
R
Ferreira
Carla
C
Frank
Ana
A
Gómez-Isla
Teresa
T
Hernández
Isabel
I
Lleó
Alberto
A
Machado
Alvaro
A
Martínez-Lage
Pablo
P
Masdeu
José
J
Molina-Porcel
Laura
L
Molinuevo
José L
JL
Pastor
Pau
P
Pérez-Tur
Jordi
J
Relvas
Rute
R
Oliveira
Catarina Resende
CR
Ribeiro
Maria Helena
MH
Rogaeva
Ekaterina
E
Sa
Alfredo
A
Samaranch
Lluís
L
Sánchez-Valle
Raquel
R
Santana
Isabel
I
Tàrraga
Lluís
L
Valdivieso
Fernando
F
Singleton
Andrew
A
Hardy
John
J
Clarimón
Jordi
J
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
D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053766:Presenilin-2