Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.
Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.
Sherrington
R
R
Department of Medicine, University of Toronto, Ontario, Canada.
Froelich
S
S
Sorbi
S
S
Campion
D
D
Chi
H
H
Rogaeva
E A
EA
Levesque
G
G
Rogaev
E I
EI
Lin
C
C
Liang
Y
Y
Ikeda
M
M
Mar
L
L
Brice
A
A
Agid
Y
Y
Percy
M E
ME
Clerget-Darpoux
F
F
Piacentini
S
S
Marcon
G
G
Nacmias
B
B
Amaducci
L
L
Frebourg
T
T
Lannfelt
L
L
Rommens
J M
JM
St George-Hyslop
P H
PH
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D053766:Presenilin-2
D001057:Apolipoproteins E; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2