Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.
Sherrington
R
R
Department of Medicine (Neurology), University of Toronto, Ontario, Canada.
Rogaev
E I
EI
Liang
Y
Y
Rogaeva
E A
EA
Levesque
G
G
Ikeda
M
M
Chi
H
H
Lin
C
C
Li
G
G
Holman
K
K
Tsuda
T
T
Mar
L
L
Foncin
J F
JF
Bruni
A C
AC
Montesi
M P
MP
Sorbi
S
S
Rainero
I
I
Pinessi
L
L
Nee
L
L
Chumakov
I
I
Pollen
D
D
Brookes
A
A
Sanseau
P
P
Polinsky
R J
RJ
Wasco
W
W
Da Silva
H A
HA
Haines
J L
JL
Perkicak-Vance
M A
MA
Tanzi
R E
RE
Roses
A D
AD
Fraser
P E
PE
Rommens
J M
JM
St George-Hyslop
P H
PH
D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D003001:Cloning, Molecular; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D010375:Pedigree; D053764:Presenilin-1; D017433:Protein Structure, Secondary; D014158:Transcription, Genetic
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1