Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations.
BACKGROUND
Three major causative genes have been implicated as the cause of early-onset familial Alzheimer's disease (AD): the amyloid precursor protein gene (APP), presenilin-1 (PSEN1) and PSEN2. Although rare, a tau-related dementia with mutations in the microtubule-associated protein tau gene (MAPT) has been identified in patients showing clinical presentations similar to those of AD.


METHODS
We performed mutational analysis of APP, PSEN1, PSEN2, and MAPT in 10 Japanese families with early-onset dementia clinically diagnosed as probable Alzheimer's disease.


RESULTS
In 4 index patients, we identified 4 missense PSEN1 mutations, namely, L286V, G378E, L381V, and L392V. The mean age at onset in the patients with PSEN1 mutations was 39 years. In 2 families, we found the R406W mutation in MAPT. The mean age at onset of the patients carrying the R406W mutation was 52 years, and they presented with the peculiar AD-like phenotype without apparent behavioral or language problems.


CONCLUSIONS
These observations suggest that although PSEN1 mutations are the most frequent cause, the MAPT R406W mutation is an important cause of early-onset familial dementia clinically diagnosed as AD. Differentiation of patients with the MAPT mutation from AD patients by genetic testing would be meaningful, considering that a different therapeutic approach should be applied.
Ikeuchi
Takeshi
T
Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata, Japan. ikeuchi@bri.niigata-u.ac.jp
Kaneko
Hiroyuki
H
Miyashita
Akinori
A
Nozaki
Hiroaki
H
Kasuga
Kensaku
K
Tsukie
Tamao
T
Tsuchiya
Miyuki
M
Imamura
Toru
T
Ishizu
Hideki
H
Aoki
Kenju
K
Ishikawa
Atsushi
A
Onodera
Osamu
O
Kuwano
Ryozo
R
Nishizawa
Masatoyo
M
D017668:Age of Onset; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D003704:Dementia / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D005820:Genetic Testing; D006801:Humans; D007564:Japan / Q000453:epidemiology; D007668:Kidney / Q000166:cytology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics; D016875:tau Proteins / Q000235:genetics*
C054369:MAPT protein, human; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D016875:tau Proteins