C9ORF72 repeat expansion in amyotrophic lateral sclerosis in the Kii peninsula of Japan.
BACKGROUND
In the Kii peninsula of Japan, high prevalences of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex have been reported. There are 2 major foci with a high prevalence, which include the southernmost region neighboring the Koza River (Kozagawa and Kushimoto towns in Wakayama prefecture) and the Hohara district (Mie prefecture).


OBJECTIVE
To delineate the molecular basis of ALS in the Kii peninsula of Japan, we analyzed hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene, which has recently been identified as a frequent cause of ALS and frontotemporal dementia in the white population.


METHODS
Case series.


METHODS
University hospitals.


METHODS
Twenty-one patients (1 familial patient and 20 sporadic patients) with ALS from Wakayama prefecture, and 16 patients with ALS and 16 patients with parkinsonism-dementia complex originating from Mie prefecture surveyed in 1994 through 2011 were enrolled in the study. In addition, 40 probands with familial ALS and 217 sporadic patients with ALS recruited from other areas of Japan were also enrolled in this study.


METHODS
After screening by repeat-primed polymerase chain reaction, Southern blot hybridization analysis was performed to confirm the expanded alleles.


RESULTS
We identified 3 patients with ALS (20%) with the repeat expansion in 1 of the 2 disease foci. The proportion is significantly higher than those in other regions in Japan. Detailed haplotype analyses revealed an extended shared haplotype in the 3 patients with ALS, suggesting a founder effect.


CONCLUSIONS
Our findings indicate that the repeat expansion partly accounts for the high prevalence of ALS in the Kii peninsula.
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hiroyuki
H
Ishiura
Yuji
Y
Takahashi
Jun
J
Mitsui
Sohei
S
Yoshida
Tameko
T
Kihira
Yasumasa
Y
Kokubo
Shigeki
S
Kuzuhara
Laura P W
LP
Ranum
Tomoko
T
Tamaoki
Yaeko
Y
Ichikawa
Hidetoshi
H
Date
Jun
J
Goto
Shoji
S
Tsuji
D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D000073885:C9orf72 Protein; D002899:Chromosomes, Human, Pair 9; D042622:DNA Repeat Expansion; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008875:Middle Aged; D015995:Prevalence; D011506:Proteins / Q000235:genetics*
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins