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ID 119214
Author
Kume, Kodai Hiroshima University
Kurashige, Takashi National Hospital Organization Kure Medical Center and Chugoku Cancer Center
Muguruma, Keiko Kansai Medical University
Tada, Yui Hiroshima University
Kikumoto, Mai Hiroshima University
Miyamoto, Tatsuo Hiroshima University|Yamaguchi University
Akutsu, Silvia Natsuko Hiroshima University
Matsuda, Yukiko Hiroshima University
Matsuura, Shinya Hiroshima University
Nakamori, Masahiro Hiroshima University
Nishiyama, Ayumi Tohoku University
Izumi, Rumiko Tohoku University
Niihori, Tetsuya Tohoku University
Ogasawara, Masashi National Centre of Neurology and Psychiatry
Eura, Nobuyuki National Centre of Neurology and Psychiatry
Kato, Tamaki Tokyo Women’s Medical University
Yokomura, Mamoru Tokyo Women’s Medical University
Nakayama, Yoshiaki Wakayama Medical University
Ito, Hidefumi Wakayama Medical University
Nakamura, Masataka Kansai Medical University
Saito, Kayoko Tokyo Women’s Medical University
Riku, Yuichi Aichi Medical University
Iwasaki, Yasushi Aichi Medical University
Maruyama, Hirofumi Hiroshima University
Aoki, Yoko Tohoku University
Nishino, Ichizo National Centre of Neurology and Psychiatry
Aoki, Masashi Tohoku University
Kawakami, Hideshi Hiroshima University
Content Type
Journal Article
Description
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn’t fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61–100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100–200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.
Journal Title
The American Journal of Human Genetics
ISSN
00029297
15376605
NCID
AA11748083
Publisher
American Society of Human Genetics
Volume
110
Issue
7
Start Page
1086
End Page
1097
Published Date
2023-06-19
Rights
Open Archive
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Publisher
departments
Medical Sciences
University Hospital