Saito Kayoko
   Department   School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine
   Position   Professor (Fixed Term)
Article types Original article
Language English
Peer review Peer reviewed
Title CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis.
Journal Formal name：American journal of human genetics
Abbreviation：Am J Hum Genet
ISSN code：15376605/00029297
Domestic / ForeginForegin
Volume, Issue, Page 110(7),pp.1086-1097
Author and coauthor Kume Kodai, Kurashige Takashi, Muguruma Keiko, Morino Hiroyuki, Tada Yui, Kikumoto Mai, Miyamoto Tatsuo, Akutsu Silvia Natsuko, Matsuda Yukiko, Matsuura Shinya, Nakamori Masahiro, Nishiyama Ayumi, Izumi Rumiko, Niihori Tetsuya, Ogasawara Masashi, Eura Nobuyuki, Kato Tamaki, Yokomura Mamoru, Nakayama Yoshiaki, Ito Hidefumi, Nakamura Masataka, Saito Kayoko, Riku Yuichi, Iwasaki Yasushi, Maruyama Hirofumi, Aoki Yoko, Nishino Ichizo, Izumi Yuishin, Aoki Masashi, Kawakami Hideshi
Publication date 2023/07
Summary 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.
DOI 10.1016/j.ajhg.2023.05.014
PMID 37339631