| 論文種別 | 原著(症例報告除く) |
| 言語種別 | 英語 |
| 査読の有無 | その他(不明) |
| 表題 | AGG repeat expansion and aggregation of BIN1 in multiple system atrophy. |
| 掲載誌名 | 正式名：Brain : a journal of neurology 略 称：Brain ISSNコード：14602156/00068950 |
| 掲載区分 | 国外 |
| 巻・号・頁 | pp.Online ahead of print |
| 著者・共著者 | Kodai Kume, Takashi Kurashige, Takeshi Itabashi, Akio Akagi, Takashi Ando, Masataka Nakamura, Mai Kikumoto, Atsushi Tamada, Masaki Kamada, Takashi Ayaki, Yuishin Izumi, Ichiro Yabe, Keiko Muguruma, Tatsuo Miyamoto, Yasuhi Iwasaki, Hideshi Kawakami |
| 発行年月 | 2026/08 |
| 概要 | Multiple system atrophy is a fatal, sporadic α-synucleinopathy characterized by glial cytoplasmic inclusions in oligodendrocytes. No causative gene for multiple system atrophy has been identified to date. Whole-genome sequencing was performed for a patient with familial multiple system atrophy, in whom an AGG repeat expansion in BIN1 was identified. Based on this finding, we screened for the AGG repeat expansion in BIN1 in a cohort comprising 224 patients with clinically diagnosed multiple system atrophy, 67 patients with pathologically confirmed multiple system atrophy, and control groups including 574 blood samples and 65 brain samples from neurologically healthy individuals. The pathological analysis was performed for four cases with the repeat expansion and five cases without the repeat expansion. The biochemical analysis was performed for nine control subjects, ten cases without the repeat expansion, and eight cases with the repeat expansion. Long-read sequencing identified an AGG repeat expansion in the first intron of BIN1 in the proband. Patients with multiple system atrophy carried a higher frequency of repeat expansions exceeding 80 repeats in the pathological multiple system atrophy group compared to the brain control group (frequency: 13.4% vs. 0%; odds ratio: infinity; 95% confidence interval [CI], 2.1 to infinity; P = 0.003, Fisher's exact test). In contrast, the difference of frequency did not reach statistical significance in the clinical multiple system atrophy group compared to the blood control group (frequency: 4.5% vs 2.4%; odds ratio: 1.87; 95% CI, 0.8 to 4.5; P = 0.16, Fisher's exact test). Neuropathological analysis revealed BIN1-positive glial cytoplasmic inclusions more frequently in the brains of patients with repeat expansions. In immunoblot analysis, insoluble BIN1 were increased in the brains of multiple system atrophy irrespective of repeat status. Our findings indicate that the AGG repeat expansion in BIN1 and BIN1 protein aggregation plays an important role in the pathogenesis of multiple system atrophy. |
| DOI | 10.1093/brain/awag194 |
| PMID | 42663379 |