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Title: Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia
Authors: Shiozawa, Yusuke
Malcovati, Luca
Gallì, Anna
Sato-Otsubo, Aiko
Kataoka, Keisuke
Sato, Yusuke
Watatani, Yosaku
Suzuki, Hiromichi
Yoshizato, Tetsuichi
Yoshida, Kenichi
Sanada, Masashi
Makishima, Hideki  kyouindb  KAKEN_id  orcid (unconfirmed)
Shiraishi, Yuichi
Chiba, Kenichi
Hellström-Lindberg, Eva
Miyano, Satoru
Ogawa, Seishi  kyouindb  KAKEN_id
Cazzola, Mario
Author's alias: 塩澤, 裕介
佐藤, 亜以子
片岡, 圭亮
佐藤, 悠佑
綿谷, 陽作
鈴木, 啓道
吉里, 哲一
吉田, 健一
真田, 昌
牧島, 秀樹
白石, 友一
千葉, 健一
宮野, 悟
小川, 誠司
Keywords: Myelodysplastic syndrome
RNA splicing
Issue Date: 7-Sep-2018
Publisher: Springer Nature America, Inc
Journal title: Nature Communications
Volume: 9
Thesis number: 3649
Abstract: Spliceosome mutations are frequently found in myelodysplasia. Splicing alterations induced by these mutations, their precise targets, and the effect at the transcript level have not been fully elucidated. Here we report transcriptomic analyses of 265 bone marrow samples from myelodysplasia patients, followed by a validation using CRISPR/Cas9-mediated gene editing and an assessment of nonsense-mediated decay susceptibility. Small but widespread reduction of intron-retaining isoforms is the most frequent splicing alteration in SF3B1-mutated samples. SF3B1 mutation is also associated with 3′ splice site alterations, leading to the most pronounced reduction of canonical transcripts. Target genes include tumor suppressors and genes of mitochondrial iron metabolism or heme biosynthesis. Alternative exon usage is predominant in SRSF2- and U2AF1-mutated samples. Usage of an EZH2 cryptic exon harboring a premature termination codon is increased in both SRSF2- and U2AF1-mutated samples. Our study reveals a landscape of splicing alterations and precise targets of various spliceosome mutations.
Rights: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
DOI(Published Version): 10.1038/s41467-018-06063-x
PubMed ID: 30194306
Appears in Collections:Journal Articles

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