Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome

作者：Madan Vikas^*; Kanojia Deepika; Li Jia; Okamoto Ryoko; Sato Otsubo Aiko; Kohlmann Alexander; Sanada Masashi; Grossmann Vera; Sundaresan Janani; Shiraishi Yuichi; Miyano Satoru; Thol Felicitas; Ganser Arnold; Yang Henry; Haferlach Torsten; Ogawa Seishi; Koeffler H Phillip

来源：Nature Communications, 2015, 6(1): 6042.

DOI：10.1038/ncomms7042

Somatic mutations in the spliceosome gene ZRSR2-located on the X chromosome-are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3'-splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here we characterize ZRSR2 as an essential component of the minor spliceosome (U12 dependent) assembly. shRNA-mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns and RNA-sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns, while splicing of the U2-type introns remain mostly unaffected. ZRSR2-deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS.

• 出版日期2015-1
• 单位河北医科大学