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

  • Author(s): 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
  • et al.
Abstract

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.

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