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

• DOI: 10.1038/ncomms7042
• Publication Date: 2015-01-14T11:08:12Z
• Authors: Vikas Madan; Deepika Kanojia; Jia Li; Ryoko Okamoto; Aiko Sato-Otsubo; Alexander Kohlmann; Masashi Sanada; Vera Grossmann; Janani Sundaresan; Yuichi Shiraishi; Satoru Miyano; Felicitas Thol; Arnold Ganser; Henry Yang; Torsten Haferlach; Seishi Ogawa; H. Phillip Koeffler
• Keywords: 0301 basic medicine; 570; Molecular Sequence Data; 610; Antigens, CD34; Bone Marrow Cells; Mice, SCID; SCID; Article; Mice; 03 medical and health sciences; Rare Diseases; Small Nuclear; Mice, Inbred NOD; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; Antigens; Cell Proliferation; Base Sequence; Human Genome; Nuclear Proteins; Cell Differentiation; Hematology; Exons; Genomics; Introns; Alternative Splicing; Ribonucleoproteins; Myelodysplastic Syndromes; Mutation; Spliceosomes; Inbred NOD; RNA; Female; CD34; K562 Cells; Neoplasm Transplantation

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