Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome (Nat Commun, Jan 2015)

Vikas Madan1, Deepika Kanojia1,*, Jia Li12,*, Ryoko Okamoto3, Aiko Sato-Otsubo4,5, Alexander Kohlmann6†, Masashi Sanada4,5, Vera Grossmann6, Janani Sundaresan1, Yuichi Shiraishi7, Satoru Miyano7, Felicitas Thol8, Arnold Ganser8, Henry Yang1, Torsten Haferlach6, Seishi Ogawa4,5, H. Phillip Koeffler1,3,9

1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, USA.
4Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
5Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
6MLL Munich Leukemia Laboratory, Munich, Germany.
7Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
8Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
9National University Cancer Institute, National University Hospital Singapore, Singapore.

Present address: AstraZeneca, Personalized Healthcare and Biomarkers, Innovative Medicines, Cambridge, UK.

*These authors contributed equally to this work.

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.



ZRSR2 mutant MDS is characterized by aberrant splicing of U12-type introns.