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Sci Rep. 2018 Jun 12;8(1):8970. doi: 10.1038/s41598-018-26624-w.

Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization.

Author information

1
Laboratory of Gene Expression, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.
2
Graduate School of Biomedical Science, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.
3
Laboratory for Integrated Research Projects on Intractable Diseases Advanced Technology Laboratories, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.
4
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.
5
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, 755-8505, Japan.
6
Department of Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
7
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
8
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.
9
Laboratory of Recombinant Animals, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.
10
Laboratory for Integrated Research Projects on Intractable Diseases Advanced Technology Laboratories, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan. akitis@mri.tmd.ac.jp.
11
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan. akitis@mri.tmd.ac.jp.
12
Laboratory of Gene Expression, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan. kuroyana.end@tmd.ac.jp.
13
Graduate School of Biomedical Science, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan. kuroyana.end@tmd.ac.jp.
14
Laboratory for Integrated Research Projects on Intractable Diseases Advanced Technology Laboratories, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan. kuroyana.end@tmd.ac.jp.
15
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. kuroyana.end@tmd.ac.jp.

Abstract

RBM20 is a major regulator of heart-specific alternative pre-mRNA splicing of TTN encoding a giant sarcomeric protein titin. Mutation in RBM20 is linked to autosomal-dominant familial dilated cardiomyopathy (DCM), yet most of the RBM20 missense mutations in familial and sporadic cases were mapped to an RSRSP stretch in an arginine/serine-rich region of which function remains unknown. In the present study, we identified an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients. We demonstrate that the two serine residues in the RSRSP stretch are constitutively phosphorylated and mutations in the stretch disturb nuclear localization of RBM20. Rbm20 S637A knock-in mouse mimicking an S635A mutation reported in a familial case showed a remarkable effect on titin isoform expression like in a patient carrying the mutation. These results revealed the function of the RSRSP stretch as a critical part of a nuclear localization signal and offer the Rbm20 S637A mouse as a good model for in vivo study.

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