A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism

Abdelaziz Beqqali, I. A. E. Bollen, T. B. Rasmussen, M. M. van den Hoogenhof, H. W. M. van Deutekom, M. Schafer-Korting, J Haas, Benjamin Meder, K. E. Sorensen, R. J. van Oort, Jens Mogensen, N. Hubner, E. E. Creemers, J. van der Velden, Yigal M Pinto

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Aim Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes. Methods and results We identified a family with DCM carrying a mutation (RBM20 E913K/+) in a glutamate-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20 E913K/+ carrier. RNA deep-sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20 E913K/+ carrier. Titin isoform analysis revealed a dramatic shift from the less compliant N2B towards the highly compliant N2BA isoforms in RBM20 E913K/+ heart. Moreover, an increased sarcomere resting-length was observed in single cardiomyocytes and isometric force measurements revealed an attenuated Frank-Starling mechanism (FSM), which was rescued by protein kinase A treatment. Conclusion A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20. This leads to disturbed alternative splicing of TTN, resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute to the early onset, and malignant course of DCM caused by RBM20 mutations. Altogether, our results demonstrate that heterozygous loss of RBM20 suffices to profoundly impair myocyte biomechanics by its disturbance of TTN splicing.

Original languageEnglish
JournalCardiovascular Research
Issue number1
Pages (from-to)452-463
Publication statusPublished - Oct 2016

Bibliographical note

ISI Document Delivery No.: EB7PC Times Cited: 0 Cited Reference Count: 32 Beqqali, Abdelaziz Bollen, Ilse A. E. Rasmussen, Torsten B. van den Hoogenhof, Maarten M. van Deutekom, Hanneke W. M. Schafer, Sebastian Haas, Jan Meder, Benjamin Sorensen, Keld E. van Oort, Ralph J. Mogensen, Jens Hubner, Norbert Creemers, Esther E. van der Velden, Jolanda Pinto, Yigal M. Beqqali, Abdelaziz/0000-0003-1390-5821; Schafer, Sebastian/0000-0002-6909-8275; van der Velden, Jolanda/0000-0001-5224-5788 Netherlands Organisation for Scientific Research (NWO) [825.13.007, 836.12.002]; Netherlands Cardiovascular Research Initiative [CVON 2011-11]; CVON young talent programme; EU FP7 project INHERITANCE [241924]; Lundbeck Foundation; Rembrandt grant; Arvid Nilsson's Foundation This work was supported by grants from the Netherlands Organisation for Scientific Research (NWO) (grants 825.13.007 and 836.12.002), the Netherlands Cardiovascular Research Initiative (CVON 2011-11), CVON young talent programme, EU FP7 project INHERITANCE 241924, the Lundbeck Foundation, Rembrandt grant 2013, and Arvid Nilsson's Foundation. 0 2 Oxford univ press Oxford 1755-3245


  • Sarcomere Cardiomyopathy Dilated cardiomyopathy Heart failure Alternative splicing RBM20 length-dependent activation calcium homeostasis troponin-i rbm20 expression gene myocardium stiffness reveals tension Cardiovascular System & Cardiology
  • Heart failure
  • Alternative splicing
  • Dilated cardiomyopathy
  • Cardiomyopathy
  • RBM20
  • Sarcomere
  • Myocytes, Cardiac/metabolism
  • Phosphorylation
  • Alternative Splicing
  • Cyclic AMP-Dependent Protein Kinases/metabolism
  • Humans
  • Male
  • RNA-Binding Proteins/genetics
  • Case-Control Studies
  • Connectin/genetics
  • Transfection
  • DNA Mutational Analysis
  • Adult
  • Female
  • Cardiomyopathy, Dilated/genetics
  • Cell Line
  • Genetic Predisposition to Disease
  • Genetic Association Studies
  • Models, Cardiovascular
  • Rats
  • Heredity
  • Haploinsufficiency
  • Phenotype
  • Animals
  • Muscle Contraction
  • Pedigree
  • Protein Isoforms
  • Heterozygote
  • Aged
  • Mutation

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