2. Academic Validation
  3. Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20

Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20

  • Hum Mutat. 2020 Nov;41(11):1931-1943. doi: 10.1002/humu.24096.
Anna Gaertner 1 2,  Baerbel Klauke 1 2,  Elina Felski 1 2,  Astrid Kassner 1 2,  Andreas Brodehl 1 2,  Désirée Gerdes 1 2,  Caroline Stanasiuk 1 2,  Hans Ebbinghaus 1 2,  Uwe Schulz 1 2,  Karl-Otto Dubowy 1 3,  Jens Tiesmeier 1 2,  Kai-Thorsten Laser 1 3,  Hendrik Bante 1 4,  Leonard Bergau 1 4,  Philipp Sommer 1 4,  Henrik Fox 1 2,  Michiel Morshuis 1 2,  Jan Gummert 1 2,  Hendrik Milting 1 2
Affiliations

Affiliations

  • 1 Herz- und Diabeteszentrum NRW, Universitätsklinikum der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
  • 2 Klinik für Thorax- und Kardiovaskularchirurgie, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, Bad Oeynhausen, Germany.
  • 3 Kinderherzzentrum und Zentrum für Angeborene Herzfehler, Bad Oeynhausen, Germany.
  • 4 Klinik für Elektrophysiologie/Rhythmologie, Bad Oeynhausen, Germany.
PMID: 32840935 DOI: 10.1002/humu.24096
Abstract

Mutations in RBM20 encoding the RNA-binding motif protein 20 (RBM20) are associated with an early onset and clinically severe forms of cardiomyopathies. Transcriptome analyses revealed RBM20 as an important regulator of cardiac alternative splicing. RBM20 mutations are especially localized in exons 9 and 11 including the highly conserved arginine and serine-rich domain (RS domain). Here, we investigated in several cardiomyopathy patients, the previously described RBM20-mutation p.Pro638Leu localized within the RS domain. In addition, we identified in a patient the novel mutation p.Val914Ala localized in the (glutamate-rich) Glu-rich domain of RBM20 encoded by exon 11. Its impact on the disease was investigated with a novel TTN- and RYR2-splicing assay based on the patients' cardiac messenger RNA. Furthermore, we showed in Cell Culture and in human cardiac tissue that mutant RBM20-p.Pro638Leu is not localized in the nuclei but causes an abnormal cytoplasmic localization of the protein. In contrast the splicing deficient RBM20-p.Val914Ala has no influence on the intracellular localization. These results indicate that disease-associated variants in RBM20 lead to aberrant splicing through different pathomechanisms dependent on the localization of the mutation. This might have an impact on the future development of therapeutic strategies for the treatment of RBM20-induced cardiomyopathies.

Keywords

RBM20; cardiomyopathy; mutation; pathomechanisms; splicing.

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