The Desmin Mutation <i>DES</i>-c.735G>C Causes Severe Restrictive Cardiomyopathy by Inducing In-Frame Skipping of Exon-3
Andreas Brodehl,
Carsten Hain,
Franziska Flottmann,
Sandra Ratnavadivel,
Anna Gaertner,
Bärbel Klauke,
Jörn Kalinowski,
Hermann Körperich,
Jan Gummert,
Lech Paluszkiewicz,
Marcus-André Deutsch,
Hendrik Milting
Affiliations
Andreas Brodehl
Heart and Diabetes Center NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Carsten Hain
Microbial Genomics and Biotechnology, Center for Biotechnology, Bielefeld University, D-33615 Bielefeld, Germany
Franziska Flottmann
Heart and Diabetes Center NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Sandra Ratnavadivel
Heart and Diabetes Center NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Anna Gaertner
Heart and Diabetes Center NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Bärbel Klauke
Heart and Diabetes Center NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Jörn Kalinowski
Microbial Genomics and Biotechnology, Center for Biotechnology, Bielefeld University, D-33615 Bielefeld, Germany
Hermann Körperich
Heart and Diabetes Center NRW, Institute for Radiology, Nuclear Medicine and Molecular Imaging, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Jan Gummert
Heart and Diabetes Center NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Lech Paluszkiewicz
Heart and Diabetes Center NRW, Department of Thoracic and Cardiovascular Surgery, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Marcus-André Deutsch
Heart and Diabetes Center NRW, Department of Thoracic and Cardiovascular Surgery, University Hospital Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Hendrik Milting
Heart and Diabetes Center NRW, Erich and Hanna Klessmann Institute, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
Currently, little is known about the genetic background of restrictive cardiomyopathy (RCM). Herein, we screened an index patient with RCM in combination with atrial fibrillation using a next generation sequencing (NGS) approach and identified the heterozygous mutation DES-c.735G>C. As DES-c.735G>C affects the last base pair of exon-3, it is unknown whether putative missense or splice site mutations are caused. Therefore, we applied nanopore amplicon sequencing revealing the expression of a transcript without exon-3 in the explanted myocardial tissue of the index patient. Western blot analysis verified this finding at the protein level. In addition, we performed cell culture experiments revealing an abnormal cytoplasmic aggregation of the truncated desmin form (p.D214-E245del) but not of the missense variant (p.E245D). In conclusion, we show that DES-c.735G>C causes a splicing defect leading to exon-3 skipping of the DES gene. DES-c.735G>C can be classified as a pathogenic mutation associated with RCM and atrial fibrillation. In the future, this finding might have relevance for the genetic understanding of similar cases.
