A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy. Issue 2 (23rd December 2017)

• Record Type: Journal Article
• Authors: Schirmer, Ilona; Dieding, Mareike; Klauke, Bärbel; Brodehl, Andreas; Gaertner‐Rommel, Anna; Walhorn, Volker; Gummert, Jan; Schulz, Uwe; Paluszkiewicz, Lech; Anselmetti, Dario; Milting, Hendrik
• Is Part Of: Molecular genetics & genomic medicine. Volume 6:Issue 2(2018)
• Page Start: 288
• Page End: 293
• Publication Date: 2017-12-23
• Subjects: cardiomyopathy -- cardiovascular genetics -- desmin -- intermediate filament proteins -- skeletal myopathy; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.358
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: DES mutations cause different cardiac and skeletal myopathies. Most of them are missense mutations. Methods: Using a next‐generation sequencing cardiac 174 gene panel, we identified a novel heterozygous in‐frame indel mutation ( DES ‐c.493_520del28insGCGT, p.Q165_A174delinsAS) in a Caucasian patient with cardiomyopathy in combination with atrioventricular block and skeletal myopathy. This indel mutation is located in the coding region of the first exon. Family anamnesis revealed a history of sudden cardiac death. We performed cell transfection experiments and in vitro assembly experiments to prove the pathogenicity of this novel DES indel mutation. Results: These experiments revealed a severe filament formation defect of mutant desmin supporting the pathogenicity. In addition, we labeled a skeletal muscle biopsy from the mutation carrier revealing cytoplasmic desmin positive protein aggregates. In summary, we identified and functionally characterized a pathogenic DES indel mutation causing cardiac and skeletal myopathy. Conclusion: Our study has relevance for the clinical and genetic interpretation of further DES indel mutations causing cardiac or skeletal myopathies and might be helpful for risk stratification. Abstract : We identified a novel indel mutation in DES, encoding the intermediate filament protein desmin, in a patient with skeletal and cardiac myopathy. Functional analysis revealed a severe filament assembly defect in transfected cells and also of the purified recombinant protein. In summary, our functional data suggest that DES‐c.493_520del28insGCGT has to be classified as a likely pathogenic mutation.