The Desmin (DES) Mutation p.A337P Is Associated with Left-Ventricular Non-Compaction Cardiomyopathy

Abstract

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, <i>DES</i>-p.A337P was identified in the genomes of both patients, whereas only the index patient carried <i>DSP</i>-p.L1348X. <i>DES</i> encodes the muscle-specific intermediate filament protein desmin and <i>DSP</i> encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of <i>DES</i> mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this <i>DES</i> mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the <i>DES</i> gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present.