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Molecular insights into cardiomyopathies associated with desmin (DES) mutations

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Abstract

Increasing usage of next-generation sequencing techniques pushed during the last decade cardiogenetic diagnostics leading to the identification of a huge number of genetic variants in about 170 genes associated with cardiomyopathies, channelopathies, or syndromes with cardiac involvement. Because of the biochemical and cellular complexity, it is challenging to understand the clinical meaning or even the relevant pathomechanisms of the majority of genetic sequence variants. However, detailed knowledge about the associated molecular pathomechanism is essential for the development of efficient therapeutic strategies in future and genetic counseling. Mutations in DES, encoding the muscle-specific intermediate filament protein desmin, have been identified in different kinds of cardiac and skeletal myopathies. Here, we review the functions of desmin in health and disease with a focus on cardiomyopathies. In addition, we will summarize the genetic and clinical literature about DES mutations and will explain relevant cell and animal models. Moreover, we discuss upcoming perspectives and consequences of novel experimental approaches like genome editing technology, which might open a novel research field contributing to the development of efficient and mutation-specific treatment options.

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Abbreviations

ACM:

Arrhythmogenic cardiomyopathy

ACMG:

American College of Medical Genetics and Genomics

AF:

Atrial fibrillation

AFM:

Atomic force microscopy

ALVC:

Arrhythmogenic left ventricular cardiomyopathy

ARVC:

Arrhythmogenic right ventricular cardiomyopathy

aSNOM:

Apertureless scanning near-field microscopy

ATP:

Adenosine triphosphate

AVB:

Atrioventricular block

CM:

Cardiomyopathy

DCM:

Dilated cardiomyopathy

DRM:

Desmin-related myopathy

DSC2:

Desmocollin-2

DSG2:

Desmoglein-2

DSP:

Desmoplakin

EPR:

Electron paramagnetic resonance

GFAP:

Glial fibrillary acidic protein

GGA:

Geranylgeranylacetone

HCM:

Hypertrophic cardiomyopathy

HOCM:

Hypertrophic obstructive cardiomyopathy

HTx:

Heart transplantation

IF:

Intermediate filament

LAFB:

Left anterior fascicular block

LBBB:

Left bundle-branched block

LGMD:

Limb-girdle muscular dystrophy

LVNC:

Left ventricular noncompaction cardiomyopathy

LW:

Limp weakness

MAF:

Minor allele frequency

MFM:

Myofibrillar myopathy

MRI:

Magnetic resonance imaging

NCM:

Noncompaction cardiomyopathy

NMD:

Nonsense-mediated RNA decay

PG:

Plakoglobin

PKP2:

Plakophilin-2

PTC:

Premature termination codon

PTM:

Posttranslational modification

RBBB:

Right bundle-branched block

RCM:

Restrictive cardiomyopathy

SCD:

Sudden cardiac death

SM:

Skeletal myopathy

SMD:

Smooth muscle defect

SNP:

Single nucleotide polymorphism

SQTS:

Short QT syndrome

TAC:

Transverse aortic constriction

TEM:

Transmission electron microscopy

ULF:

Unit length filament

VUS:

Variant of unknown significance

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Acknowledgements

The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. We thank Dr. Volker Walhorn (Experimental Biophysics and Applied Nanoscience, Faculty of Physics and Bielefeld Institute for Biophysics and Nanoscience (BINAS), Bielefeld University, Germany) for providing Fig. 5e.

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Authors and Affiliations

  1. Erich and Hanna Klessmann Institute for Cardiovascular Research & Development, Heart and Diabetes Centre NRW, Ruhr-University Bochum, Georgstrasse 11, 32545, Bad Oeynhausen, Germany

    Andreas Brodehl, Anna Gaertner-Rommel & Hendrik Milting

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  1. Andreas Brodehl
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  2. Anna Gaertner-Rommel
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  3. Hendrik Milting
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Correspondence to Andreas Brodehl or Hendrik Milting.

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Funding

AB received a grant of the German Society of Heart Research (DSHF, F/07/17) and a grant of the University Bielefeld (Reseach fond OWL). AGR is supported by the Medical Faculty of the Ruhr-University Bochum (FoRUM). HM is thankful for funding of the German Research Foundation (DFG, MI 1146/2-1) and the Erich and Hanna Klessmann Foundation (Gütersloh, Germany).

Conflicts of interest

Andreas Brodehl declares that he has no conflicts of interest. Anna Gaertner-Rommel declares that she has no conflicts of interest. Hendrik Milting declares that he has no conflicts of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Additional databases

1. Human Intermediate Filament Database, www.interfil.org (Szeverenyi et al. 2008).

2. The Human Protein Atlas, https://www.proteinatlas.org (Uhlen et al. 2015).

3. ClinVar, https://www.ncbi.nlm.nih.gov/clinvar (Landrum et al. 2016).

4. Leiden Open Variation Database, http://www.dmd.nl.

5. Exome Aggregation Consortium (ExAC), http://exac.broadinstitute.org/ (Lek et al. 2016).

6. Genome Aggregation Database (gnomAD), http://gnomad.broadinstitute.org/ (Lek et al. 2016).

This article is part of a Special Issue on ‘Heart Failure Due to Non-Myofibrillar Defects’ edited by Elisabeth Ehler and Katja Gehmlich.

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Brodehl, A., Gaertner-Rommel, A. & Milting, H. Molecular insights into cardiomyopathies associated with desmin (DES) mutations. Biophys Rev 10, 983–1006 (2018). https://doi.org/10.1007/s12551-018-0429-0

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