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A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy.

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.

SUBMITTER: Schirmer I

PROVIDER: S-EPMC5902401 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy.

Schirmer Ilona I Dieding Mareike M Klauke Bärbel B Brodehl Andreas A Gaertner-Rommel Anna A Walhorn Volker V Gummert Jan J Schulz Uwe U Paluszkiewicz Lech L Anselmetti Dario D Milting Hendrik H

Molecular genetics & genomic medicine 20171223 2

<h4>Background</h4>DES mutations cause different cardiac and skeletal myopathies. Most of them are missense mutations.<h4>Methods</h4>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 re ...[more]

PMID: 29274115

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Project description:BACKGROUND:Skeletal muscle myopathy and exercise intolerance are diagnostic hallmarks of heart failure (HF). However, the molecular adaptations of skeletal muscles during dilated cardiomyopathy (DCM)-mediated HF are not completely understood. METHODS:Skeletal muscle structure and function were compared in wild-type (WT) and cardiac myosin binding protein-C null mice (t/t), which develop DCM-induced HF. Cardiac function was examined by echocardiography. Exercise tolerance was measured using a graded maximum treadmill running test. Hindlimb muscle function was assessed in vivo from measurements of plantar flexor strength. Inflammatory status was evaluated from the expression of inflammatory markers and the presence of specific immune cell types in gastrocnemius muscles. Muscle regenerative capacityat days 3, 7, and 14 after eccentric contraction-induced injury was determined from the number of phenotypically new and adult fibers in the gastrocnemius, and functional recovery of plantar flexion torque. RESULTS:t/t mice developed DCM-induced HF in association with profound exercise intolerance, consistent with previous reports. Compared to WT, t/t mouse hearts show significant hypertrophy of the atria and ventricles and reduced fractional shortening, both systolic and diastolic. In parallel, the skeletal muscles of t/t mice exhibit weakness and myopathy. Compared to WT, plantar flexor muscles of t/t null mice produce less peak isometric plantar torque (Po), develop torque more slowly (+?dF/dt), and relax more slowly (-?dF/dt, longer half-relaxation times,1/2RT). Gastrocnemius muscles of t/t mice have a greater number of fibers with smaller diameters and central nuclei. Oxidative fibers, both type I and type IIa, show significantly smaller cross-sectional areas and more central nuclei. These fiber phenotypes suggest ongoing repair and regeneration under homeostatic conditions. In addition, the ability of muscles to recover and regenerate after acute injury is impaired in t/t mice. CONCLUSIONS:Our studies concluded that DCM-induced HF induces a unique skeletal myopathy characterized by decreased muscle strength, atrophy of oxidative fiber types, ongoing inflammation and damage under homeostasis, and impaired regeneration after acute muscle injury. Furthermore, this unique myopathy in DCM-induced HF likely contributes to and exacerbates exercise intolerance. Therefore, efforts to develop therapeutic interventions to treat skeletal myopathy during DCM-induced HF should be considered.

Dataset Information

A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy.

Publications

A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy.

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