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Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc
Harald Herrmann1,2, Eva Cabet3, Nicolas R Chevalier4
1Institute of Neuropathology (H.H., D.S., M.S., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
Circulation
|October 7, 2020
Summary
The R406W-desmin mutation causes severe cardiomyopathy by disrupting desmin filaments at intercalated discs. This study reveals a novel mechanism involving dual functional states of mutant desmin assembly, leading to cardiac dysfunction.
Area of Science:
- Cardiovascular Biology
- Muscle Physiology
- Genetics
Background:
- Mutations in the human desmin gene are linked to myopathies and cardiomyopathies.
- This study investigates the R406W-desmin mutation's role in severe, early-onset cardiac phenotypes.
Observation:
- Analysis of an explanted heart revealed desmin aggregates and absent desmin filaments at intercalated discs.
- Abnormal organization of key intercalated disc proteins (desmoplakin, plectin, N-cadherin, connexin-43) was observed.
- R406W-desmin exhibited dual behavior in cells, integrating into filaments and forming aggregates.
Findings:
- In vitro, R406W-desmin formed abnormal filaments and aggregates.
- Knock-in mouse models recapitulated patient histopathology, showing myopathy and cardiomyopathy.
- Homozygous knock-in mice exhibited a fatal gastrointestinal phenotype due to smooth muscle dysfunction.
Implications:
- The R406W-desmin mutation triggers cardiotoxicity through a novel pathomechanism.
- Disruption of desmin filament assembly and intercalated disc integrity underlies the observed cardiac dysfunction.
- Understanding this mechanism may inform therapeutic strategies for desmin-related cardiomyopathies.
Keywords:
cardiomyopathiesdesmindesmosomesintermediate filamentsintestinal pseudo-obstructionmuscle, smoothmuscle, striatedMore Related Videos
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