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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe
Francisco José Bermúdez-Jiménez1,2,3, Víctor Carriel2,3, Andreas Brodehl4
1Cardiology Department, Virgen de las Nieves University Hospital, Granada, Spain (F.J.B.-J., B.A.A., M. Álvarez, S.L.-F., L.T., J.J.-J.). bermudezfrancisco23y@gmail.com.
Circulation
|December 8, 2017
Summary
A novel desmin (DES) mutation, p.Glu401Asp, causes inherited left ventricular arrhythmogenic cardiomyopathy. This genetic defect leads to severe cardiac events without skeletal muscle issues.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Muscle Diseases
Background:
- Desmin (DES) mutations are linked to various muscle diseases.
- The role of DES mutations in arrhythmogenic cardiomyopathy (ACM) is emerging.
- Specific pathomechanisms of DES mutations in ACM require further elucidation.
Observation:
- A novel DES mutation, p.Glu401Asp, was identified in a large Spanish family with inherited left ventricular ACM.
- Genotype-positive carriers exhibited a consistent ACM phenotype with high incidence of sudden cardiac death.
- No skeletal myopathy or conduction system disorders were observed in affected individuals.
Findings:
- Immunohistochemistry revealed alterations consistent with ACM.
- Functional studies showed impaired cellular growth, adhesion, and reduced desmin RNA expression.
- Mutant desmin formed aggregates in transfected cells, suggesting disrupted protein assembly.
Implications:
- The DES-p.Glu401Asp mutation is a cause of predominant left ventricular ACM.
- Pathogenic mechanisms likely involve disrupted desmin assembly and intercalated disc protein interactions.
- Understanding this mutation provides insights into desminopathies and inherited cardiomyopathies.
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