Journal
HUMAN MUTATION
Volume 40, Issue 6, Pages 734-741Publisher
WILEY
DOI: 10.1002/humu.23747
Keywords
1A coiled-coil rod segment; desmin; left ventricular noncompaction cardiomyopathy (LVNC); small in-frame deletion
Categories
Funding
- Deutsche Forschungsgemeinschaft [MI1146/2-1]
- Russian Science Foundation [17-15-01051]
- Forschungsfonds
- Russian Foundation for Basic Research [17-04-00521]
- German Center for Cardiovascular Research
- German Foundation for Heart Research
- University of Bielefeld (Forschungsfonds OWL)
- Russian Science Foundation [17-15-01051] Funding Source: Russian Science Foundation
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Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in-frame deletion within the DES gene, p.Q113_L115del, affecting the alpha-helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild-type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.
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