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Phenotypic Diversity Caused by the DES Missense Mutation p.R127P (c.380G>C) Contributing to Significant Cardiac
Mohammad A Ebrahim1, Naser M Ali2,3, Buthaina Y Albash2
1Department of Pediatrics, Kuwait University Faculty of Medicine, Affiliated with Chest Diseases Hospital, Jabriya (M.A.E.).
Insights
A genetic mutation in the DES gene (p.R127P) causes severe desmin filament defects, leading to high rates of cardiomyopathy and sudden cardiac death in a large family. This finding aids in understanding DES variants and genetic counseling.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Cell Biology
Background:
- Nonischemic cardiomyopathies often stem from genetic mutations affecting approximately 100 genes.
- The DES gene encodes desmin, a crucial intermediate filament protein for cardiomyocyte structural integrity.
Purpose of the Study:
- To investigate a heterozygous DES missense mutation (p.R127P) identified in a large, multi-generation family with high cardiac mortality.
- To characterize the functional and structural impact of the DES-p.R127P mutation on desmin filament assembly.
Main Methods:
- Next-generation sequencing for cascade screening of the DES-p.R127P mutation.
- Cell transfection experiments with induced pluripotent stem cell-derived cardiomyocytes.
- Confocal and atomic force microscopy to analyze desmin filament assembly and protein aggregation.
Main Results:
- The DES-p.R127P mutation caused a severe defect in desmin filament assembly.
- Aberrant cytoplasmic desmin aggregates formed even with co-expression of wild-type desmin.
- Analysis of 20 variants showed most disturbed filament assembly similarly to p.R127P.
Conclusions:
- The DES-p.R127P mutation is likely pathogenic, responsible for significant cardiac morbidity and mortality in the studied family.
- This research aids in classifying DES variants and provides valuable information for genetic counseling.
- The study highlights the critical role of desmin in maintaining cardiac structure and function.
Background:
Nonischemic cardiomyopathies are frequently caused by genetic mutations in about 100 different genes. The cardiomyopathy-associated gene DES encodes the intermediate filament protein desmin, which is important for the structural integrity of the cardiomyocytes.
Methods:
Using a next-generation sequencing approach, we performed cascade screening of a previously identified heterozygous DES missense mutation (c.380G>C, p.R127P) segregating in a large 6-generation Kuwaiti family, where several members died from sudden cardiac death or developed different cardiomyopathies, partially in combination with conduction disease and atrial fibrillation. DES-p.R127P affects a highly conserved position and is absent or super rare in different genetic human population databases. In silico predictions support the pathogenicity of DES-p.R127P. To investigate the detrimental impact of desmin-p.R127P, we performed cell transfection experiments using different cell lines and cardiomyocytes derived from induced pluripotent stem cells in combination with confocal microscopy.
Results:
These experiments demonstrated a severe desmin filament assembly defect leading to aberrant cytoplasmic desmin aggregates, even when co-expressed with wild-type desmin. Atomic force microscopy analysis supported the filament assembly defect of mutant recombinant desmin-p.R127P. To investigate the physicochemical impact of the amino acid at this position, we generated a set of 20 different variants and analyzed their filament formation in cell culture. Most of these variants disturbed the filament assembly comparable to p.R127P.
Conclusions:
In summary, we present and characterize a likely pathogenic missense mutation DES-p.R127P, which causes high cardiac mortality and morbidity in the described family. Our study has relevance for the interpretation and classification of further DES variants and might be helpful for the genetic counseling of patients and their relatives in future cases.
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