Desmin-p.L112Q Disturbs Filament Formation and Is a Likely-Pathogenic Variant Associated with Dilated Cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Cell Biology

Background:

• The desmin (DES) gene encodes the intermediate filament protein desmin, crucial for cardiomyocyte structural integrity.
• Mutations in DES are linked to various cardiomyopathies, notably dilated cardiomyopathy.
• Understanding the functional impact of specific DES variants is vital for diagnosing and treating heart conditions.

Purpose of the Study:

• To functionally validate the DES-p.L112Q variant.
• To investigate the cellular mechanisms by which this mutation affects desmin protein.
• To support the re-classification of DES-p.L112Q as a likely pathogenic variant for dilated cardiomyopathy.

Main Methods:

• Utilized SW-13 and H9c2 cell lines for in vitro studies.
• Generated induced pluripotent stem cells (iPSCs) and differentiated them into cardiomyocytes.
• Employed confocal microscopy with deconvolution analysis to visualize desmin protein localization and aggregation.

Main Results:

• Aberrant cytoplasmic aggregation of the mutant desmin protein (DES-p.L112Q) was observed.
• The cellular localization and structural role of desmin were significantly disrupted by the mutation.
• Functional analysis demonstrated a clear link between the DES-p.L112Q variant and cellular abnormalities.

Conclusions:

• The functional analyses provide strong evidence for the pathogenic nature of the DES-p.L112Q variant.
• DES-p.L112Q is re-classified as a likely pathogenic variant contributing to dilated cardiomyopathy.
• These findings enhance the understanding of genotype-phenotype correlations in inherited cardiomyopathies.