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Published on: September 20, 2016
Distinct molecular features of FLNC mutations, associated with different clinical phenotypes
Klimenko E S1, Zaytseva A K1, Sorokina M Yu1
1Almazov National Medical Research Centre, Institute of Molecular Biology and Genetics, Saint-Petersburg, Russia.
Abstract:
Filamin С is a key an actin-binding protein of muscle cells playing a critical role in maintaining structural integrity and sarcomere organization. FLNC mutations contribute to various types of cardiomyopathies and myopathies through potentially different molecular mechanisms. Here, we described the impact of two clinically distinct FLNC variants (R1267Q associated with arrhythmogenic cardiomyopathy and V2264M associated with restrictive cardiomyopathy) on calcium homeostasis, electrophysiology, and gene expression profile of iPSC-derived patient-specific cardiomyocytes. We demonstrated that R1267Q FLNC variant leads to greater disturbances in calcium dynamics, Nav1.5 kinetics and action potentials compared to V2264M variant. These functional characteristics were accompanied by transcriptome changes in genes linked to action potential and sodium transport as well as structural cardiomyocyte genes. We suggest distinct molecular effects of two FLNC variants linked to different types of cardiomyopathies in terms of myofilament structure, electrophysiology, ion channel function and intracellular calcium homeostasis providing the molecular the bases for their different clinical phenotypes.
Insights
Filamin C (FLNC) mutations cause cardiomyopathies. Distinct FLNC variants impact cardiac function differently, affecting calcium handling and electrical activity, explaining varied clinical outcomes.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetics of Heart Disease
Background:
- Filamin C (FLNC) is a crucial actin-binding protein essential for muscle structural integrity and sarcomere organization.
- Mutations in the FLNC gene are implicated in diverse cardiomyopathies and myopathies, potentially via distinct molecular pathways.
Purpose of the Study:
- To investigate the distinct molecular impacts of two clinically divergent FLNC variants (R1267Q and V2264M) on patient-specific cardiomyocytes.
- To elucidate how these variants affect calcium homeostasis, cardiac electrophysiology, and gene expression profiles.
Main Methods:
- Utilized induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients harboring specific FLNC variants.
- Assessed calcium dynamics, cardiac electrophysiology (including Nav1.5 channel kinetics and action potentials), and transcriptome profiles.
Main Results:
- The R1267Q FLNC variant, associated with arrhythmogenic cardiomyopathy, induced more significant disturbances in calcium dynamics and electrophysiology compared to the V2264M variant (restrictive cardiomyopathy).
- Transcriptome analysis revealed differential gene expression related to action potential, sodium transport, and cardiomyocyte structure, correlating with variant-specific functional deficits.
- Observed distinct molecular effects on myofilament structure, ion channel function, and intracellular calcium handling for each FLNC variant.
Conclusions:
- Two distinct FLNC variants (R1267Q and V2264M) exert different molecular effects on cardiomyocytes.
- These variant-specific molecular alterations provide a mechanistic basis for the differing clinical phenotypes observed in arrhythmogenic and restrictive cardiomyopathies.
- Highlights the importance of genotype-phenotype correlations in FLNC-associated cardiomyopathies.
