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Updated: Jul 25, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Drosophila CRISPR/Cas9 mutants as tools to analyse cardiac filamin function and pathogenicity of human FLNC variants
Flavie Ader1,2,3, Maria Russi4, Laura Tixier-Cardoso4
1APHP, Hôpital Universitaire Pitié-Salpêtrière, Département Médico-Universitaire BioGEM, UF Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, F-75013 Paris, France.
Abstract:
Filamins are large proteins with actin-binding properties. Mutations in FLNC, one of the three filamin genes in humans, have recently been implicated in dominant cardiomyopathies, but the underlying mechanisms are not well understood. Here, we aimed to use Drosophila melanogaster as a new in vivo model to study these diseases. First, we show that adult-specific cardiac RNAi-induced depletion of Drosophila Filamin (dFil) induced cardiac dilatation, impaired systolic function and sarcomeric alterations, highlighting its requirement for cardiac function and maintenance of sarcomere integrity in the adult stage. Next, we introduced in the cheerio gene, using CRISPR/Cas9 gene editing, three missense variants, previously identified in patients with hypertrophic cardiomyopathy. Flies carrying these variants did not exhibit cardiac defects or increased propensity to form filamin aggregates, arguing against their pathogenicity. Finally, we show that deletions of the C-term part of dFil carrying the last four Ig-like domains are dispensable for cardiac function. Collectively, these results highlight the relevance of this model to explore the cardiac function of filamins and increase our understanding of physio-pathological mechanisms involved in FLNC-related cardiomyopathies. This article has an associated First Person interview with the first author of the paper.
Insights
Drosophila melanogaster models reveal that filamin is crucial for heart function and sarcomere integrity. This study questions the pathogenicity of certain filamin variants linked to hypertrophic cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Biochemistry
Background:
- Filamins are actin-binding proteins essential for cellular structure.
- Mutations in the human FLNC gene are linked to dominant cardiomyopathies.
- The precise mechanisms underlying FLNC-related cardiomyopathies remain unclear.
Purpose of the Study:
- To establish Drosophila melanogaster as an in vivo model for studying filamin-related cardiomyopathies.
- To investigate the role of Drosophila Filamin (dFil) in cardiac function.
- To assess the pathogenicity of specific FLNC variants identified in hypertrophic cardiomyopathy patients.
Main Methods:
- Cardiac-specific RNA interference (RNAi) to deplete dFil in adult flies.
- CRISPR/Cas9 gene editing to introduce patient-derived FLNC missense variants into the cheerio gene.
- Analysis of cardiac structure, function, and filamin aggregation in Drosophila models.
Main Results:
- Depletion of dFil in adult flies caused cardiac dilatation, impaired systolic function, and sarcomeric defects.
- Flies carrying three specific FLNC variants showed no cardiac defects or increased filamin aggregation, suggesting low pathogenicity.
- Deletions in the C-terminal region of dFil, including the last four Ig-like domains, did not affect cardiac function.
Conclusions:
- Drosophila melanogaster serves as a valuable in vivo model for exploring filamin's cardiac function.
- The study provides insights into the physio-pathological mechanisms of FLNC-related cardiomyopathies.
- Certain FLNC variants previously associated with hypertrophic cardiomyopathy may not be pathogenic, warranting further investigation.
