ArticleJCI insight2023
Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 7 citations in OpenAlex.
- Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- A novel Notch and WNT signaling mechanism contribute to paediatric DCM: a pathway to new therapeutics.bioRxiv : the preprint server for biology · 2025Article
- A systems genetics approach identifies roles for proteasome factors in heart development and congenital heart defects.PLoS genetics · 2025Article
- Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy.Molecular genetics & genomic medicine · 2024Article
- Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies.Nature cardiovascular research · 2023Article
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Authors and funding
21 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pediatric cardiomyopathy (CM) represents a group of rare, severe disorders that affect the myocardium. To date, the etiology and mechanisms underlying pediatric CM are incompletely understood, hampering accurate diagnosis and individualized therapy development. Here, we identified biallelic variants in the highly conserved flightless-I (FLII) gene in 3 families with idiopathic, early-onset dilated CM. We demonstrated that patient-specific FLII variants, when brought into the zebrafish genome using CRISPR/Cas9 genome editing, resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in our patients. Importantly, using these genetic animal models, complemented with in-depth loss-of-function studies, we provided insights into the function of Flii during ventricular chamber morphogenesis in vivo, including myofibril organization and cardiomyocyte cell adhesion, as well as trabeculation. In addition, we identified Flii function to be important for the regulation of Notch and Hippo signaling, crucial pathways associated with cardiac morphogenesis and function. Taken together, our data provide experimental evidence for a role for FLII in the pathogenesis of pediatric CM and report biallelic variants as a genetic cause of pediatric CM.
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