PUBLICATION
Bi-allelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization
- Authors
- Ruijmbeek, C.W., Housley, F., Idrees, H., Housley, M.P., Pestel, J., Keller, L., Lai, J.K.H., van der Linde, H.C., Willemsen, R., Piesker, J., Al-Hassnan, Z.N., Almesned, A., Dalinghaus, M., van den Bersselaar, L.M., van Slegtenhorst, M.A., Tessadori, F., Bakkers, J., van Ham, T.J., Stainier, D.Y., Verhagen, J.M., Reischauer, S.
- ID
- ZDB-PUB-230811-42
- Date
- 2023
- Source
- JCI insight 8(17): (Journal)
- Registered Authors
- Bakkers, Jeroen, Reischauer, Sven, Stainier, Didier, van der Linde, Herma, van Ham, Tjakko
- Keywords
- Cardiology, Cardiovascular disease, Embryonic development, Genetics, Molecular genetics
- MeSH Terms
-
- Animals
- Cardiomyopathies*/genetics
- Cell Adhesion/genetics
- Microfilament Proteins*/genetics
- Myocytes, Cardiac/metabolism
- Myofibrils/metabolism
- Trans-Activators
- Zebrafish/genetics
- PubMed
- 37561591 Full text @ JCI Insight
Citation
Ruijmbeek, C.W., Housley, F., Idrees, H., Housley, M.P., Pestel, J., Keller, L., Lai, J.K.H., van der Linde, H.C., Willemsen, R., Piesker, J., Al-Hassnan, Z.N., Almesned, A., Dalinghaus, M., van den Bersselaar, L.M., van Slegtenhorst, M.A., Tessadori, F., Bakkers, J., van Ham, T.J., Stainier, D.Y., Verhagen, J.M., Reischauer, S. (2023) Bi-allelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization. JCI insight. 8(17):.
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, bi-allelic variants in the highly conserved flightless-1 (FLII) gene were identified in three families with idiopathic early-onset dilated CM. We demonstrate that patient-specific FLII variants, when brought into the zebrafish genome using CRISPR/Cas9 genome editing, result 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 provide 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 identify 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 bi-allelic variants as a novel genetic cause of pediatric CM.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping