| RRC ID |
79160
|
| Author |
Ruijmbeek CW, Housley F, Idrees H, Housley MP, Pestel J, Keller L, Lai JK, der Linde HCV, Willemsen R, Piesker J, Al-Hassnan ZN, Almesned A, Dalinghaus M, den Bersselaar LMV, van Slegtenhorst MA, Tessadori F, Bakkers J, van Ham TJ, Stainier DY, Verhagen JM, Reischauer S.
|
| Title |
Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
|
| Journal |
JCI Insight
|
| 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.
|
| Volume |
8(17)
|
| Published |
2023-9-8
|
| DOI |
10.1172/jci.insight.168247
|
| PII |
168247
|
| PMID |
37561591
|
| PMC |
PMC10544232
|
| MeSH |
Animals
Cardiomyopathies* / genetics
Cell Adhesion / genetics
Microfilament Proteins* / genetics
Myocytes, Cardiac / metabolism
Myofibrils / metabolism
Trans-Activators
Zebrafish / genetics
|
| Resource |
| Zebrafish |
flightless mi372 |
