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Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization

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...

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Autores principales: Ruijmbeek, Claudine W.B., Housley, Filomena, Idrees, Hafiza, Housley, Michael P., Pestel, Jenny, Keller, Leonie, Lai, Jason K.H., van der Linde, Herma C., Willemsen, Rob, Piesker, Janett, Al-Hassnan, Zuhair N., Almesned, Abdulrahman, Dalinghaus, Michiel, van den Bersselaar, Lisa M., van Slegtenhorst, Marjon A., Tessadori, Federico, Bakkers, Jeroen, van Ham, Tjakko J., Stainier, Didier Y.R., Verhagen, Judith M.A., Reischauer, Sven
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544232/
https://www.ncbi.nlm.nih.gov/pubmed/37561591
http://dx.doi.org/10.1172/jci.insight.168247
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author Ruijmbeek, Claudine W.B.
Housley, Filomena
Idrees, Hafiza
Housley, Michael P.
Pestel, Jenny
Keller, Leonie
Lai, Jason K.H.
van der Linde, Herma C.
Willemsen, Rob
Piesker, Janett
Al-Hassnan, Zuhair N.
Almesned, Abdulrahman
Dalinghaus, Michiel
van den Bersselaar, Lisa M.
van Slegtenhorst, Marjon A.
Tessadori, Federico
Bakkers, Jeroen
van Ham, Tjakko J.
Stainier, Didier Y.R.
Verhagen, Judith M.A.
Reischauer, Sven
author_facet Ruijmbeek, Claudine W.B.
Housley, Filomena
Idrees, Hafiza
Housley, Michael P.
Pestel, Jenny
Keller, Leonie
Lai, Jason K.H.
van der Linde, Herma C.
Willemsen, Rob
Piesker, Janett
Al-Hassnan, Zuhair N.
Almesned, Abdulrahman
Dalinghaus, Michiel
van den Bersselaar, Lisa M.
van Slegtenhorst, Marjon A.
Tessadori, Federico
Bakkers, Jeroen
van Ham, Tjakko J.
Stainier, Didier Y.R.
Verhagen, Judith M.A.
Reischauer, Sven
author_sort Ruijmbeek, Claudine W.B.
collection PubMed
description 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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spelling pubmed-105442322023-10-03 Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization Ruijmbeek, Claudine W.B. Housley, Filomena Idrees, Hafiza Housley, Michael P. Pestel, Jenny Keller, Leonie Lai, Jason K.H. van der Linde, Herma C. Willemsen, Rob Piesker, Janett Al-Hassnan, Zuhair N. Almesned, Abdulrahman Dalinghaus, Michiel van den Bersselaar, Lisa M. van Slegtenhorst, Marjon A. Tessadori, Federico Bakkers, Jeroen van Ham, Tjakko J. Stainier, Didier Y.R. Verhagen, Judith M.A. Reischauer, Sven JCI Insight Research Article 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. American Society for Clinical Investigation 2023-09-08 /pmc/articles/PMC10544232/ /pubmed/37561591 http://dx.doi.org/10.1172/jci.insight.168247 Text en © 2023 Ruijmbeek et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Ruijmbeek, Claudine W.B.
Housley, Filomena
Idrees, Hafiza
Housley, Michael P.
Pestel, Jenny
Keller, Leonie
Lai, Jason K.H.
van der Linde, Herma C.
Willemsen, Rob
Piesker, Janett
Al-Hassnan, Zuhair N.
Almesned, Abdulrahman
Dalinghaus, Michiel
van den Bersselaar, Lisa M.
van Slegtenhorst, Marjon A.
Tessadori, Federico
Bakkers, Jeroen
van Ham, Tjakko J.
Stainier, Didier Y.R.
Verhagen, Judith M.A.
Reischauer, Sven
Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization
title Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization
title_full Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization
title_fullStr Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization
title_full_unstemmed Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization
title_short Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization
title_sort biallelic variants in flii cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544232/
https://www.ncbi.nlm.nih.gov/pubmed/37561591
http://dx.doi.org/10.1172/jci.insight.168247
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