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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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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. |
format | Online Article Text |
id | pubmed-10544232 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
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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