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

Claudine Wb Ruijmbeek; Filomena Housley; Hafiza Idrees; Michael P Housley; Jenny Pestel; Leonie Keller; Jason Kh Lai; Herma C van der Linde; Rob Willemsen; Janett Piesker; Zuhair N Al-Hassnan; Abdulrahman Almesned; Michiel Dalinghaus; Lisa M van den Bersselaar; Marjon A van Slegtenhorst; Federico Tessadori; Jeroen Bakkers; Tjakko J van Ham; Didier Yr Stainier; Judith Ma Verhagen; Sven Reischauer

doi:10.1172/jci.insight.168247

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

Claudine Wb Ruijmbeek, Filomena Housley, Hafiza Idrees, Michael P Housley, Jenny Pestel, Leonie Keller, Jason Kh Lai, Herma C van der Linde, Rob Willemsen, Janett Piesker, Zuhair N Al-Hassnan, Abdulrahman Almesned, Michiel Dalinghaus, Lisa M van den Bersselaar, Marjon A van Slegtenhorst, Federico Tessadori, Jeroen Bakkers, Tjakko J van Ham, Didier Yr Stainier, Judith Ma VerhagenSven Reischauer

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

2 Citaten (Scopus)

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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.

Originele taal-2	Engels
Tijdschrift	JCI insight
Volume	8
Nummer van het tijdschrift	17
DOI's	https://doi.org/10.1172/jci.insight.168247
Status	Gepubliceerd - 08 sep. 2023

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10.1172/jci.insight.168247

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Ruijmbeek, C. W., Housley, F., Idrees, H., Housley, M. P., Pestel, J., Keller, L., Lai, J. K., der Linde, H. C. V., Willemsen, R., Piesker, J., Al-Hassnan, Z. N., Almesned, A., Dalinghaus, M., den Bersselaar, L. M. V., van Slegtenhorst, M. A., Tessadori, F., Bakkers, J., van Ham, T. J., Stainier, D. Y., ... Reischauer, S. (2023). Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization. JCI insight, 8(17). https://doi.org/10.1172/jci.insight.168247

@article{78cdfffa05754270867de9f09db4c9c3,

title = "Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization",

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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author = "Ruijmbeek, {Claudine Wb} and Filomena Housley and Hafiza Idrees and Housley, {Michael P} and Jenny Pestel and Leonie Keller and Lai, {Jason Kh} and {der Linde}, {Herma C van} and Rob Willemsen and Janett Piesker and Al-Hassnan, {Zuhair N} and Abdulrahman Almesned and Michiel Dalinghaus and {den Bersselaar}, {Lisa M van} and {van Slegtenhorst}, {Marjon A} and Federico Tessadori and Jeroen Bakkers and {van Ham}, {Tjakko J} and Stainier, {Didier Yr} and Verhagen, {Judith Ma} and Sven Reischauer",

year = "2023",

month = sep,

day = "8",

doi = "10.1172/jci.insight.168247",

language = "English",

volume = "8",

journal = "JCI insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "17",

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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 2023, 'Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization', JCI insight, vol. 8, nr. 17. https://doi.org/10.1172/jci.insight.168247

TY - JOUR

T1 - Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization

AU - Ruijmbeek, Claudine Wb

AU - Housley, Filomena

AU - Idrees, Hafiza

AU - Housley, Michael P

AU - Pestel, Jenny

AU - Keller, Leonie

AU - Lai, Jason Kh

AU - der Linde, Herma C van

AU - Willemsen, Rob

AU - Piesker, Janett

AU - Al-Hassnan, Zuhair N

AU - Almesned, Abdulrahman

AU - Dalinghaus, Michiel

AU - den Bersselaar, Lisa M van

AU - van Slegtenhorst, Marjon A

AU - Tessadori, Federico

AU - Bakkers, Jeroen

AU - van Ham, Tjakko J

AU - Stainier, Didier Yr

AU - Verhagen, Judith Ma

AU - Reischauer, Sven

PY - 2023/9/8

Y1 - 2023/9/8

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Adhesion/genetics

KW - Microfilament Proteins/genetics

KW - Myocytes, Cardiac/metabolism

KW - Myofibrils/metabolism

KW - Zebrafish/genetics

KW - Trans-Activators

KW - Cardiomyopathies/genetics

U2 - 10.1172/jci.insight.168247

DO - 10.1172/jci.insight.168247

M3 - Article

C2 - 37561591

SN - 2379-3708

VL - 8

JO - JCI insight

JF - JCI insight

IS - 17

ER -

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

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