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Published on: July 18, 2014
Patient-informed CRISPR screen identifies FLNB as a congenital heart disease and ciliopathy gene
Angelo Arrigo1, Venkatraman Rao2, Aakrosh Ratan3
1Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, USA; Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
Insights
Filamin B (FLNB) gene variants cause heterotaxy and congenital heart defects by disrupting cilia function. This study validates FLNB as a key gene in these developmental disorders.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Heterotaxy (HTX) is a congenital disorder with abnormal organ placement, often associated with severe congenital heart disease (CHD).
- Many genes linked to CHD and HTX lack functional validation, impeding clinical diagnosis and treatment.
- The genetic underpinnings of ciliopathies and their connection to organ asymmetry remain incompletely understood.
Purpose of the Study:
- To functionally validate candidate genes associated with congenital heart disease (CHD) and heterotaxy (HTX) using a high-throughput screening approach.
- To investigate the role of Filamin B (FLNB) in ciliogenesis, left-right patterning, and congenital heart development.
- To establish a link between FLNB variants and human CHD/HTX phenotypes.
Main Methods:
- Utilized CRISPR/Cas9 screening in Xenopus to evaluate candidate genes from whole-exome sequencing of human CHD patients.
- Identified and characterized FLNB variants in human probands with CHD and HTX.
- Disrupted flnb in Xenopus to model HTX phenotypes and assessed cardiac development and cilia function.
- Performed rescue experiments to confirm the functional conservation of human FLNB.
Main Results:
- Filamin B (FLNB), an actin-binding protein, was identified as a novel gene associated with CHD and HTX.
- Five human probands with CHD and HTX harbored either recessive or damaging heterozygous FLNB variants.
- Xenopus models with disrupted flnb exhibited cardiac defects and impaired motile cilia function, mirroring human HTX.
- Rescue experiments confirmed that human FLNB can restore normal development in the Xenopus model.
Conclusions:
- FLNB dysfunction, impacting the actin cytoskeleton, is directly implicated in ciliogenesis and left-right patterning defects.
- This study provides critical evidence linking human FLNB variants to ciliopathies, CHD, and HTX.
- FLNB is a newly identified causative gene for a subset of patients with congenital heart disease and heterotaxy.
Abstract:
Heterotaxy (HTX) is a congenital disorder characterized by abnormal left-right organ placement, often leading to severe congenital heart disease (CHD). Despite advances in sequencing, many CHD and HTX-associated genes remain functionally unvalidated, hindering effective clinical diagnosis and management. Here, we leveraged a high-throughput CRISPR-Cas9 screening approach in the Xenopus model to rapidly evaluate candidate genes identified from whole-exome sequencing of human CHD patients. Our screen identified Filamin B (FLNB), an actin-binding protein previously linked to skeletal disorders but not to ciliopathies or CHD. We identified 5 probands with CHD and HTX, 3 with recessive and 2 with damaging heterozygous variants in FLNB. Disrupting flnb in Xenopus reproduced key features of the human HTX phenotype, including defects in cardiac development and impaired motile cilia function. Rescue experiments confirmed the functional conservation of human FLNB, directly implicating actin cytoskeletal disruption in ciliogenesis and left-right patterning defects. Our results provide crucial evidence linking human FLNB dysfunction to ciliopathies and CHD and HTX.
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