Key result
Zebrafish taf1 and taf5 deletion causes ventricular hypoplasia and heart failure, driven by metabolic misregulation.
Why the study?
The mechanisms by which TAFopathies cause neurodevelopmental, craniofacial, and cardiac abnormalities remain undefined.
Deletion of taf1 and taf5 in zebrafish causes cardiac and craniofacial abnormalities, suggesting TAFopathies may be driven by metabolic perturbations.
Answers are grounded in this paper and cite their sources.
Zebrafish taf1/taf5 models link TAFopathies to metabolic dysregulation; leaves open whether metabolic targets modify cardiac or neurodevelopmental phenotypes in patients.
Intellectual disability is a neurodevelopmental disorder that affects 2-3% of the general population. Syndromic forms of intellectual disability frequently have a genetic basis and are often accompanied by additional developmental anomalies. Pathogenic variants in components of TATA-binding protein associated factors (TAFs) have recently been identified in a subset of patients with intellectual disability, craniofacial hypoplasia, and congenital heart disease. This syndrome has been termed as a TAFopathy and includes mutations in TATA binding protein (TBP), TAF1, TAF2, and TAF6. The underlying mechanism by which TAFopathies give rise to neurodevelopmental, craniofacial, and cardiac abnormalities remains to be defined. Through a forward genetic screen in zebrafish, we have recovered a recessive mutant phenotype characterized by craniofacial hypoplasia, ventricular hypoplasia, heart failure at 96 h post-fertilization and lethality, and show it is caused by a nonsense mutation in taf5. CRISPR/CAS9 mediated gene editing revealed that these defects where phenocopied by mutations in taf1 and taf5. Mechanistically, taf5-/- zebrafish displayed misregulation in metabolic gene expression and metabolism as evidenced by RNA sequencing, respiration assays, and metabolite studies. Collectively, these findings suggest that the TAF complex may contribute to neurologic, craniofacial, and cardiac development through regulation of metabolism.
No takes yet. Share an insight, caveat, or question.
Leid et al. (2023) studied TAFopathies. Deletion of taf1 and taf5 vs. Wild-type was evaluated on Craniofacial hypoplasia, ventricular hypoplasia, heart failure, and lethality. Deletion of taf1 and taf5 in zebrafish caused craniofacial hypoplasia, ventricular hypoplasia, and heart failure, driven by misregulation in metabolic gene expression and metabolism.
Synapse has enriched 10 related papers. Consider them for comparative context: