Thyroid Hormone Receptor α Mutations Cause Heart Defects in Zebrafish

Area of Science:

• Developmental Biology
• Endocrinology
• Cardiovascular Research

Background:

• Mutations in thyroid hormone receptor alpha 1 (TRα1) cause resistance to thyroid hormone (RTHα), manifesting as growth retardation and bradycardia.
• Previous studies in mouse models elucidated TRα1 mutant actions in adults, but effects during development remained unclear.

Purpose of the Study:

• To investigate the impact of TRα1 mutations on heart development and function in zebrafish.
• To understand the molecular mechanisms underlying cardiac abnormalities in RTHα.

Main Methods:

• CRISPR/Cas9-mediated mutagenesis to create TRα1 C-terminal mutations in zebrafish (thraa and thrab genes).
• Histological analysis, gene expression profiling, confocal fluorescence, and transmission electron microscopy (TEM) were employed.
• Phenotypic analysis of mutant fish hearts at various developmental stages.

Main Results:

• Mutant zebrafish exhibited dilated atria and abnormally shaped ventricles.
• Weakened cardiac contractility was indicated by red blood cell retention, reduced blood speed, and suppressed contractile gene expression.
• TEM revealed disrupted sarcomere organization, linked to bradycardia in mutant fish.

Conclusions:

• TRα1 mutants cause abnormal heart structure, impaired contractility, and disrupted sarcomere organization in zebrafish.
• These findings provide novel insights into the cardiac dysfunction, particularly bradycardia, observed in RTHα patients.