Thyroid hormone receptor α mutations cause heart defects in zebrafish

Han, C.R., Wang, H., Hoffmann, V., Zerfas, P., Kruhlak, M., Cheng, S.Y.
Thyroid : official journal of the American Thyroid Association   31(2): 315-326 (Journal)
Registered Authors
Cheng, Sheue-yann
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Bradycardia/genetics*
  • Bradycardia/metabolism
  • Bradycardia/pathology
  • Bradycardia/physiopathology
  • Genetic Predisposition to Disease
  • Heart Defects, Congenital/genetics*
  • Heart Defects, Congenital/metabolism
  • Heart Defects, Congenital/pathology
  • Heart Defects, Congenital/physiopathology
  • Mutation*
  • Myocardial Contraction
  • Myocardium/metabolism
  • Myocardium/ultrastructure
  • Thyroid Hormone Receptors alpha/genetics*
  • Thyroid Hormone Receptors alpha/metabolism
  • Thyroid Hormone Receptors beta/genetics
  • Thyroid Hormone Receptors beta/metabolism
  • Ventricular Function
  • Zebrafish/abnormalities
  • Zebrafish/genetics*
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
32762296 Full text @ Thyroid
Mutations of thyroid hormone receptor alpha 1 (TRalpha1) cause resistance to thyroid hormone (RTHalpha). Patients exhibit growth retardation, delayed bone development, anemia, and bradycardia. By using mouse models of RTHalpha much has been learned about the molecular actions of TRalpha 1 mutants that underlie these abnormalities in adults. Using zebrafish models of RTHalpha that we have recently created, we aimed to understand how TRalpha1 mutants affect the heart function during this period.
In contrast to human and mice, the thra gene is duplicated, thraa and thrab, in zebrafish. Using CRISPR/Cas9-mediated targeted mutagenesis, we created C-terminal mutations in the each of two duplicated thra genes in zebrafish (thraa 8-bp insertion or thrab 1-bp insertion mutations). We recently showed that these mutant fish faithfully recapitulated growth retardation as found in patients and thra mutant mice. In the present studies, we used histological analysis, gene expression profiles, confocal fluorescence and transmission electron microscopy (TEM) to comprehensively analyze the phenotypic characteristics of mutant fish heart during development.
We found both a dilated atrium and an abnormally shaped ventricle in adult mutant fish. The retention of red blood cells in the two abnormal heart chambers, and decreased circulating blood speed and reduced expression of contractile genes indicated the weakened contractility in the heart of mutant fish. These abnormalities were detected in mutant fish as early as 35 days post fertilization (juveniles). Further, the expression of genes associated with the sarcomere assembly was suppressed in the heart of mutant fish, resulting in abnormalities of sarcomere organization as revealed by TEM. The abnormal sarcomere organization could underlie the bradycardia exhibited in mutant fish.
Using a zebrafish model of RTHalpha, the present studies demonstrated for the first time that TRalpha mutants could act to cause abnormal heart structure, weaken contractility and disrupt sarcomere organization that affect heart functions. These findings provide new insights into the bradycardia found in RTHalpha patients.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes