In vivo Functional Consequences of Human THRA Variants Expressed in the Zebrafish.
BACKGROUND
Heterozygous mutations in the thyroid hormone receptor alpha (THRA) gene cause resistance to thyroid hormone alpha (RTHα), a disease characterized by variable manifestations reminiscent of untreated congenital hypothyroidism but a raised triiodothyronine/thyroxine ratio and normal thyrotropin levels. It was recently described that zebrafish embryos expressing a dominant negative (DN) form of thraa recapitulate the key features of RTHα, and that zebrafish and human receptors are functionally interchangeable.


METHODS
This study expressed several human thyroid hormone receptor alpha (hTRα) variants in zebrafish embryos and analyzed the resulting phenotypes.


RESULTS
All hTRα-injected embryos showed variable defects, including cerebral and cardiac edema likely caused by an aberrant looping during heart development, anemia, and an incomplete formation of the vascular network. Moreover, the hTRα-injected embryos presented severe defects of motorneurons and craniofacial development, thus affecting their autonomous feeding and swimming behaviors. Surprisingly, expression of all hTRα mutants had no detectable effect on thyrotropin beta and thyrotropin-releasing hormone transcripts, indicating that their DN action is limited on the thyroid hormone reception beta 2 targets at the hypothalamic/pituitary level in vivo. As previously described in vitro, treatment with high triiodothyronine doses can efficiently revert the observed defects only in embryos injected with missense hTRα variants.


CONCLUSION
Injection of human THRA variants in zebrafish embryos causes tissue-specific defects recapitulating most of the RTHα clinical and biochemical manifestations. The described manipulation of zebrafish embryos represents a novel in vivo model to screen the functional consequences of THRA variants and the rescue potential of new therapeutic compounds.
['Marelli|Federica|F|', 'Carra|Silvia|S|', 'Rurale|Giuditta|G|', 'Cotelli|Franco|F|', 'Persani|Luca|L|']
D000740:Anemia D000818:Animals D030801:Animals, Genetically Modified D001929:Brain Edema D003409:Congenital Hypothyroidism D019465:Craniofacial Abnormalities D004195:Disease Models, Animal D004489:Edema, Cardiac D004625:Embryo, Nonmammalian D018507:Gene Expression Regulation, Developmental D014644:Genetic Variation D006801:Humans D016472:Motor Neuron Disease D037021:Thyroid Hormone Receptors alpha D013972:Thyrotropin D037322:Thyrotropin, beta Subunit D013973:Thyrotropin-Releasing Hormone D013974:Thyroxine D014284:Triiodothyronine D015027:Zebrafish
THRA zebrafish thyroid resistance to thyroid hormone heart development embryonic development