Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2006) 11 S5

ECE2006 Plenary Lecturers’ Biographical Notes British Thyroid Association Pitt-Rivers Lecture (1 abstracts)

Neurological abnormalities in mice with a dominant negative thyroid hormone alpha 1

B Vennström


CMB, Karolinska Institute, Stockholm, Sweden.


The syndrome of Resistance to Thyroid Hormone (RTH), found in about 300 patient families, is characterized by multiple somatic abnormalities, varying levels of mental retardation, and tachycardia. It is caused by mutations in thyroid hormone receptor beta 1 (TRb) which confer dominant negative effects. No patient with a germline mutant TRa gene has yet been found. We therefore introduced a patient’s mutation into the mouse TRa1 gene. The mutation allows T3 binding with a 10x lower affinity thus causing the receptor to act as a transcriptional repressor unless challenged with high levels of T3. The heterozygous knock-in mice have a profound phenotype: a severe retardation of postnatal maturation that however is largely normalized in adult mice.

We have subsequently identified several neurological deficiencies that persist into adulthood. Neuromuscular dysfunctions include abnormal gait, poor hind limb coordination, inability to climb properly, and poor performance on the Rotarod. Some but not all of these deficiencies could be ameliorated by T3 treatment of the animals during postnatal days P10-P35, indicating that the mutant TR causes developmental defects affecting the motor system.

The adult mice also exhibit an extreme anxiety in the open field and elevated plus maze tests, and are impaired in tests for exploration and recognition of novel objects. All tests were fully normalized by adult but not juvenile T3 treatment, suggesting that these deficiencies are caused by an adult, neurophysiological function of the mutant TR.

Our data thus suggest that the mice exhibit two distinct features similar to those of thyroid hormone depletion: a neuromuscular one caused by hormone deficiency during development and that is irreversible in the adult, and a psychiatric one that can be ameliorated by treating the adult animal, suggesting an effect of the mutant receptor on central neurophysiological functions.

Volume 11

8th European Congress of Endocrinology incorporating the British Endocrine Societies

European Society of Endocrinology 
British Endocrine Societies 

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