Endocrine Abstracts (2001) 2 SP1

Phenotype of mice harboring a thyroid hormone receptor alpha 1 gene with transdominant negative properties

B Vennström1, A Tinnikov1, M Adams3, P Thorén1, J Kindblom2, S Malin1, B Rozell1, S Pettersson1, C Ohlsson2 & K Chatterjee3

1Karolinska Institute, Stockholm; 2Gothenburgs University, Göteborg; 3University of Cambridge, Cambridge.

Patients with the syndrome Resistance to Thyroid Hormone (RTH) exhibit purturbances in regulation of serum thyroxine and often suffer from hypermetabolism, tachycardia, hyperactivity and mental retardation. Most of these patients express a mutant thyroid hormone receptor beta (TRb) unable to bind ligand, resulting in transdominant negative effects in transcription. As no patient with a mutant TRa has been identified, we introduced into the mouse TRa1 gene a point mutation found in a patient's TRb gene. Juvenile mice exhibit a mild reduction in serum thyroxine levels, retardation of postnatal development and growth, decreased growth hormone gene expression, cardiac abnormalities and low levels of IgM presenting B cells. Animals homozygous for the mutation fail to develop a thyroid gland and die before 3 weeks of age while whereas heterozygotes overcome most of the juvenile defects except for deficits in cardiac function. The results may provide important clues for identification of a new class of patients.

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