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Hypothyroidism in Thyroid Transcription Factor 1 Haploinsufficiency Is Caused by Reduced Expression of the Thyroid-Stimulating Hormone Receptor

Departments of Medicine (L.C.M., X.-H.L., S.R.), Pediatrics (S.R.), and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; Laboratory of Metabolism (S.K., T.K.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (J.V.S.), University of Brussels, School of Medicine, Erasmus Hospital, B 1070 Brussels, Belgium

Address all correspondence and requests for reprints to: Samuel Refetoff, The University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}uchicago.edu.

Humans expressing one allele of the thyroid transcription factor 1 (TTF1) gene have neurological symptoms and increased serum TSH with variable degrees of hypothyroidism. Ttf1^+/- mice have also poor coordination and increased serum TSH concentration (205 ± 22 vs. 92 ± 12 mU/liter; P < 0.001) and slightly lower T₄ (46 ± 3 vs. 63 ± 6 nmol/liter; P < 0.02) as compared with Ttf1^+/+ mice. To determine whether the hypothyroidism is of central or primary origin, we examined the bioactivity of TSH, thyroidal response to exogenous TSH and the expression of genes regulated by TTF1. TSH bioactivity was normal, but T₄ response to a low but not high dose of TSH was significantly reduced in the Ttf1^+/- mice (5.5 ± 2.2 vs. 15.3 ± 4.1 nmol/liter; P < 0.03), indicating a reduced thyroidal response. Thyroid mRNAs were measured by real-time PCR (Ttf1^+/+ littermates = 100%). Ttf1^+/- mice had half the levels of TTF1 mRNA (54 ± 9; P < 0.01) and protein, confirming their haploinsufficiency. Significantly lower levels of mRNAs were observed for two of the three genes with TTF1 cis elements: TSH receptor (TSHr, 57 ± 4%; P < 0.002), thyroglobulin (63 ± 7%; P < 0.005), but not thyroid peroxidase (81 ± 12%; P > 0.05). No significant difference between the two genotypes was found for Pax8, sodium iodide symporter, and iodothyronine deiodinase 1. These results show that Ttf1 haploinsufficiency causes a reduction in the expression of TSHr and thyroglobulin, genes with TTF1 binding sites in their promoter regions. The low TSHr is only partially compensated by an increase in TSH secretion because T₄ remains mildly reduced. However, administration of a larger amount of TSH obliterates the response differences by saturating a reduced amount of receptor.

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