Three genes, TTF1, TTF2, and PAX8, involved in thyroid gland development and migration have been identified. Yet systematic screening for defects in these genes in thyroid dysgenesis gave essentially negative results. In particular, no TTF1 gene defects were found in 76 individuals with thyroid dysgenesis even though a deletion of this gene in the mouse results in thyroid and lung agenesis and defective diencephalon. We report a 6-year-old boy with predominant dyskinesia, neonatal respiratory distress, and mild hyperthyrotropinemia. One allele of his TTF1 gene had a guanidine inserted into codon 86 producing a nonsense protein of 407, rather than 371, amino acids. The mutant TTF1 did not bind to its canonical cis-element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TTF1. Failure of the mutant TTF1 to interfere with binding and transactivation functions of the wild-type TTF1 suggested that the syndrome was caused by haploinsufficiency. This was confirmed in mice heterozygous for Ttf1 gene deletion, heretofore considered to be normal. Compared with wild-type littermates, Ttf1+/- mice had poor coordination and a significant elevation of serum thyrotropin. Therefore, haploinsufficiency of the TTF1 gene results in a predominantly neurological phenotype and secondary hyperthyrotropinemia.
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