Polymorphism of the polyalanine tract of thyroid transcription factor-2 gene in patients with thyroid dysgenesis

Objective: One of the thyroid-specific transcription factors, thyroid trans cription factor-2 (TTF-2), performs a crucial role in the development of th e thyroid gland. We performed genetic analysis of the TITF2 gene (encoding TTF-2) in patients with thyroid dysgenesis. Methods: By direct sequencing of the PCR products of TITF2, we screened the genomic DNA from 46 patients with thyroid dysgenesis (five had agenesis, s ix had hypoplasia, 15 had ectopy, and 20 were undetermined). We also studie d the transcriptional activities of TITF2 by co-expressing the luciferase g ene directed by the human thyroglobulin gene promoter. Results: Human TITF2 consists of a forkhead domain, a polyalanine tract, an d unique C-terminal residues. In one of the patients with an ectopic sublin gual thyroid, we found a polyalanine tract of 11 alanine residues on one ch romosome instead of the 14 alanine residues found in normal controls. In on e patient with hypoplasia, the polyalanine tract consisted of 12 heterozygo us alanine residues. The reduced polyalanine tracts were not detected in 10 1 normal individuals. However, the expression study showed that the transcr iptional activities of TITF2 with reduced polyalanine-tract lengths were eq ual to that of TITF2 with an unreduced polyalanine tract. Conclusion: These results suggest that the polymorphism of the polyalanine tract of TITF2 is not a frequent cause of developmental defects of the huma n thyroid gland.