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

Abstract

Objective: One of the thyroid-speci®c transcription factors, thyroid transcription factor-2 (TTF-2), performs a crucial role in the development of the 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 (®ve had agenesis, six had hypoplasia, 15 had ectopy, and 20 were undetermined). We also studied the transcriptional activities of TITF2 by co-expressing the luciferase gene directed by the human thyroglobulin gene promoter. Results: Human TITF2 consists of a forkhead domain, a polyalanine tract, and unique C-terminal residues. In one of the patients with an ectopic sublingual thyroid, we found a polyalanine tract of 11 alanine residues on one chromosome instead of the 14 alanine residues found in normal controls. In one patient with hypoplasia, the polyalanine tract consisted of 12 heterozygous alanine residues. The reduced polyalanine tracts were not detected in 101 normal individuals. However, the expression study showed that the transcriptional activities of TITF2 with reduced polyalanine-tract lengths were equal 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 human thyroid gland.

FOXE1 Polyalanine Tract Length Polymorphism in Patients with Thyroid Hemiagenesis and Subjects with Normal Thyroid

“…The length of FOXE1 -polyAla reported in this study varied from 12 to 18 alanines, compared to previous reports [8,10,11,12,13]where a total number of alanine coding triplets ranged from 11 to 19. Alanine expansion may lead to disturbances in protein conformation and potentially affect the process of transcription regulation by impairing specific binding to DNA.…”

“…Hence, in the study on a Japanese population by Hishinuma et al [10], 46 patients with TD were for the first time analyzed with regard to the length of FOXE1 -polyAla. Two of the patients had a heterozygous short variant of FOXE1 -polyAla, containing 11 and 12 alanine codons, which were not detected in any of the 101 control subjects with a normally developed thyroid gland.…”

“…Thus, it is still to be elucidated whether the same factors are responsible for the development of TH and other forms of TD. A few studies have pointed to the potential role of FOXE1 -polyAla length polymorphism in determining the susceptibility to TD [8,10,11,12,13]. However, the evaluation of its length in a large group of patients with TH has not been conducted so far.…”

Population Differences in the Polyalanine Domain and 6 New Mutations in HLXB9 in Patients with Currarino Syndrome

“…Although both pathologic and nonpathologic polyalanine polymorphisms for several genes have been found in the general population, there is little information regarding their distribution in different ethnic populations (8,(27)(28)(29)(30)(31). To our knowledge, ethnic differences in polyalanine polymorphism frequencies have been described only for the RPL14 and the MICA genes (27,28 ).…”

Familial non-medullary thyroid cancer: unraveling the genetic maze

“…The FOXE1 protein consists of a forkhead/winged helix DNA-binding domain and polyalanine (polyAla) tract, with a variable length ranging from 11 to 22 alanine (Ala) residues, with 14-Ala being the most frequently occurring allele of this gene in the population. This common length polymorphism could lead to a gain-of-function mutation (Macchia et al 1999, Hishinuma et al 2001, Carré et al 2007, Santarpia et al 2007, Szczepanek et al 2011, Bullock et al 2012.…”