Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia

Abstract

Congenital hypothyroidism occurs in one of every three to four thousand newborns, owing to complete or partial failure of thyroid gland development. Although thyroid hypoplasia has recently been associated with mutations in the thyrotropin (TSH) receptor, the cause of thyroid agenesis is unknown. Proteins including thyroid transcription factors 1 (TTF-1; refs 4,5) and 2 (TTF-2; refs 6,7) and Pax8 (refs 8,9) are abundant in the developing mouse thyroid and are known to regulate genes expressed during its differentiation (for example, thyroid peroxidase and thyroglobulin genes). TTF-2 is a member of the forkhead/winged-helix domain transcription factor family, many of which are key regulators of embryogenesis. Here we report that the transcription factor FKHL15 (ref. 11) is the human homologue of mouse TTF-2 (encoded by the Titf2 gene) and that two siblings with thyroid agenesis, cleft palate and choanal atresia are homozygous for a missense mutation (Ala65Val) within its forkhead domain. The mutant protein exhibits impaired DNA binding and loss of transcriptional function. Our observations represent the first description of a genetic cause for thyroid agenesis.

Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair

“…The phenotype of patients affected by Bamforth syndrome, that includes atresia of choanae and spiky hair (Clifton-Bligh et al, 1998), is consistent with the expression pattern of TTF-2 in choanae and hair follicles. The same phenotype was not reported in the titf2 null mice.…”

“…Gene targeting experiments have demonstrated that titf2/foxe1 null mice exhibit cleft palate and either a sublingual or completely absent thyroid gland (De Felice et al, 1998). In humans, mutations of the gene encoding for TTF-2 result in the Bamforth syndrome, characterized by thyroid agenesis, cleft palate, spiky hair, and choanal atresia (Clifton-Bligh et al, 1998).…”

Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms

“…23 The importance of these three transcription factors is evidenced by congenital thyroid agenesis, which results from mutations in any of the transcription factors. [26][27][28][29][30][31][32] We found consistent nuclear expressions of Pax8, TTF-1, and TTF-2 in well-differentiated neoplasms of follicular cell origin, that is, papillary carcinomas, follicular adenomas, follicular carcinomas, and poorly differentiated carcinomas. Seventy-nine percent of anaplastic carcinomas variably showed Pax8 reaction, whereas TTF-1 and TTF2 were expressed in only 18 and 7% of anaplastic carcinomas, respectively.…”

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

“…PAX8-NKX2-1 cotransfection experiments were performed with 130 ng of PAX8 [Vilain et al, 2001] and 130 ng of NKX2-1. Transfection efficiency was normalized with 150 ng of plasmid Bosβ-gal [Clifton-Bligh et al, 1998]. After 48 hours, the cells were harvested, and luciferase (Firefly and Renilla) and β-gal assays were performed.…”