MUTATION OF THE GENE ENCODING HUMAN TTF-2 ASSOCIATED WITH THYROID AGENESIS, CLEFT-PALATE AND CHOANAL ATRESIA

Congenital hypothyroidism occurs in one of every three to four thousan d newborns, owing to complete or partial failure of thyroid gland deve lopment(1). Although thyroid hypoplasia has recently been associated w ith mutations in the thyrotropin (TSH) receptor(2,3), the cause of thy roid agenesis is unknown. Proteins including thyroid transcription fac tors 1 (TTF-l; refs 4,5) and 2 (TTF-2; refs 6,7) and Pax8 (refs 8,9) a re abundant in the developing mouse thyroid and are known to regulate genes expressed during its differentiation (for example, thyroid perox idase and thyroglobulin genes). TTF-2 is a member of the forkhead/wing ed-helix domain transcription factor family, many of which are key reg ulators of embryogenesis(10). Here we report that the transcription fa ctor FKHL15 (ref. 11) is the human homologue of mouse TTF-2 (encoded b y the Titf2 gene) and that two siblings with thyroid agenesis, cleft p alate and choanal atresia(12) are homozygous for a missense mutation ( Ala65Val) within its forkhead domain. The mutant protein exhibits impa ired DNA binding and loss of transcriptional function. Our observation s represent the first description of a genetic cause for thyroid agene sis.