Congenital hypothyroidism occurs in one of every three to four thousand newborns, owing to complete or partial failure of thyroid gland development1. Although thyroid hypoplasia has recently been associated with mutations in the thyrotropin (TSH) receptor2,3, 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 embryogenesis10. 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 atresia12 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.
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We thank M. Ferguson-Smith for the gift of the cosmid containing the FKHL15 genomic clone and D. Halsall for help in preparing this manuscript. R.C.-B. is a Commonwealth Scholar, J.W. is supported by an Elmore Studentship. This work was supported by the Wellcome Trust (V.K.K.C.) and the Medical Research Council (M.L.).
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