Clifton-Bligh R J, Wentworth J M, Heinz P, Crisp M S, John R, Lazarus J H, Ludgate M, Chatterjee V K
Department of Medicine, Level 5 Addenbrooke's Hospital, Cambridge, UK.
Nat Genet. 1998 Aug;19(4):399-401. doi: 10.1038/1294.
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.
先天性甲状腺功能减退症发生于每三千到四千名新生儿中的一名，是由于甲状腺发育完全或部分失败所致。尽管最近甲状腺发育不全与促甲状腺激素（TSH）受体突变有关，但甲状腺发育不全的原因尚不清楚。包括甲状腺转录因子1（TTF-1；参考文献4,5）、2（TTF-2；参考文献6,7）和Pax8（参考文献8,9）在内的蛋白质在发育中的小鼠甲状腺中含量丰富，并且已知它们可调节甲状腺分化过程中表达的基因（例如，甲状腺过氧化物酶和甲状腺球蛋白基因）。TTF-2是叉头/翼状螺旋结构域转录因子家族的成员，其中许多是胚胎发生的关键调节因子。在此我们报告，转录因子FKHL15（参考文献11）是小鼠TTF-2（由Titf2基因编码）的人类同源物，并且两名患有甲状腺发育不全、腭裂和后鼻孔闭锁的同胞在其叉头结构域内存在错义突变（Ala65Val）的纯合子。突变蛋白表现出DNA结合受损和转录功能丧失。我们的观察结果首次描述了甲状腺发育不全的遗传原因。
