A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate
A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate
复制标题
DOI：
10.1093/hmg/11.17.2051
复制
发表时间：
2002-08-15
影响因子：
3.5
通讯作者：
Polak, M
中科院分区：
文献类型：
--
作者：
Castanet, M;Park, SM;Polak, M
甲状腺发育不良是先天性甲状腺功能减退症(CH)最常见的原因，其遗传基础很大程度上是未知的。在这里，我们描述了TTF-2(或FOXE1)的第二个纯合错义突变，TTF-2(或FOXE1)是一种与甲状腺发育有关的转录因子。两个近亲父母所生的男性兄弟姐妹，表现为CH，甲状旁腺功能不全和腭裂，发现TTF-2叉头DNA结合区57(S57N)密码子上的丝氨酸到天冬酰胺替换对应的突变是纯合子。他们的杂合子父母没有受到影响，在31例无关的甲状旁腺功能亢进症病例或正常对照组中没有发现这种突变。与其定位一致，S57N TTF-2突变蛋白显示DNA结合受损和部分转录功能丧失。这种TTF-2功能的不完全丧失可能是我们的患者没有后鼻孔闭锁和会厌裂的原因，在另外两个人中，伴随着CH和腭裂而出现的异常，以及前面描述的唯一另一个更有害的TTF-2突变(A65V)。我们的观察支持TTF-2在甲状腺和腭部发育中的作用，但提示这种综合征形式的CH具有表型异质性。
Thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH) and its genetic basis is largely unknown. Here, we describe the second homozygous missense mutation in TTF-2 (or FOXE1), a transcription factor that has been implicated in thyroid development. Two male siblings, born to consanguineous parents, presented with CH, athyreosis and cleft palate and were found to be homozygous for a mutation corresponding to a serine to asparagine substitution at codon 57 (S57N) in the forkhead DNA binding domain of TTF-2. Their heterozygous parents were unaffected and this mutation was not found in 31 unrelated cases of athyreosis or normal controls. Consistent with its location, the S57N TTF-2 mutant protein showed impaired DNA binding and partial loss of transcriptional function. Such incomplete loss of TTF-2 function may account for the absence of choanal atresia and bifid epiglottis in our patients, anomalies which were present together with CH and cleft palate in two other individuals with the only other, more deleterious, TTF-2 mutation (A65V) described previously. Our observations support the role of TTF-2 in both thyroid and palate development but suggest phenotypic heterogeneity of this syndromic form of CH.