Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
J Clin Endocrinol Metab. 2010 Apr;95(4):1981-5. doi: 10.1210/jc.2009-2373. Epub 2010 Feb 15.
Gene mutations of transcription factors that are predominantly expressed in the thyroid gland cause congenital hypothyroidism (CH). The prevalence of CH due to transcription factor mutations remains undetermined.
This study was designed to define the prevalence of CH due to mutations of PAX8, NKX2-1 [encoding thyroid transcription factor (TTF)-1], FOXE1 (encoding TTF-2), and NKX2-5 among patients with permanent primary CH and in the general population in Japan.
We enrolled 102 CH patients that represent 353,000 newborns born in Kanagawa prefecture from October 1979 to June 2006. We sequenced PAX8, NKX2-1, FOXE1, and NKX2-5 using PCR-based methods. Additionally, deletion/duplication of PAX8, NKX2-1, and FOXE1 was screened by multiplex ligation-dependent probe amplification. Molecular functions of putative mutations were verified in vitro.
We identified a novel small duplication of PAX8 (p.K80_A84dup) in two half-sibling patients with thyroid hypoplasia. We also found a novel NKX2-1 variation (p.H60W) in a sporadic nonsyndromic CH patient. In vitro experiments showed that K80_A84dup PAX8 had impaired transactivation of the thyroglobulin promoter. H60W TTF-1 exhibited a comparable transactivating capacity with wild-type TTF-1, suggesting a benign variation. We estimate the prevalence of PAX8 mutations to be 2.0% (two in 102) among Japanese CH patients and one in 176,000 (two in 353,000) in the general Japanese population.
Using a population-based sample, we confirmed that a minor subset of CH patients has transcription factor mutations, but they are rare. In our cohort, PAX8 mutations were the leading cause of such a rare condition.
主要在甲状腺中表达的转录因子的基因突变导致先天性甲状腺功能减退症（CH）。由于转录因子突变导致的 CH 的患病率仍未确定。
本研究旨在定义日本永久性原发性 CH 患者和普通人群中 PAX8、NKX2-1（编码甲状腺转录因子（TTF）-1）、FOXE1（编码 TTF-2）和 NKX2-5 基因突变导致的 CH 的患病率。
我们招募了 102 名 CH 患者，代表 1979 年 10 月至 2006 年 6 月期间在神奈川县出生的 353000 名新生儿。我们使用基于 PCR 的方法对 PAX8、NKX2-1、FOXE1 和 NKX2-5 进行测序。此外，通过多重连接依赖性探针扩增筛选 PAX8、NKX2-1 和 FOXE1 的缺失/重复。在体外验证了假定突变的分子功能。
我们在两名甲状腺发育不全的半同胞患者中发现了 PAX8 的新小重复（p.K80_A84dup）。我们还在一名散发的非综合征性 CH 患者中发现了一个新的 NKX2-1 变异（p.H60W）。体外实验表明，K80_A84dup PAX8 对甲状腺球蛋白启动子的转录激活受损。H60W TTF-1 与野生型 TTF-1 具有相当的转录激活能力，提示为良性变异。我们估计 PAX8 突变在日本 CH 患者中的患病率为 2.0%（102 例中有 2 例），在普通日本人群中的患病率为 1/176000（353000 例中有 2 例）。
使用基于人群的样本，我们证实了一小部分 CH 患者存在转录因子突变，但这些突变很少见。在我们的队列中，PAX8 突变是这种罕见疾病的主要原因。
