Transcription Factor Mutations and Congenital Hypothyroidism: Systematic Genetic Screening of a Population-Based Cohort of Japanese Patients
Transcription Factor Mutations and Congenital Hypothyroidism: Systematic Genetic Screening of a Population-Based Cohort of Japanese Patients
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DOI：
10.1210/jc.2009-2373
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发表时间：
2010-04-01
影响因子：
5.8
通讯作者：
Hasegawa, Tomonobu
中科院分区：
文献类型：
--
作者：
Narumi, Satoshi;Muroya, Koji;Hasegawa, Tomonobu
背景：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）。目的：本研究旨在确定由于PAX 8、NKX 2 -1 [编码甲状腺转录因子（TTF）-1]、FOXE 1（编码TTF-2）和NKX 2 -5在日本的永久性原发CH患者和一般人群中的表达。我们招募了102名CH患者，代表1979年10月至2006年6月在神奈川县出生的353，000名新生儿。我们使用基于PCR的方法对PAX 8、NKX 2 -1、FOXE 1和NKX 2 -5进行测序。此外，通过多重连接依赖性探针扩增筛选PAX 8、NKX 2 -1和FOXE 1的缺失/重复。结果：我们在两个同父异母的甲状腺发育不良患者中发现了一个新的PAX 8小重复序列（p.K80_A84dup）。我们还发现了一个新的NKX 2 -1变异（p.H60W）在散发性非综合征CH患者。体外实验表明，K80_A84dup PAX 8对甲状腺球蛋白启动子的反式激活有损害。H60 W TTF-1表现出与野生型TTF-1相当的反式激活能力，表明是良性变异。我们估计PAX 8突变的患病率为2.0%（两个在102）在日本CH患者和一个在176，000（两个在353，000）在一般Japanese population.Conclusions：使用一个基于人群的样本，我们证实，一个小的子集CH患者有转录因子突变，但他们是罕见的。在我们的队列中，PAX 8突变是这种罕见疾病的主要原因。（临床内分泌代谢杂志95：1981-1985，2010）
Context: 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.Objective: 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.Subjects and Methods: 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.Results: 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.Conclusions: 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. (J Clin Endocrinol Metab 95: 1981-1985, 2010)