TSHR Mutations as a Cause of Congenital Hypothyroidism in Japan: A Population-Based Genetic Epidemiology Study
TSHR Mutations as a Cause of Congenital Hypothyroidism in Japan: A Population-Based Genetic Epidemiology Study
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DOI：
10.1210/jc.2008-1767
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发表时间：
2009-04-01
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：与TSH受体基因（TSHR）突变相关的先天性甲状腺功能减退症（CH）的患病率尚未确定。目的：我们研究了日本永久性原发性CH患者和普通人群中TSHR突变的频率。研究对象和方法：我们从1979年10月至2006年6月在神奈川县出生的35.3万名新生儿中通过新生儿筛查发现102例永久性原发性CH患者[70例为“中重度CH”（TSH, >= 10 mU/l）， 32例为“轻度CH”（TSH, 5-10 mU/l）]。通过基于pcr的直接测序对这些受试者进行TSHR突变检测。我们进一步在体外鉴定了已鉴定的突变TSHRs的分子功能。结果：我们发现3例中重度CH患者TSHR中存在双等位基因突变，3例轻度CH患者TSHR中存在单等位基因突变。观察到的突变包括一个先前表征的突变（p.R450H）和三个未表征的突变（p.G132R、p.A204V和p.D403N）。体外实验证实了这四种突变体的功能丧失。在四个突变中，p.R450H尤为常见：9个突变等位基因中有6个携带p.R450H。所有6个带有p.R450H的等位基因通常携带少量的单核苷酸多态性，提示奠基人效应。我们估计，在日本中重度CH患者中，双等位基因TSHR突变的患病率为4.3%（70人中有3人），而在日本普通人群中，双等位基因TSHR突变的患病率为118,000人中有1人（35.3万人中有3人）。结论：在日本，TSHR突变在CH患者中较为常见，其中创始突变（p.R450H）约占突变体的70%。[J] .中华内分泌杂志，2009,31(5):557 - 557。
Context: The prevalence of congenital hypothyroidism (CH) associated with mutations in the TSH receptor gene (TSHR) has not been established.Objective: We examined the frequency of TSHR mutations among patients with permanent primary CH and in the general population in Japan.Subjects and Methods: We enrolled 102 patients with permanent primary CH [70 with "moderate to severe CH" (TSH, >= 10 mU/liter) and 32 with "mild CH" (TSH, 5-10 mU/liter)], who were identified through newborn screening among 353,000 newborns born in Kanagawa prefecture from October 1979 to June 2006. These subjects were tested for TSHR mutations by PCR-based direct sequencing. We further characterized molecular functions of identified mutant TSHRs in vitro.Results: We found three patients with moderate to severe CH who had biallelic mutations in TSHR and three patients with mild CH who had monoallelic mutations. Observed mutations included one previously characterized mutation (p.R450H) and three uncharacterized mutations (p.G132R, p.A204V, and p.D403N). In vitro experiments confirmed loss of functions of these four mutants. Among four mutations, p.R450H was particularly frequent: six of nine mutant alleles harbored p.R450H. All six alleles with p.R450H commonly carried a minor single nucleotide polymorphism, suggesting a founder effect. We estimated the prevalence of biallelic TSHR mutations to be 4.3% (three in 70) in Japanese patients with moderate to severe CH, and 1 in 118,000 (three in 353,000) in the general Japanese population.Conclusions: In Japan, TSHR mutations are relatively common among patients with CH, and a founder mutation (p.R450H) accounts for about 70% of mutants. (J Clin Endocrinol Metab 94: 1317-1323, 2009)