Two novel missense mutations in the thyroid peroxidase gene, R665W and G771R, result in a localization defect and cause congenital hypothyroidism.
Two novel missense mutations in the thyroid peroxidase gene, R665W and G771R, result in a localization defect and cause congenital hypothyroidism.
复制标题
甲状腺过氧化物酶基因 R665W 和 G771R 中的两个新错义突变导致定位缺陷并导致先天性甲状腺功能减退症。
DOI：
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复制
发表时间：
2002
影响因子：
5.8
通讯作者：
Y. Ichiba
中科院分区：
文献类型：
--
作者：
K. Umeki;T. Kotani;J. Kawano;T. Suganuma;I. Yamamoto;Y. Aratake;M. Furujo;Y. Ichiba
客观化
甲状腺过氧化物酶(TPO)缺乏是导致甲状腺功能紊乱的原因之一，因为TPO在甲状腺激素的生物合成中起着关键作用。为了确定TPO异常的频率和模式，我们一直在筛查先天性甲状腺功能减退症患者的TPO基因。
研究对象和方法
对1例先天性甲状腺功能减退症患者及其父母的TPO基因进行了直接测序，发现了两个新的错义突变(R665W和G771R)。前者来自她的父亲，后者来自她的母亲。R665和G771在过氧化物酶超家族中保守。当含有每个突变的mRNAs被导入CHO-K1细胞时，每个细胞都表现出微弱的TPO酶活性。然而，免疫荧光和免疫电子显微镜分析表明，突变的两种TPO均未到达质膜。
结论
在TPO基因中发现两个新的错义突变。这些突变的等位基因编码的TPO蛋白显示出异常的细胞定位，即质膜上的定位受到干扰。突变型TPO的质膜定位缺失导致碘有机化缺陷，诊断为先天性甲状腺功能减退症。
OBJECTIVE
Thyroid peroxidase (TPO) deficiency is one of the causes of thyroid dyshormonogenesis, because TPO plays a key role in thyroid hormone biosynthesis. To determine the frequency and pattern of TPO abnormalities, we have been screening TPO genes of patients with congenital goitrous hypothyroidism.
SUBJECTS AND METHODS
TPO genes of a patient with congenital goitrous hypothyroidism and her parents were directly sequenced, and two novel missense mutations (R665W and G771R) were found. The former was derived from her father and the latter from her mother. R665 and G771 were well conserved in the peroxidase superfamily. When mRNAs containing each of the mutations were transfected into CHO-K1 cells, each cell showed faint TPO enzyme activity. However, immunofluorescence and immunoelectron microscopic analyses revealed that neither of the mutated TPOs reached the plasma membrane.
CONCLUSIONS
Two novel missense mutations in the TPO gene were found. TPO proteins encoded by these mutated alleles showed abnormal cellular localization; namely, localization on the plasma membrane was disturbed. The loss of plasma membrane localization in mutated TPOs brought about the iodide organification defect, which was diagnosed as congenital hypothyroidism.
DOI：
10.1210/jcem.84.3.5541
发表时间：
1999-03
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
Silvana Pannain;R. E. Weiss;Charles E. Jackson;Donald Dian;John S. Beck;V. C. Sheffield;Nancy J. Cox;Samuel Refetoff
通讯作者：
Silvana Pannain;R. E. Weiss;Charles E. Jackson;Donald Dian;John S. Beck;V. C. Sheffield;Nancy J. Cox;Samuel Refetoff
影响因子：
15.9
作者：
MedeirosNeto, G;Kim, PS;Arvan, P
通讯作者：
Arvan, P