Umeki Kazumi, Kotani Tomio, Kawano Jun-ichi, Suganuma Tatsuo, Yamamoto Ikuo, Aratake Yatsuki, Furujo Mahoko, Ichiba Yozo
Laboratory for Clinical Investigation, Miyazaki Medical College, Kihara 5200, Kiyotake, Miyazaki 889-1692, Japan.
Eur J Endocrinol. 2002 Apr;146(4):491-8. doi: 10.1530/eje.0.1460491.
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.
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.
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.
甲状腺过氧化物酶（TPO）缺乏是甲状腺激素合成障碍的原因之一，因为TPO在甲状腺激素生物合成中起关键作用。为了确定TPO异常的频率和模式，我们一直在对先天性甲状腺肿性甲状腺功能减退症患者的TPO基因进行筛查。
对一名先天性甲状腺肿性甲状腺功能减退症患者及其父母的TPO基因进行直接测序，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高度保守。当将含有每个突变的mRNA转染到CHO-K1细胞中时，每个细胞都显示出微弱的TPO酶活性。然而，免疫荧光和免疫电子显微镜分析显示，两种突变的TPO均未到达质膜。
发现了TPO基因中的两个新的错义突变。由这些突变等位基因编码的TPO蛋白显示出异常的细胞定位；即，质膜上的定位受到干扰。突变的TPO质膜定位的丧失导致碘有机化缺陷，被诊断为先天性甲状腺功能减退症。
