A Novel Homozygous Mutation of Thyroid Peroxidase Gene Abolishes a Disulfide Bond Leading to Congenital Hypothyroidism
A Novel Homozygous Mutation of Thyroid Peroxidase Gene Abolishes a Disulfide Bond Leading to Congenital Hypothyroidism
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甲状腺过氧化物酶基因的新型纯合突变消除了导致先天性甲状腺功能减退症的二硫键
DOI：
10.1155/2020/9132372
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发表时间：
2020
影响因子：
2.8
通讯作者：
Odawara Masato
中科院分区：
文献类型：
--
作者：
Yakou Fumiyoshi;Suwanai Hirotsugu;Ishikawa Takuya;Itou Mariko;Shikuma Jumpei;Miwa Takashi;Sakai Hiroyuki;Kanekura Kohsuke;Narumi Satoshi;Suzuki Ryo;Odawara Masato
先天性甲状腺功能减退症(CH)是最常见的先天性内分泌疾病，可导致智力低下。一名日本男性患者，父母是近亲，在10个月大时被诊断为先天性肝炎。他出生在大规模CH筛查之前。通过持续的甲状腺激素替代治疗，正常的甲状腺激素状态一直维持到成年。我们在52岁时进行了下一代测序的遗传筛查，我们发现了一个新的纯合性甲状腺过氧化物酶基因突变(GRCh38.p13，第2染色体1493997位，C.1964 G>；T，p.Cys655Phe)。TPO是一种产生甲状腺激素的重要酶。不同物种TPO蛋白的同源性分析表明，半胱氨酸655残基高度保守，在维持TPO的功能和结构中起着重要作用。对新突变的三维结构进行了电子计算机研究，结果表明该突变消除了598和655位半胱氨酸之间的二硫键。HEK293细胞体外功能分析表明，与野生型相比，突变体的TPO活性明显降低。此外，免疫组织化学研究表明，TPO在细胞中的定位在野生型和突变体之间没有差异。总之，TPO纯合突变p.Cys655Phe的这一单二硫键缺失突变降低了TPO活性，并导致先天性甲状腺功能减退，但不影响TPO蛋白的亚细胞定位。
Congenital hypothyroidism (CH) is the most prevalent congenital endocrine disorder and causes mental retardation. A male Japanese patient with first cousin marriage parents was diagnosed as CH at 10 months. He was born before introduction of mass screening for CH. With continuous thyroid hormone replacement therapy, normal thyroid hormone status was maintained until adulthood. Genetic screening of next‐generation sequencing was performed at the age of 52 years, and we identified a new homozygous thyroid peroxidase (TPO) gene mutation (GRCh38.p13, chromosome 2 at position 1493997, c.1964 G>T, p.Cys655Phe). TPO is an important enzyme to produce thyroid hormone. As demonstrated by a homology analysis of TPO proteins among different species, cysteine 655 residue is highly conserved, suggesting an important role in maintaining TPO function and structure. Anin silicostudy with three‐dimensional structure of the novel mutation was performed and suggested that the mutation abolished disulfide bond between cysteines at positions 598 and 655. Anin vitrofunctional analysis using HEK293 cells revealed that TPO activity of the mutant was significantly impaired compared with that of the wild type. Furthermore, study of immunohistochemistry showed that localization of TPO in cells did not differ between the wild type and the mutant. In conclusion, this single disulfide bond loss mutation of a new TPO homozygous mutation, p.Cys655Phe, reduced TPO activity and caused congenital hypothyroidism without affecting subcellular localization of TPO proteins.
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192 名中国先天性甲状腺功能减退症患者的 TPO 基因突变筛查。
影响因子：
2.9
作者：
Fu C;Xie B;Zhang S;Wang J;Luo S;Zheng H;Su J;Hu X;Chen R;Fan X;Luo J;Gu X;Chen S
通讯作者：
Chen S
由影响 DUOX2 的 NADPH 氧化酶结构域的复合杂合突变引起的暂时性先天性甲状腺功能减退症
影响因子：
1.4
作者：
Atsuko Yoshizawa;K. Abe;Sayaka Ogikubo;S. Narumi;T. Hasegawa;M. Satoh
通讯作者：
M. Satoh
新生儿筛查发现先天性甲状腺功能减退症患者的诊断及随访
DOI：
--
发表时间：
2019
期刊：
Anales de Pediatría (English Edition)
影响因子：
--
作者：
Amparo Rodríguez Sánchez;María Jesús Chueca Guindulain;M. A. Merillas;S. A. Segura;José Carlos Moreno Navarro;M. D. Arnao
通讯作者：
M. D. Arnao
影响因子：
7
作者：
McKenna, Aaron;Hanna, Matthew;DePristo, Mark A.
通讯作者：
DePristo, Mark A.
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。
影响因子：
5.8
作者：
K. Umeki;T. Kotani;J. Kawano;T. Suganuma;I. Yamamoto;Y. Aratake;M. Furujo;Y. Ichiba
通讯作者：
Y. Ichiba