The National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an, China.
Pediatrics, Urumqi Maternal and Child Health Care Hospital, Urumqi, China.
Front Endocrinol (Lausanne). 2021 Dec 21;12:774941. doi: 10.3389/fendo.2021.774941. eCollection 2021.
As a crucial enzyme in thyroid hormone synthesis, the genetic defective thyroid peroxidase () was one of the main genetic factors leading to congenital hypothyroidism (CH).
Mutations in the gene were screened and identified in 219 patients with CH from northwest China by using high-throughput sequencing and bioinformatics analysis. The biological function of detected variants was studied by experiments and homology modeling.
Nineteen rare variants, including seven novel ones, were detected in 17 of 219 patients (7.8%). Most cases were detected with one single heterozygous variant, and only two patients were detected with multiple variants, i.e., compounds for (1) IVS7-1G>A, p.Ala443Val, and p.Arg769Trp and (2) p.Asn592Ser and p.Asn798Lys. The biological function of the four missense mutations (i.e., p.Ala443Val, p.Arg769Trp, p.Asn592Ser, and p.Asn798Lys) they carried were further studied. Experimental data showed that these four mutations did not affect the protein expression level of the gene but remarkably reduced the peroxidase activity toward guaiacol oxidation, retaining 8-32% of activity of the wild-type protein. The comparison of the predicted 3-D structures of wild-type and mutant TPO proteins showed that these four amino acid substitutions changed the non-covalent interactions of studied residues that might alter the structure and function of the TPO protein.
This study was the first to analyze the mutation spectrum of patients with CH in northwest China. Our data indicated that the mutation was not a common reason to cause CH in China. The functional data may help to clarify the structure-function relationship of the TPO protein and provide further evidence for the elucidation of the genetic etiology of CH.
甲状腺过氧化物酶（）作为甲状腺激素合成的关键酶，是导致先天性甲状腺功能减退症（CH）的主要遗传因素之一。
采用高通量测序和生物信息学分析，对来自中国西北地区的 219 例 CH 患者进行基因筛查和鉴定。通过实验和同源建模研究检测到的变异体的生物学功能。
在 219 例患者中发现了 19 种罕见变异，包括 7 种新变异，其中 17 例患者（7.8%）存在基因突变。大多数病例仅检测到一种单杂合变异，仅 2 例患者检测到多种变异，即（1）IVS7-1G>A、p.Ala443Val 和 p.Arg769Trp 以及（2）p.Asn592Ser 和 p.Asn798Lys 的复合变异。进一步研究了他们携带的四个错义突变（即 p.Ala443Val、p.Arg769Trp、p.Asn592Ser 和 p.Asn798Lys）的生物学功能。实验数据表明，这四个突变并未影响基因的蛋白表达水平，但明显降低了对愈创木酚氧化的过氧化物酶活性，保留了野生型蛋白 8-32%的活性。野生型和突变型 TPO 蛋白的预测 3D 结构比较表明，这四个氨基酸取代改变了研究残基的非共价相互作用，可能改变 TPO 蛋白的结构和功能。
本研究首次分析了中国西北地区 CH 患者的基因突变谱。我们的数据表明，突变不是导致中国 CH 的常见原因。功能数据可能有助于阐明 TPO 蛋白的结构-功能关系，并为阐明 CH 的遗传病因提供进一步证据。
