Functional Characterization of Thyroid Peroxidase Missense Variants Causing Thyroid Dyshormonogenesis in Asian Indian Population.

IF 2.6 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM
Asodu Sandeep Sarma, Ankush Desai, Madhava Rao, Jaya Prakash Sahoo, Channabasappa Shivaprasad, Prajnya Ranganath, Pragna Lakshmi, Lorraine D'Sa, Ashwin Dalal
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引用次数: 0

Abstract

Introduction: Thyroid dyshormonogenesis (TDH) is a subgroup of congenital hypothyroidism with recessive inheritance resulting from disease-causing variants in thyroid hormone biosynthesis pathway genes, like DUOX2, TG, TPO, SLC5A5, SLC26A4, IYD, DUOXA2, and SLC26A7. Thyroid peroxidase (TPO) is a crucial enzyme involved in thyroid hormone biosynthesis and is one of the frequently mutated genes in patients with TDH. The purpose of the study was to describe the in silico and functional characterization of novel variants in TPO gene identified in patients with TDH.

Methods: We performed exome sequencing in Indian patients with TDH. In the current study, we describe the results of patients with TPO gene mutations. Exome sequencing results were further analysed by Sanger sequencing, computational studies, and in vitro functional studies such as immunofluorescence and enzyme assay.

Results: We identified nine biallelic disease-causing variants in the TPO gene in 12 patients from nine unrelated Indian families. Eight of the nine variants were novel. No recurrent variants were identified. Computational analysis of six missense variants showed that these amino acid substitutions caused changes in non-covalent interactions with the adjacent residues that may affect the TPO protein structure and function. In vitro experimental data using immunofluorescence assay showed that these variants did not affect the plasma membrane localization of the TPO protein but caused a significant loss of TPO enzymatic activity compared to the wild type.

Conclusion: Our study revealed multiple novel pathogenic variants in TPO gene in Indian patients, thereby expanding the genotype spectrum. Functional studies helped us to reveal the pathogenicity of the missense variants.

导致亚洲印度人群甲状腺激素生成障碍的甲状腺过氧化物酶错义变体的功能特征。
简介甲状腺激素生成障碍(TDH)是先天性甲状腺功能减退症的一个亚型,具有隐性遗传性,是由甲状腺激素生物合成途径基因(如DUOX2、TG、TPO、SLC5A5、SLC26A4、IYD、DUOXA2、SLC26A7和SECISBP2)中的致病变异引起的。甲状腺过氧化物酶(TPO)是参与甲状腺激素生物合成的一种重要酶,也是 TDH 患者的常见突变基因之一。本研究的目的是描述在甲状腺激素生成障碍患者中发现的 TPO 基因新型变异的分子内和功能特征:我们对印度 TDH 患者进行了外显子组测序。在本研究中,我们描述了 TPO 基因突变患者的结果。外显子组测序结果通过桑格测序、计算研究以及免疫荧光和酶测定等体外功能研究进行了进一步分析:结果:我们在来自 9 个无血缘关系的印度家庭的 12 名患者中发现了 TPO 基因中的 9 个双拷贝致病变异。九个变体中有八个是新变体。没有发现复发性变异。对六个错义变异的计算分析表明,这些氨基酸置换导致与相邻残基的非共价相互作用发生变化,从而可能影响 TPO 蛋白的结构和功能。利用免疫荧光法进行的体外实验数据显示,与野生型相比,这些变体不会影响TPO蛋白的质膜定位,但会导致TPO酶活性显著下降:我们的研究揭示了印度患者 TPO 基因中的多种新型致病变异,从而扩大了基因型谱。功能研究帮助我们揭示了错义变体的致病性。
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来源期刊
Hormone Research in Paediatrics
Hormone Research in Paediatrics ENDOCRINOLOGY & METABOLISM-PEDIATRICS
CiteScore
4.90
自引率
6.20%
发文量
88
审稿时长
4-8 weeks
期刊介绍: The mission of ''Hormone Research in Paediatrics'' is to improve the care of children with endocrine disorders by promoting basic and clinical knowledge. The journal facilitates the dissemination of information through original papers, mini reviews, clinical guidelines and papers on novel insights from clinical practice. Periodic editorials from outstanding paediatric endocrinologists address the main published novelties by critically reviewing the major strengths and weaknesses of the studies.
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