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Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism

BACKGROUNDS: As a crucial enzyme in thyroid hormone synthesis, the genetic defective thyroid peroxidase (TPO) was one of the main genetic factors leading to congenital hypothyroidism (CH). METHODS: Mutations in the TPO gene were screened and identified in 219 patients with CH from northwest China by...

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Autores principales: Wang, Huijjuan, Wang, Wenxia, Chen, Xi, Shi, Hailong, Shi, Yinmin, Ding, Guifeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729100/
https://www.ncbi.nlm.nih.gov/pubmed/35002963
http://dx.doi.org/10.3389/fendo.2021.774941
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author Wang, Huijjuan
Wang, Wenxia
Chen, Xi
Shi, Hailong
Shi, Yinmin
Ding, Guifeng
author_facet Wang, Huijjuan
Wang, Wenxia
Chen, Xi
Shi, Hailong
Shi, Yinmin
Ding, Guifeng
author_sort Wang, Huijjuan
collection PubMed
description BACKGROUNDS: As a crucial enzyme in thyroid hormone synthesis, the genetic defective thyroid peroxidase (TPO) was one of the main genetic factors leading to congenital hypothyroidism (CH). METHODS: Mutations in the TPO 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 in vitro experiments and homology modeling. RESULTS: 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 TPO 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. CONCLUSION: This study was the first to analyze the TPO mutation spectrum of patients with CH in northwest China. Our data indicated that the TPO 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.
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spelling pubmed-87291002022-01-06 Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism Wang, Huijjuan Wang, Wenxia Chen, Xi Shi, Hailong Shi, Yinmin Ding, Guifeng Front Endocrinol (Lausanne) Endocrinology BACKGROUNDS: As a crucial enzyme in thyroid hormone synthesis, the genetic defective thyroid peroxidase (TPO) was one of the main genetic factors leading to congenital hypothyroidism (CH). METHODS: Mutations in the TPO 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 in vitro experiments and homology modeling. RESULTS: 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 TPO 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. CONCLUSION: This study was the first to analyze the TPO mutation spectrum of patients with CH in northwest China. Our data indicated that the TPO 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. Frontiers Media S.A. 2021-12-21 /pmc/articles/PMC8729100/ /pubmed/35002963 http://dx.doi.org/10.3389/fendo.2021.774941 Text en Copyright © 2021 Wang, Wang, Chen, Shi, Shi and Ding https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Wang, Huijjuan
Wang, Wenxia
Chen, Xi
Shi, Hailong
Shi, Yinmin
Ding, Guifeng
Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism
title Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism
title_full Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism
title_fullStr Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism
title_full_unstemmed Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism
title_short Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism
title_sort screening and functional analysis of tpo gene mutations in a cohort of chinese patients with congenital hypothyroidism
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729100/
https://www.ncbi.nlm.nih.gov/pubmed/35002963
http://dx.doi.org/10.3389/fendo.2021.774941
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