Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1784626869485699072 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8729100 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT wanghuijjuan screeningandfunctionalanalysisoftpogenemutationsinacohortofchinesepatientswithcongenitalhypothyroidism AT wangwenxia screeningandfunctionalanalysisoftpogenemutationsinacohortofchinesepatientswithcongenitalhypothyroidism AT chenxi screeningandfunctionalanalysisoftpogenemutationsinacohortofchinesepatientswithcongenitalhypothyroidism AT shihailong screeningandfunctionalanalysisoftpogenemutationsinacohortofchinesepatientswithcongenitalhypothyroidism AT shiyinmin screeningandfunctionalanalysisoftpogenemutationsinacohortofchinesepatientswithcongenitalhypothyroidism AT dingguifeng screeningandfunctionalanalysisoftpogenemutationsinacohortofchinesepatientswithcongenitalhypothyroidism |