Cargando…

Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients

The disorder of thyroid gland development or thyroid dysgenesis accounts for 80–85% of congenital hypothyroidism (CH) cases. Mutations in the TSHR gene are mostly associated with thyroid dysgenesis, and prevent or disrupt normal development of the gland. There is limited data available on the geneti...

Descripción completa

Detalles Bibliográficos
Autores principales: Begum, Mst. Noorjahan, Mahtarin, Rumana, Islam, Md. Tarikul, Ahmed, Sinthyia, Konika, Tasnia Kawsar, Mannoor, Kaiissar, Akhteruzzaman, Sharif, Qadri, Firdausi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10414570/
https://www.ncbi.nlm.nih.gov/pubmed/37561783
http://dx.doi.org/10.1371/journal.pone.0282553
_version_ 1785087367556628480
author Begum, Mst. Noorjahan
Mahtarin, Rumana
Islam, Md. Tarikul
Ahmed, Sinthyia
Konika, Tasnia Kawsar
Mannoor, Kaiissar
Akhteruzzaman, Sharif
Qadri, Firdausi
author_facet Begum, Mst. Noorjahan
Mahtarin, Rumana
Islam, Md. Tarikul
Ahmed, Sinthyia
Konika, Tasnia Kawsar
Mannoor, Kaiissar
Akhteruzzaman, Sharif
Qadri, Firdausi
author_sort Begum, Mst. Noorjahan
collection PubMed
description The disorder of thyroid gland development or thyroid dysgenesis accounts for 80–85% of congenital hypothyroidism (CH) cases. Mutations in the TSHR gene are mostly associated with thyroid dysgenesis, and prevent or disrupt normal development of the gland. There is limited data available on the genetic spectrum of congenital hypothyroid children in Bangladesh. Thus, an understanding of the molecular aetiology of thyroid dysgenesis is a prerequisite. The aim of the study was to investigate the effect of mutations in the TSHR gene on the small molecule thyrogenic drug-binding site of the protein. We identified two nonsynonymous mutations (p.Ser508Leu, p.Glu727Asp) in the exon 10 of the TSHR gene in 21 patients with dysgenesis by sequencing-based analysis. Later, the TSHR(368-764) protein was modeled by the I-TASSER server for wild-type and mutant structures. The model proteins were targeted by thyrogenic drugs, MS437 and MS438 to perceive the effect of mutations. The damaging effect in drug-protein complexes of mutants was explored by molecular docking and molecular dynamics simulations. The binding affinity of wild-type protein was much higher than the mutant cases for both of the drug ligands (MS437 and MS438). Molecular dynamics simulates the dynamic behavior of wild-type and mutant complexes. MS437-TSHR(368-764)MT2 and MS438-TSHR(368-764)MT1 showed stable conformations in biological environments. Finally, Principle Component Analysis revealed structural and energy profile discrepancies. TSHR(368-764)MT1 exhibited much more variations than TSHR(368-764)WT and TSHR(368-764)MT2, emphasizing a more damaging pattern in TSHR(368-764)MT1. This genetic study might be helpful to explore the mutational impact on drug binding sites of TSHR protein which is important for future drug design and selection for the treatment of congenital hypothyroid children with dysgenesis.
format Online
Article
Text
id pubmed-10414570
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-104145702023-08-11 Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients Begum, Mst. Noorjahan Mahtarin, Rumana Islam, Md. Tarikul Ahmed, Sinthyia Konika, Tasnia Kawsar Mannoor, Kaiissar Akhteruzzaman, Sharif Qadri, Firdausi PLoS One Research Article The disorder of thyroid gland development or thyroid dysgenesis accounts for 80–85% of congenital hypothyroidism (CH) cases. Mutations in the TSHR gene are mostly associated with thyroid dysgenesis, and prevent or disrupt normal development of the gland. There is limited data available on the genetic spectrum of congenital hypothyroid children in Bangladesh. Thus, an understanding of the molecular aetiology of thyroid dysgenesis is a prerequisite. The aim of the study was to investigate the effect of mutations in the TSHR gene on the small molecule thyrogenic drug-binding site of the protein. We identified two nonsynonymous mutations (p.Ser508Leu, p.Glu727Asp) in the exon 10 of the TSHR gene in 21 patients with dysgenesis by sequencing-based analysis. Later, the TSHR(368-764) protein was modeled by the I-TASSER server for wild-type and mutant structures. The model proteins were targeted by thyrogenic drugs, MS437 and MS438 to perceive the effect of mutations. The damaging effect in drug-protein complexes of mutants was explored by molecular docking and molecular dynamics simulations. The binding affinity of wild-type protein was much higher than the mutant cases for both of the drug ligands (MS437 and MS438). Molecular dynamics simulates the dynamic behavior of wild-type and mutant complexes. MS437-TSHR(368-764)MT2 and MS438-TSHR(368-764)MT1 showed stable conformations in biological environments. Finally, Principle Component Analysis revealed structural and energy profile discrepancies. TSHR(368-764)MT1 exhibited much more variations than TSHR(368-764)WT and TSHR(368-764)MT2, emphasizing a more damaging pattern in TSHR(368-764)MT1. This genetic study might be helpful to explore the mutational impact on drug binding sites of TSHR protein which is important for future drug design and selection for the treatment of congenital hypothyroid children with dysgenesis. Public Library of Science 2023-08-10 /pmc/articles/PMC10414570/ /pubmed/37561783 http://dx.doi.org/10.1371/journal.pone.0282553 Text en © 2023 Begum et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Begum, Mst. Noorjahan
Mahtarin, Rumana
Islam, Md. Tarikul
Ahmed, Sinthyia
Konika, Tasnia Kawsar
Mannoor, Kaiissar
Akhteruzzaman, Sharif
Qadri, Firdausi
Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients
title Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients
title_full Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients
title_fullStr Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients
title_full_unstemmed Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients
title_short Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients
title_sort molecular investigation of tshr gene in bangladeshi congenital hypothyroid patients
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10414570/
https://www.ncbi.nlm.nih.gov/pubmed/37561783
http://dx.doi.org/10.1371/journal.pone.0282553
work_keys_str_mv AT begummstnoorjahan molecularinvestigationoftshrgeneinbangladeshicongenitalhypothyroidpatients
AT mahtarinrumana molecularinvestigationoftshrgeneinbangladeshicongenitalhypothyroidpatients
AT islammdtarikul molecularinvestigationoftshrgeneinbangladeshicongenitalhypothyroidpatients
AT ahmedsinthyia molecularinvestigationoftshrgeneinbangladeshicongenitalhypothyroidpatients
AT konikatasniakawsar molecularinvestigationoftshrgeneinbangladeshicongenitalhypothyroidpatients
AT mannoorkaiissar molecularinvestigationoftshrgeneinbangladeshicongenitalhypothyroidpatients
AT akhteruzzamansharif molecularinvestigationoftshrgeneinbangladeshicongenitalhypothyroidpatients
AT qadrifirdausi molecularinvestigationoftshrgeneinbangladeshicongenitalhypothyroidpatients