Cargando…
A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2
The nuclear thyroid hormone receptors (THRs) are key mediators of thyroid hormone function on the cellular level via modulation of gene expression. Two different genes encode THRs (THRA and THRB), and are pleiotropically involved in development, metabolism, and growth. The THRA1 and THRA2 isoforms,...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159125/ https://www.ncbi.nlm.nih.gov/pubmed/34069457 http://dx.doi.org/10.3390/ijms22105338 |
_version_ | 1783700015645982720 |
---|---|
author | Paisdzior, Sarah Knierim, Ellen Kleinau, Gunnar Biebermann, Heike Krude, Heiko Straussberg, Rachel Schuelke, Markus |
author_facet | Paisdzior, Sarah Knierim, Ellen Kleinau, Gunnar Biebermann, Heike Krude, Heiko Straussberg, Rachel Schuelke, Markus |
author_sort | Paisdzior, Sarah |
collection | PubMed |
description | The nuclear thyroid hormone receptors (THRs) are key mediators of thyroid hormone function on the cellular level via modulation of gene expression. Two different genes encode THRs (THRA and THRB), and are pleiotropically involved in development, metabolism, and growth. The THRA1 and THRA2 isoforms, which result from alternative splicing of THRA, differ in their C-terminal ligand-binding domain (LBD). Most published disease-associated THRA variants are located in the LBD of THRA1 and impede triiodothyronine (T3) binding. This keeps the nuclear receptor in an inactive state and inhibits target gene expression. Here, we investigated a new dominant THRA variant (chr17:g.38,241,010A > G, GRCh37.13 | c.518A > G, NM_199334 | p.(E173G), NP_955366), which is located between the DNA- and ligand-binding domains and affects both splicing isoforms. Patients presented partially with hypothyroid (intellectual disability, motor developmental delay, brain atrophy, and constipation) and partially with hyperthyroid symptoms (tachycardia and behavioral abnormalities) to varying degrees. Functional characterization of THRA1p.(E173G) by reporter gene assays revealed increased transcriptional activity in contrast to THRA1(WT), unexpectedly revealing the first gain-of-function mutation found in THRA1. The THRA2 isoform does not bind T3 and antagonizes THRA1 action. Introduction of p.(E173G) into THRA2 increased its inhibitory effect on THRA1, which helps to explain the hypothyroid symptoms seen in our patients. We used protein structure models to investigate possible underlying pathomechanisms of this variant with a gain-of-antagonistic function and suggest that the p.(E173G) variant may have an influence on the dimerization domain of the nuclear receptor. |
format | Online Article Text |
id | pubmed-8159125 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81591252021-05-28 A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2 Paisdzior, Sarah Knierim, Ellen Kleinau, Gunnar Biebermann, Heike Krude, Heiko Straussberg, Rachel Schuelke, Markus Int J Mol Sci Article The nuclear thyroid hormone receptors (THRs) are key mediators of thyroid hormone function on the cellular level via modulation of gene expression. Two different genes encode THRs (THRA and THRB), and are pleiotropically involved in development, metabolism, and growth. The THRA1 and THRA2 isoforms, which result from alternative splicing of THRA, differ in their C-terminal ligand-binding domain (LBD). Most published disease-associated THRA variants are located in the LBD of THRA1 and impede triiodothyronine (T3) binding. This keeps the nuclear receptor in an inactive state and inhibits target gene expression. Here, we investigated a new dominant THRA variant (chr17:g.38,241,010A > G, GRCh37.13 | c.518A > G, NM_199334 | p.(E173G), NP_955366), which is located between the DNA- and ligand-binding domains and affects both splicing isoforms. Patients presented partially with hypothyroid (intellectual disability, motor developmental delay, brain atrophy, and constipation) and partially with hyperthyroid symptoms (tachycardia and behavioral abnormalities) to varying degrees. Functional characterization of THRA1p.(E173G) by reporter gene assays revealed increased transcriptional activity in contrast to THRA1(WT), unexpectedly revealing the first gain-of-function mutation found in THRA1. The THRA2 isoform does not bind T3 and antagonizes THRA1 action. Introduction of p.(E173G) into THRA2 increased its inhibitory effect on THRA1, which helps to explain the hypothyroid symptoms seen in our patients. We used protein structure models to investigate possible underlying pathomechanisms of this variant with a gain-of-antagonistic function and suggest that the p.(E173G) variant may have an influence on the dimerization domain of the nuclear receptor. MDPI 2021-05-19 /pmc/articles/PMC8159125/ /pubmed/34069457 http://dx.doi.org/10.3390/ijms22105338 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Paisdzior, Sarah Knierim, Ellen Kleinau, Gunnar Biebermann, Heike Krude, Heiko Straussberg, Rachel Schuelke, Markus A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2 |
title | A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2 |
title_full | A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2 |
title_fullStr | A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2 |
title_full_unstemmed | A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2 |
title_short | A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2 |
title_sort | new mechanism in thra resistance: the first disease-associated variant leading to an increased inhibitory function of thra2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159125/ https://www.ncbi.nlm.nih.gov/pubmed/34069457 http://dx.doi.org/10.3390/ijms22105338 |
work_keys_str_mv | AT paisdziorsarah anewmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT knierimellen anewmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT kleinaugunnar anewmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT biebermannheike anewmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT krudeheiko anewmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT straussbergrachel anewmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT schuelkemarkus anewmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT paisdziorsarah newmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT knierimellen newmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT kleinaugunnar newmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT biebermannheike newmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT krudeheiko newmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT straussbergrachel newmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 AT schuelkemarkus newmechanisminthraresistancethefirstdiseaseassociatedvariantleadingtoanincreasedinhibitoryfunctionofthra2 |