Zebrafish duox mutations provide a model for human congenital hypothyroidism
Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone (TH) synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2019-02-01
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| Series: | Biology Open |
| Subjects: | |
| Online Access: | http://bio.biologists.org/content/8/2/bio037655 |
| _version_ | 1818734471363428352 |
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| author | Kunal Chopra Shoko Ishibashi Enrique Amaya |
| author_facet | Kunal Chopra Shoko Ishibashi Enrique Amaya |
| author_sort | Kunal Chopra |
| collection | DOAJ |
| description | Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone (TH) synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidases DUOX1 and DUOX2. Indeed, mutations in DUOX1 and DUOX2 have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for DUOX1 and DUOX2. In this study, we investigated the phenotypes associated with two nonsense mutant alleles, sa9892 and sa13017, of the single duox gene in zebrafish. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine external and internal phenotypes, we discovered a strong correlation between TH synthesis and duox function, beginning from an early larval stage, when T4 levels are already noticeably absent in the mutants. Loss of T4 production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia/external goiter and infertility. Remarkably, all of these defects associated with chronic congenital hypothyroidism could be rescued with T4 treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish duox mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advanced stages of development. This article has an associated First Person interview with the first author of the paper. |
| first_indexed | 2024-12-18T00:05:53Z |
| format | Article |
| id | doaj.art-0778256ce11f4cfaa209a71ab4ed6d15 |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-18T00:05:53Z |
| publishDate | 2019-02-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-0778256ce11f4cfaa209a71ab4ed6d152022-12-21T21:27:48ZengThe Company of BiologistsBiology Open2046-63902019-02-018210.1242/bio.037655037655Zebrafish duox mutations provide a model for human congenital hypothyroidismKunal Chopra0Shoko Ishibashi1Enrique Amaya2 Division of Cell Matrix Biology & Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK Division of Cell Matrix Biology & Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK Division of Cell Matrix Biology & Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone (TH) synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidases DUOX1 and DUOX2. Indeed, mutations in DUOX1 and DUOX2 have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for DUOX1 and DUOX2. In this study, we investigated the phenotypes associated with two nonsense mutant alleles, sa9892 and sa13017, of the single duox gene in zebrafish. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine external and internal phenotypes, we discovered a strong correlation between TH synthesis and duox function, beginning from an early larval stage, when T4 levels are already noticeably absent in the mutants. Loss of T4 production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia/external goiter and infertility. Remarkably, all of these defects associated with chronic congenital hypothyroidism could be rescued with T4 treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish duox mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advanced stages of development. This article has an associated First Person interview with the first author of the paper.http://bio.biologists.org/content/8/2/bio037655Congenital hypothyroidismGrowth retardationInfertilityThyroid |
| spellingShingle | Kunal Chopra Shoko Ishibashi Enrique Amaya Zebrafish duox mutations provide a model for human congenital hypothyroidism Biology Open Congenital hypothyroidism Growth retardation Infertility Thyroid |
| title | Zebrafish duox mutations provide a model for human congenital hypothyroidism |
| title_full | Zebrafish duox mutations provide a model for human congenital hypothyroidism |
| title_fullStr | Zebrafish duox mutations provide a model for human congenital hypothyroidism |
| title_full_unstemmed | Zebrafish duox mutations provide a model for human congenital hypothyroidism |
| title_short | Zebrafish duox mutations provide a model for human congenital hypothyroidism |
| title_sort | zebrafish duox mutations provide a model for human congenital hypothyroidism |
| topic | Congenital hypothyroidism Growth retardation Infertility Thyroid |
| url | http://bio.biologists.org/content/8/2/bio037655 |
| work_keys_str_mv | AT kunalchopra zebrafishduoxmutationsprovideamodelforhumancongenitalhypothyroidism AT shokoishibashi zebrafishduoxmutationsprovideamodelforhumancongenitalhypothyroidism AT enriqueamaya zebrafishduoxmutationsprovideamodelforhumancongenitalhypothyroidism |