Zebrafish duox mutations provide a model for human congenital hypothyroidism

[helvella]

Do bear in mind that this paper is about fish - not humans. But I am posting it for this observation:

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.

Even allowing that this might be exaggerating, we can imagine that cursory inspection might not reveal more subtle issues that cannot be fully rescued, it is quite something.

Biol Open. 2019 Jan 30. pii: bio.037655. doi: 10.1242/bio.037655. [Epub ahead of print]

Zebrafish duox mutations provide a model for human congenital hypothyroidism.

Chopra K1, Ishibashi S1, Amaya E2.

Author information

1 Division of Cell Matrix Biology & Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.

2 Division of Cell Matrix Biology & Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK [e-mail].

Abstract

Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone 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 advance stages of development.

© 2019. Published by The Company of Biologists Ltd.

KEYWORDS:

Congenital hypothyroidism; Growth retardation; Infertility; Thyroid

PMID: 30700401

DOI: 10.1242/bio.037655

ncbi.nlm.nih.gov/pubmed/307...

[Hidden]

Interesting!

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.

If I remember, most fish, amphibians and reptiles continue to grow (although more slowly than when younger) after maturity. Some amphibians, such as the famous Axolotl, can even reproduce in the larval stage. So in that aspect they can't be compared with humans. I don't know if a child with untreated congenital hypothyroidism would survive to adulthood

But all the same....

[helvella Administrator in reply to Hidden]

Definitely not truly comparable.

But remember that humans can regrow livers to an amazing extent.

Even if not possible for humans to respond as well as axolotls, it again underscores the vital importance of thyroid hormones.

[WildDeer]

I have been wondering whether the polymorphisms I now know I have in my DIO2 gave rise to the the Hashimotos, rather than it being two separate inheritances?

[helvella Administrator in reply to WildDeer]

Given how many SNPs we all have, I suspect it will be a very long time before we can have any certainty.

[SilverAvocado]

Nice to see a mention of congenital hypothyroid on the forum. A good friend of mine has it, and it must be quite rare, as hardly ever turns up here.

I'll just say a bit in case people are searching in future. He was fine with Levothyroxine in his young life, but at 28 had a few scuffles with doctors insisting he was overmedicated. A year or so after dose reductions I saw his blood results, and his TSH was about 9 with over range freeT4. Turns out his conversion was absolutely atrocious and when we finally got it freeT3 was of course very low.

He must have had over range freeT4 for a long time, as he'd been on much higher doses, so the conversion problems must have been an issue for ages. I've come to doubt that he ever was 'fine', as he seems to have been very low energy and quiet all his life, and had periods when he struggled with work and study, interspersed with times when he was very high achieving.

Hearing his life story, I'd definitely suggest anyone with this condition needs to be knowledgeable about thyroid blood tests and confirm they're doing well. As with any thyroid patient, doctors can't be relied on to dose effectively, and it's possible to just zombie through the decades assuming everyone feels as just as bad as you do