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Impaired T3 transport and action underlies the pathophisiology of the Allan-Herdon-Dudley syndrome

ABSTRACT: Impaired T3 transport and action underlies the pathophisiology of the Allan-Herdon-Dudley syndrome

PROVIDER: PRJNA1065480 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27585766_1.fastq.gz	Fastqsanger.gz
	SRR27585766_2.fastq.gz	Fastqsanger.gz
	SRR27585767_1.fastq.gz	Fastqsanger.gz
	SRR27585767_2.fastq.gz	Fastqsanger.gz
	SRR27585768_1.fastq.gz	Fastqsanger.gz

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Impaired T3 transport and action underlies the pathophisiology of the Allan-Herdon-Dudley syndrome

Project description:Patients with mutations in the thyroid hormone (TH) cell transporter MCT8 gene develop severe neuropsychomotor retardation known as the Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human iPSCs from MCT8-deficient patients. We found that MCT8-deficient COs exhibit (i) alterations in early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired T3 transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3-inducibility of TH-regulated genes. In contrast, the TH-analogs 3,5-diiodothyropropionic acid and 3,3’,5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting a proof-of-concept that lack of T3 transport underlies the pathophysiology of AHDS, and demonstrating the clinical potential for TH analogues to be used in treating AHDS patients. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for AHDS patients.

2024-03-11 | GSE253412 | GEO

Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes

Project description:To investigate the role of THRβ1 action in human iPSC-derived hepatocytes. We then performed gene expression profiling analysis using data obtained from RNA-seq of WT and THRBKO human iPSCs-derived hepatocytes in presence and absence of T3.

2024-11-01 | GSE270233 | GEO

Brain gene expression in systemic hypothyroidism and in mouse models of MCT8 deficiency: The Mct8-Oatp1c1-Dio2 triad.

Project description:The monocarboxylate transporter 8 (Mct8) protein is a primary T4 and T3 (TH) transporter. Mutations of the MCT8-encoding, SLC16A2 gene alters thyroid function and thyroid hormone metabolism, and severely impairs neurodevelopment (Allan-Herndon-Dudley syndrome, AHDS). Mct8-deficient mice manifest thyroid alterations but lack neurological signs. It is thought that Mct8 deficiency in mice is compensated by T4 transport through the Slco1c1-encoded organic anion transporter polypeptide 1c1 (Oatp1c1). This allows local brain generation of sufficient T3 by the Dio2-encoded type 2 deiodinase (D2). The Slc16a2/Slco1c1 (MO) and Slc16a2/Dio2 (MD) double knock out mice lacking T4 and T3 transport, or T3 transport and T4 deiodination, would be more approriate models of AHDS. The goal of this work was to compare the cerebral hypothyroidism of systemic hypothyroidism (SH) caused by thyroid gland blockade with that present in the double KOs.

2020-12-15 | GSE155185 | GEO

Bacillus sp. T3 strain:T3

Project description:Bacillus sp. T3 strain:T3 Genome sequencing

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Halorubrum sp. T3 strain:T3

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T3-EC

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Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation

Project description:Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3 associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 – 15 % of the liver transcriptome as rhythmic in control and T3 groups, but only 4 % of the liver transcriptome (1,033 genes) were rhythmic across both conditions – amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

2022-07-26 | GSE199998 | GEO

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Project description:The following CGH experiments were conducted on four sectors (S1-S4) from a single primary ductal carcinoma tumor (T3).

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A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver

Project description:A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver

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Stem cells respond to triiodothytonine (T3) treatment

Project description:Analysis of T3 response in KCL034, iKCL004 and BJ cells at gene expression level. Results provide information of the T3 response in different lines.

2015-06-01 | GSE58273 | GEO

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