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Allan-Herndon-Dudley syndrome: molecular mechanisms and a therapeutic approach in the murine model of the disease

16th national competition for scientific and technical research

Rare diseases

Senior Researcher : Beatriz Morte Molina

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Research Centre or Institution : Centros de Investigación Biomédica en Red (CIBER). Madrid


The Allan-Herndon-Dudley syndrome is a serious neurological alteration with deep mental and psychomotor retardation, and it is linked to chromosome X. It is due to mutations in the MCT8 (SLC16A2) gene, which codes for a thyroid hormone transporter. Among other locations, MCT8 is present in the blood-brain barrier and the choroid plexi, and it has a crucial function in the transport of thyroid hormones to the brain, where it is indispensable for correct working and function.

The brain requires highly precise regulation in time and space of active levels of the T3 thyroid hormone. The concentration of T3 depends on direct entry through membrane transporters, MCT8, or local generation based on T4 by the action of deiodinase 2. T3 acts through regulating gene expression by binding to nuclear receptors. It is thought that neurological alterations in these patients are due to defective signalling by T3 in critical stages for the brain, arising due to the transport defect.

To study signalling by T3 and its possible alteration, the genes regulated by the thyroid hormone are being studied in the brain at post-natal ages, and the sensitivity of these genes to the deletion of MCT8 is being analysed. By means of an overall analysis of the action of the thyroid hormone on gene expression, it has been determined that the cerebral cortex of knock-out animals for MCT8 is in a state compensated by the action of deiodinase 2 and not by the presence of another alternative transporter of thyroid hormones, SLC7A8.

The effect of MCT8 deficiency is currently being analysed, together with the role of deiodinase 2, as well as the thyroid hormone receptors in the gene expression in other regions of the brain, the caudate lobe, cerebellum and the hippocampus. Preliminary results show the differing sensitivity of these regions to the absence of these factors, and also indicate differences in the modulation of the local concentration of T3.

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