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Projects. Life and Earth Sciences

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

Lead Researcher:
Beatriz Morte Molina

Research Centre:
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-Instituto de Investigaciones Biomédicas. CSIC-Universidad Autónoma de Madrid.

Synopsis: 

Beatriz Morte MolinaThe 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.


Scientific production
1 paper at international conferences


Beatriz Morte Molina

Graduate and Doctor in Pharmacy from the Complutense University, Madrid in 1997. She wrote her doctoral thesis in the "Alberto Sols" Biomedical Research Institute (CSIC).

She was Visiting Researcher in the Scripps Research Institute, La Jolla, California, where she commenced her education in the field of genomic techniques. This has led her to international recognition in the application of these techniques to the understanding of thyroid pathologies.

Since 2007 she has held a PhD contract at the Rare Diseases Network (CIBERER) of the Biomedical Research Institute, Madrid.

Her main line of research has centred on study of the action of thyroid hormones in the development and working of the brain and the pathologies resulting from their inappropriate action. She has made major contributions in this field, most especially the contribution of the hypothesis now accepted regarding the role of the receptor without a ligand in hypothyroidism, the proof at a genic level of the effect of thyroid hormone on the development of the foetal brain, and study of the effect on the brain of thyroid hormone analogues, all of which are highly relevant for understanding the pathology of the Allan-Herdon-Dudley syndrome.

Currently, as well as her research work, she is making a major effort in the identification of patients with this disease by preparing and publishing a clinical guide and offering genetic diagnosis, which had not previously been available in our country.


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