Pathophysiology of MCT8 deficiency: Allan-Herndon-Dudley Syndrome
Mutations in the gene SLC16A2, encoding the specific thyroid hormone (TH) transporter MCT8 (monocarboxylate transporter 8), lead to the Allan-Herndon-Dudley syndrome (AHDS). This X-linked mental retardation syndrome is characterized by neuromotor disorders and altered TH concentrations in serum. Alt...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2015 |
| País: | Chile |
| OAI Identifier: | oai:repositorio.anid.cl:10533/246386 |
| Acceso en línea: | https://hdl.handle.net/10533/246386 |
| Access Level: | acceso abierto |
| Palabra clave: | Medicina y Ciencias de la Salud Medicina Básica Neurociencias |
| Sumario: | Mutations in the gene SLC16A2, encoding the specific thyroid hormone (TH) transporter MCT8 (monocarboxylate transporter 8), lead to the Allan-Herndon-Dudley syndrome (AHDS). This X-linked mental retardation syndrome is characterized by neuromotor disorders and altered TH concentrations in serum. Although it has not been formally proved, it is believed that the central nervous system damage is caused by an insufficient TH transport to nerve cells. In order to understand the developmental stages and processes in which MCT8 is involved, we have studied its expression at different fetal stages and during infancy in normal and MCT8-deficient brain tissue, from a 30 gestational week (gwk) fetus and an 11-year old boy, both with mutations in the SLC16A2 gene. Our results revealed that MCT8 is expressed in the brain at least during the second and third trimester of pregnancy and that the most important function is to allow the entry of TH through the brain barriers, mainly the blood-brain barrier (BBB). Furthermore, MCT8 expression in the radial glia, Cajal- Retzius cells, neurons, glial cells, immature neural cells, and axons, suggest the involvement of MCT8 in the cellular migration and differentiation processes during development and in the maintenance of brain function during childhood and probably in adulthood. In MCT8 deficient subjects, MCT8 is minimally expressed or not expressed at all in blood capillaries and its expression is absent or aberrant in cells, where is accumulated in the cytoplasm. To further explore the pathophysiological mechanisms of the neurological component of AHDS, we performed a histopathological analysis in brain samples of two MCT8-deficient subjects. Our results indicated that brain damage is compatible with a reduction in TH supply to the brain during development, causing alterations which are present at least since the 30thgwk. As a result, there is a delay in brain development and apparent permanent alterations in cell differentiation, such as a decreased proportion of myelinated axons of large caliber and alterations in synaptogenesis and myelination. Aiming at knowing the function during brain development of the TH transporter OATP1C1 and DIO2 and DIO3 deiodinases, enzymes involved in the metabolism of TH, we studied their expression at different fetal ages. The results point to a minor role of OATP1C1 in the entry of TH to the brain at the BBB and that its main function is to provide TH to the neural cells, probably involved in processes such as proliferation, migration and cell differentiation. On the other hand, the expression of deiodinases suggest that apart from being involved in modulating the TH concentrations available at the parenchyma, numerous cell types have the ability to control the intracellular levels of T3 and T4 during pregnancy. Coexpression of MCT8, OATP1C1, DIO2 and DIO3 in different cell types and brain structures during the prenatal period, indicate that there is very tight regulation of the concentrations of T3 and T4 in the TH- target cells during the progression of the different developmental processes. |
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