Analysis of mice mutants deficient in the thyroid hormone transporter MCT8

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Thyroid hormone actions and metabolism are intracellular events that require the transport of iodothyronines across the plasma membrane. This process is facilitated by thyroid hormone transporters of which the monocarboxylate transporter 8 (MCT8) has been most intensively analyzed. In humans, inactivating mutations in the X-linked MCT8 gene are associated with a severe form of psychomotor retardation in combination with abnormal serum thyroid hormone parameters. Based on these findings it has been speculated that absence of MCT8 results in insufficient neuronal thyroid hormone supply during critical stages of development. We recently provided a first description of MCT8 deficient mice that despite the absence of overt neurological symptoms exhibit the same unusual thyroid hormone parameters as found in patients carrying MCT8 mutations. Here, we aim to unravel the pathogenic mechanisms that lead to the altered serum thyroid state. For this purpose, we will especially focus on the analysis of the thyroid gland and kidney as putative tissues that contribute significantly to the generation of the abnormal thyroid hormone levels. Furthermore, we will analyze in great detail the central resistance to thyroid hormone within the hypothalamus-pituitary axis. By defining the mechanisms that cause the abnormal serum thyroid parameters in MCT8 null mice we hope our studies will provide also an insight to ameliorate the devastating conditions of patients with MCT8 mutations.