Mice deficient in Mct8 and Dio2 as a new tool to go in depth in the neuropathology of human MCT8 deficiency and to explore new therapeutic strategies

Abstract

Allan-Herndon-Dudley syndrome is a rare disease caused by mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8). Defects in this transporter cause peripheral hyperthyroidism and profound psychomotor alterations in humans. Mice lacking Mct8 were the first murine model used for the study of this disease; they presented peripheral hyperthyroidism but unfortunately no gross neurological abnormalities. This seems to be due to a compensatory mechanism in brain involving the enzyme deiodinase type 2 (Dio2) which converts T4 into T3. Therefore, a new animal model has been proposed: mice lacking both Mct8 transporter and Dio2 enzyme. Here we have analysed the endocrine and neurologic phenotype of these mice at 3 and 6 months of age. Our results show that these animals present peripheral hyperthyroidism and brain hypothyroidism that seems to be permanent and to vary across regions, being the striatum the most sensitive area. Immunohistochemical studies in brain show alterations compatible with thyroid hormone deficiency. We have also found alterations in motor skills evaluations. All these data support the potential of Mct8/Dio2-deficient mice as a new tool to understand the mechanism underlying the pathophysiology of human Mct8 deficiency and to explore new therapeutic strategies.