MCT8 deficiency, has been recently recognized to cause a severe form of X-linked mental retardation and neuromotor impairment in more than 150 individuals. Full gene sequencing is available at The University of Chicago Genetic Services Laboratory and research on this condition is conducted in Dr. Samuel Refetoff's laboratory, also at The University of Chicago. The condition is characterized by a unique combination of thyroid hormone (TH) test abnormalities. These include a high serum level of the TH precursor, T4, with high levels of the active metabolite T3, (generated by 5’-monodeiodination of T4 by two deiodinases, D1 and D2) and low levels of the inactive metabolite, reverse-T3 (rT3), also produced from T4 by 5-monodeiodination through a different deiodinase, D3. T3 is also inactivated by D3 to form the metabolite T2. The concentration of the thyroid stimulating hormone (TSH) is normal or slightly elevated. As the sole function of MCT8 so far identified is TH-specific cell membrane transport, the phenotype has been attributed to the resulting perturbations in TH. Given that the TH test abnormalities observed in man have been fully reproduced in the Mct8 knock out (Mct8KO) mouse, this mouse model continues to provide insights into the pathophysiology of MCT8 defects.
Initial studies of Mct8KO mice by us and another group of investigators demonstrated TH deprivation of brain through severe impairment of T3 transport reducing itsaccess to neurons. In contrast, retention of T3 in serum increased its supply to tissues, such as liver, that have other TH transporters. This suggested that the psychoneuromotor defect in the presence of inability to gain weight observed in humans could be due to a combination of tissue specific TH deprivation and excess. The high liver D1 expression, stimulated by T3, was considered responsible of increased T4 metabolism and consumption, further increase in serum T3 concentration and reduction in rT3 levels. By generating mice with combined of Mct8 and D1 (Mct8D1KO) and Mct8 and D2 (Mct8D2KO) deficiencies, we determined to what extent each of the 5’-deiodinases, present predominantly in brain (D2) and in peripheral tissues (D1) contributes to the serum TH abnormalities of the Mct8KO mice. The absence D1 corrected the serum T3 and rT3 abnormalities of Mct8 deficiency and partially corrected the brain depletion of TH. In contrast, the Mct8D2KO mice maintained the serum TH abnormalities of Mct8 deficiency and aggravated the TH deprivation of brain. Collectively, these data suggest that in Mct8 deficiency, D2 is crucial for the local generation of T3 compensating for distinct regional TH depletion, whereas D1 is the main cause for the high serum T3 level and contributes to the low serum T4 concentration.
Several findings indicated that increased 5’-deiodination cannot fully account for the low serum T4 levels. Indeed, we observed that the development of low serum T4 concentration in Mct8KO mice precedes the increase of serum T3 and serum TH concentration was relatively lower in Mct8KO mice following the release of endogenous hormone synthesis blockade. These findings and the localization of Mct8 at the basolateral membrane of thyroid follicular cells suggested the possible involvement of the transporter in TH secretion. This novel function of Mct8 was confirmed by the retarded release of labeled iodothyronines from the thyroid gland and its appearance in serum following the administration of radioiodide to Mct8KO mice. Finally, recent work by Heuer’s laboratory in Germany, demonstrated increased T4 metabolism in kidneys and loss of TH in the urinary tract of Mct8KO mice.
From the foregoing it is evident that the low serum T4 of MCT8 deficiency is the result of alterations in TH secretion, metabolism and excretion, each mediated trough different mechanisms partially controlled by MCT8.
By: Caterina Di Cosmo1 and Samuel Refetoff 1,2,3
Departments of 1 Medicine, 2 Pediatrics and 3 Committee on Genetics, University of Chicago, Chicago, IL.