Extended clinical phenotype, endocrine investigations and functional studies of a loss-of-function mutation A150V in the thyroid hormone specific transporter MCT8

Abstract

Objective: Thyroid hormones, besides having other functions, are known to be essential for the development of the human brain. Recently the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter which is expressed in different regions of the human brain. Here we describe in detail the clinical and biochemical features in response to thyroid hormone administration of a boy carrying an MCT8 mutation (A150V) in the second transmembrane domain. Methods: To study the functional impact of the mutation we performed triiodothyronine (T3) uptake, immunofluorescence and dimerization studies. Results: Thyroid hormone (L-thyroxine (LT4) and LT3) administration did not result in any significant clinical changes; however, with high doses of LT4, alone or in combination with T3, TSH suppression was achieved. We could show a robust uptake of 125 I-T3 for wild type (WT) MCT8, whereas no specific uptake could be detected for the mutant A150V. Subcellular localization of WT and mutant MCT8 revealed a strong cell surface expression for the WT MCT8, in contrast to A150V, which is mostly retained intracellularly with only weak cell surface expression. We could also demonstrate for the first time that WT MCT8 as well as the mutant are able to form multimers. Conclusion: Our findings open a wide field of possible interaction within the central nervous system and will help to understand the crucial role of MCT8 in early fetal brain development.

Novel mutation in MCT8 gene in a Brazilian boy with thyroid hormone resistance and severe neurologic abnormalities

“…(14). The patient we have described, like other patients with inactivating mutations of MCT8, had no signs or symptoms typically associated to congenital hypothyroidism (prolonged jaundice, umbilical hernia, bradycardia, growth retardation, myxedema and tendency to overweight or obesity) (12). This clinical finding reinforces the concept that tissues like bone, fat and liver are not as dependent on MCT8 for TH transport as the brain is.…”

“…During hypothyroid states it is important that the intracellular concentration of T3, the active TH, be maintained at a safe range, especially in vital organs like the brain. In the brain this is achieved by means of increased brain uptake of serum T3 through increased action of transporters like MCT8, increased conversion of T4 to T3 through increased action of D2 and decreased conversion of T3 to T2 through reduced action tant for TH transport in bone cells (7,12,13). Similarly, the patient evaluated by Herzovich and cols.…”

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…A prominent and common feature in MCT8 deficient patients is the failure to thrive, which may require in some cases a gastric feeding tube. Possible reasons for low weight and muscle wasting are difficulty swallowing on neurological basis, and increased metabolism due to the thyrotoxic state of peripheral tissues caused by the high serum T 3 levels [82,[85][86][87].…”

“…Other MRI abnormalities reported in single cases might be non-specific. They include subtle cortical and subcortical atrophy [85], mild cerebellar atrophy [86], putaminal lesions [99] and a small corpus callosum [Dumitrescu, A.M. and Refetoff, S, unpublished data]. Increased choline and myoinositol levels and decreased N-acetyl aspartate detected by MRspectroscopy were associated with the degree of dysmyelination found on MRI [100].…”

Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8

“…A comparison of 12 missense mutants revealed that pathogenic MCT8 mutations may affect expression, surface translocation, or specifically the substrate transport mechanism (14). Possibly, homodimerization may also play a role that we currently do not understand (15,16). To our knowledge, no data are yet available relating structural features and transport mechanism of MCT8.…”