A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene

Abstract

Thyroid hormones are iodothyronines that control growth and development, as well as brain function and metabolism. Although thyroid hormone deficiency can be caused by defects of hormone synthesis and action, it has not been linked to a defect in cellular hormone transport. In fact, the physiological role of the several classes of membrane transporters remains unknown. We now report, for the first time, mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, that encodes a 613-amino acid protein with 12 predicted transmembrane domains. The propositi of two unrelated families are males with abnormal relative concentrations of three circulating iodothyronines, as well as neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. These findings establish the physiological importance of MCT8 as a thyroid hormone transporter.

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…In 2004, loss‐of‐function mutations within the SLC16A2 gene, located on the X chromosome, encoding for the thyroid hormone transporter MCT8, have been identified as the monogenetic cause of AHDS 75, 76. Thyroid hormones play essential roles in growth and development of various tissues, especially the brain, and rely on cellular uptake to fulfill their physiological functions 77.…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Solute carriers known to transport thyroid hormones include monocarboxylate transporters (MCTs), Na + /taurocholate co-transporting polypeptide, organic anion transporters (OATs), amino acid transporters (e.g., L-type amino acid transporters), and organic anion transporting polypeptides (OATPs) (102)(103)(104)(105)(106). The importance of thyroid hormone transporters is illustrated by the fact that mutations in human MCT8 cause psychomotor retardation and altered iodothyronine levels (107,108). With the exception of OATP1C1 (T 4 and 3,3¢,5¢-triiodothyronine [rT 3 ] transport only), most thyroid hormone transporters transport both T 4 and T 3 .…”

Thyroid hormone action during brain development: More questions than answers

“…The physiological significance of thyroid hormone transport for proper brain development and function was highlighted by the identification of patients exhibiting inactivating mutations in the X-linked MCT8 gene (Dumitrescu et al, 2004;Friesema et al, 2004;Schwartz et al, 2005). All patients suffered from a unique syndrome consisting of a severe form of psychomotor retardation in combination with abnormal serum thyroid hormone levels (Friesema et al, 2006).…”