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This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: JME-09-0043v1 43/6/263    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kinne, A. Articles by Schweizer, U. PubMed PubMed Citation Articles by Kinne, A. Articles by Schweizer, U.

¹ Institute for Experimental Endocrinology
² Institute for Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany

(Correspondence should be addressed to A Grüters; Email: annette.grueters{at}charite.de; U Schweizer; Email: ulrich.schweizer{at}charite.de)

^* *(A Kinne and S Roth contributed equally to the experiments presented in this manuscript)

Mutations in the gene encoding the thyroid hormone transporter, monocarboxylate transporter 8 (MCT8), underlie severe mental retardation. We wanted to understand the functional consequences of a series of missense mutations in MCT8 in order to identify therapeutic options for affected patients. We established cell lines stably expressing 12 MCT8 variants in JEG1 and MDCK1 cells. The cell lines were characterized according to MCT8 mRNA and protein expression, tri-iodothyronine (T₃) transport activity, substrate K_M characteristics, surface expression, and responsiveness to T₃ preincubation and chemical chaperones. Functional activities of ins235V and L568P MCT8 mutants depend on the cell type in which they are expressed. These mutants and R271H exhibited considerable transport activity when present at the cell surface as verified by surface biotinylation and kinetic analysis. Most mutants, however, were inactive in T₃ transport even when present at the cell surface (e.g. S194F, A224V, F230, L512P). Preincubation of G558D with T₃ increased T₃ uptake in MDCK1 cells to a small, but significant, extent. Chemical chaperones were ineffective. The finding that the cell type determines surface expression and T₃ transport activities of missense mutants in MCT8 may be important to understand phenotypic variability among carriers of different mutations. In particular, the clinical observation that the severity of derangements of thyroid hormone levels does not correlate with mental impairments of the patients may be based on different residual activity of mutant MCT8 in different cell types.