THE PRESENTATION OF A NOVEL SYNDROME CAUSED BY MUTATIONS IN THE - PDF document

Editorial THE PRESENTATION OF A NOVEL SYNDROME CAUSED BY MUTATIONS IN THE X-LINKED THYROID HORMONE TRANSPORTER, MCT8 # Alexandra M. Dumitrescu 1,* , S. Refetoff 2 1 M.D, Ph.D, Postdoctoral Scholar, Department of Medicine University of Chicago 2 M.D, Professor of Medicine, Pediatrics, Molecular Medicine and Genetics, University of Chicago INTRODUCTION The effects of thyroid hormone (TH) are dependent on the quantity of the hormone that reaches peripheral tissues, its intracellular availability and the presence of unaltered TH receptors (TR). Until recently it was believed that TH enters the cells passively. However, the characterization of several classes of TH membrane transporters with different kinetics and substrate preferences that actively transport TH across cell membranes has changed this paradigm. These proteins belong to different families of solute carriers, organic anions (OATP), amino acids, and monocarboxylate transporters (1-5). Their characteristics in terms of tissue distribution and kinetics, as well as binding of other possible ligands, provide them with potentially distinctive roles in the fine tuning of organ-specific TH availability (6). Once intracellularly, the hormone precursor thyroxine (T 4 ) is metabolized by removal of the outer ring iodine (5’-deiodination) to form triiodothyronine (T 3 ) or, inactivate T 4 and T 3 by inner ring, 5-deiodination to form reverse T 3 (rT 3 ) and T 2 , respectively. The activating deiodinases are D1 and D2, while the inactivating enzyme is D3 and to a lesser extent D1 (Fig. 1). Their presence in changing concentrations in various cell types allows an additional level of local regulation of hormone supply (7). Finally, the presence and abundance of TRs, through which TH action is mediated, determine the type and degree of hormonal response (8). Since the identification of TH membrane transporters, their physiological role has remained elusive as no genetic defects were known in humans or animals, and the consequence of a putative defect # Partially reproduced from Dumitrescu, AM and Refetoff, S: Conditions with Variable Effects: Cell Transport Defects. In Clinical Management of Thyroid Diseases, Wondisford, F and Radovick, S (eds.), Elsevier, Philadelphia, PA and Amsterdam, the Netherlands, 2007, with permission. *Correspondence to: Alexandra M. Dumitrescu, M.D. Ph.D., Postdoctoral Scholar, Department of Medicine University of Chicago, 5841 S. Maryland Avenue, MC3090, Room M367, Chicago, IL 60615, Phone: 773-702-9273, Fax: 773-702-6940, Email: alexd@uchicago.edu Acta Endocrinologica (Buc), vol. III, no. 1, p. 69 - 80, 2007 69

Alexandra Dumitrescu and S. Refetoff was unknown. In particular, a defect in liver specific transporter (LST) 1 was considered as a possible cause of resistance to TH (RTH). Linkage analysis in several families with RTH has excluded LST1 involvement (9). However, the recent identification of patients with mutations in the X-linked TH transporter, monocarboxylate transporter 8 (MCT8) (10-16), has revealed the role played by one such transmembrane carrier in the intracellular availability of TH. Figure 1. Regulation of intracellular TH bioactivity. TH, T4 and T3, are actively transported across the cell membrane. T4, the main hormonal precursor secreted by the thyroid gland, undergoes intracellular stepwise deiodination. 5'-deiodination through D1 and D2 activates T4 by converting it to T3, while 5-deiodination by D3 converts T4 to the inactive rT3. T3 is inactivated by D3 and, to a lesser extent, by D1. Being an X-linked disease, hemizygous males are affected while the carrier females are clinically normal. The phenotype of patients with MCT8 gene mutations has two components 1) thyroid function tests (TFT) abnormalities that include high T3, low T4, low rT3 and slightly elevated TSH (Fig. 2) found in both males and to a lesser degree in carrier females and 2) severe motor and developmental delay, gait disturbance, dystonia, and poor head control, found only in males. These neuropsychiatric manifestations have not been previously described in the context of abnormal thyroid function and cannot be explained by the current knowledge and the observed TFT. This is the first genetic defect of a TH transporter and understanding the underlying mechanisms responsible for the phenotype manifested by patients with MCT8 defect will provide new insights into thyroid physiology. 70

Thyroid hormone transporter MCT8 mutations Figure 2. Thyroid function tests from six families studied at the University of Chicago: seven affected males (M), eleven carrier females (F), and fifteen unaffected family members (N). (* P <0.05; ** P<0.01, *** P<0.001). Shaded area depicts the normal range for the corresponding test. Bars represent 2 SDs. EPIDEMIOLOGY, ETIOLOGY AND PATHOGENESIS The MCT8 gene was first cloned during the physical characterization of the Xq13.2 region known to contain the X-inactivation center (17). It has 6 exons and a very long (more than 100kb) first intron. It belongs to a family of genes, officially named SLC16 , the products of which catalyze proton-linked transport of monocarboxylates, such as lactate, pyruvate and ketone bodies. The deduced products of the MCT8 ( SLC16A2 ) gene are proteins of 613 and 539 amino acids (translated from two in-frame start sites) containing 12 transmembrane domains with both amino- and carboxyl- termini located within the cell (18). In 2003, Friesema et al (2) demonstrated that the rat homologue was a specific transporter of TH into cells. A form of mental retardation associated with motor abnormalities was described in 1944 (19) and subsequently named the Allan-Herndon-Dudley (A-H- D) syndrome. This condition was further mapped to a locus on chromosome X: Xq13-q21 (20) and Xq12-q13 (21). In 2004, two laboratories identified independently mutations in the MCT8 gene in 7 unrelated families, in which males presented with high serum T 3 , low T 4 and low rT 3 concentrations together with psychomotor abnormalities reminiscent of the A-H-D syndrome (10, 11). The following year it was shown that families previously identified as suffering from the A-H-D syndrome, including the first family reported in 1944, harbored mutations 71

Alexandra Dumitrescu and S. Refetoff in the MCT8 gene and had high serum T 3 levels (12). We know of 26 families with MCT8 gene mutations (14, 22) (and personal observations). The mutations are distributed throughout the coding region of the gene (Fig. 3) Single amino acid substitutions causing missense mutations were found in 10 families and in 4 families they resulted in nonsense mutations. Single amino acid deletions or insertions were reported in two families each. One or two nucleotide deletions or insertions produced 2 stop codons and in one case a 64 amino acid extension of the carboxyl terminus of the MCT8 molecule. Deletions of 10 nucleotides or more were reported in four families, and an intronic mutation, affecting the splice site, in one. It is of note that two mutations, F229 ∆ and S448X, occurred in two unrelated families each. Figure 3. Schematic representation of MCT8 gene mutations in 26 families. Their type and location are presented graphically. (M, missense; X, nonsense; I, insertion; D, deletion). The identification of 26 families with MCT8 defect in less than three years indicates that this syndrome is more common than initially suspected. From a population genetics point of view, the spontaneous MCT8 mutations could have been maintained in the population since carrier females are asymptomatic, thus preventing any negative selection to take place. Currently, penetrance is thought to be complete. Ethnic origins reported to date include German, Greek, Amerindian, English, Irish, French, Japanese, Hispanic, Brazilian, Argentinean, Chilean, Mexican and Dutch. Genotype/Phenotype Correlation Given the variability in the severity of the disease for correlations between phenotypes and genotypes were sought. A comparison of the clinical picture in the families with identical mutations would have been helpful in determining if such correlations exist. Unfortunately, detailed clinical information in one of each of the 72