The sodium iodide symporter: its emerging relevance to clinical thyroidology.

The sodium iodide symporter (NIS), an integral basolateral cell membrane protein of thyroid follicular cells, is responsible for active accumulation of iodide within the thyroid gland, a critical step in the biosynthesis of thyroid hormones. After cloning of rat NIS cDNA and of its human counterpart (hNIS), molecular characterization of the human NIS gene has revealed that the hNIS coding region contains 15 exons interrupted by 14 introns, encoding a protein of 643 amino acids. While not definitively resolved, the predicted structure of NIS comprises 12 putative transmembrane domains (1). Analysis by reverse transcriptase (RT)-PCR of hNIS mRNA in various tissues revealed its expression primarily in thyroid tissue as well as in breast, colon and ovary. Compared with normal thyroid tissue, Northern blot analysis has indicated markedly reduced levels of hNIS expression in thyroid carcinomas, which may account for the reduced radioiodide uptake activity observed in scintigraphically cold thyroid nodules and certain thyroid cancers. Interestingly, in follicular thyroid carcinoma cell lines that have lost the capacity to accumulate iodide, treatment with all-trans retinoic acid has recently been shown to upregulate NIS mRNA levels (2). If this leads to reexpression of functional NIS protein, an extended in vivo evaluation of such effects is desirable since it could have therapeutic consequences. Regulation of NIS gene expression has been examined by several groups of investigators. Thyroid-stimulating hormone (TSH) has been shown to increase NIS gene and protein expression in FRTL-5 cells and human thyrocyte monolayers, and this increase was accompanied by an enhanced iodide transport activity (3). However, the presence of abundant amounts of NIS protein in FRTL-5 cells with very low iodide transport activity (i.e. dissociation between NIS expression and function) also suggested that other TSH-regulated events may participate in activation or repression of NIS function. Furthermore, 3to 4-fold elevated levels of NIS RNA and protein have been observed in Graves’ thyroid tissue compared with normal thyroid tissue, perhaps as a result of stimulation by TSH receptor antibodies that act to stimulate cAMP accumulation and, consequently, NIS expression (4). Interestingly, NIS RNA levels correlated well with thyroperoxidase (TPO) and thyroglobulin (Tg) (but not TSH receptor (TSHR)) gene expression, suggesting a similar mechanism of gene regulation. Further, prolactin stimulation of iodide uptake by cultured mouse mammary tissues has recently been reported (5). Subsequent studies by the same authors have suggested the existence of a prolactin-regulated sodium iodide symporter in mammary gland that shares characteristic features of NIS in the thyroid gland, such as sodium dependence and inhibition of iodide transport by thiocyanate and perchlorate. From these studies, it is apparent that prolactin stimulation of NIS expression by mammary gland tissue provides an important regulatory mechanism for iodide accumulation in milk during lactation (6). In contrast to agents stimulating NIS expression and function, transforming growth factor-b1, a potent inhibitor of growth and DNA synthesis in thyroid cells, has been found to suppress TSH-induced NIS mRNA and protein levels as well as TSH-stimulated iodide uptake activity in FRTL-5 cells (7). Further, in hyperplastic dog thyroid glands that had been stimulated chronically by iodide depletion and revealed increased levels of NIS, TPO and Tg mRNA expression, low doses of potassium iodide acutely inhibited both NIS and TPO, but not TSHR and Tg gene expression (8). Given its essential role in thyroid physiology, one would predict that changes in hNIS expression and/or function due to genetic alterations of this protein should give rise to a broad spectrum of thyroid disorders. Since the cloning and molecular characterization of hNIS, several reports have confirmed involvement of hNIS in the pathogenesis and propagation of various thyroid diseases. Particularly high on this list are iodide transport defects that result in congenital or acquired abnormalities of iodine trapping. Even prior to cloning of hNIS, close to 40 cases of congenital hypothyroidism have been attributed to a defect in the iodide transport system. The molecular defects in some of these patients have now been deciphered using molecular analysis of the hNIS gene. A homozygous missense mutation in the NIS gene has been demonstrated in a patient born to consanguinous parents who presented with congenital hypothyroidism caused by an iodide transport defect (9). RT-PCR amplification of the entire coding region of NIS revealed a single base change of an adenine to a cytosine at the first nucleotide of codon 354, resulting in an exchange of threonine to proline. Expression of the mutated symporter in vitro revealed a complete loss of European Journal of Endocrinology (1998) 138 374–375 ISSN 0804-4643