Mayo Clinic and Medical School Rochester, Minnesota 55902
Address correspondence and requests for reprints to: Dr. John C. Morris, Department of Endocrinology, Mayo Clinic and Medical School, 200 First Street SW, Rochester, Minnesota 55902.
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Introduction |
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It is evident that the elucidation of the genetic basis of diseases involving specific proteins closely follows the molecular cloning and DNA sequence determination of that protein. For example, the first descriptions of mutations of TSHR in disease states followed shortly after its molecular cloning, and reports of new mutations responsible for thyroid disorders continue to appear frequently in the literature. Thus "waves" of new diagnoses and new disease mechanisms can be observed in the literature following the elucidation and cloning of structurally or functionally important proteins.
Recently, another thyroid specific protein has been characterized by molecular cloning, the thyroid sodium-iodide symporter (NIS), also known as the thyroid iodide transporter (6). The protein functions by transporting iodide in concert with sodium ions, upon which the transport is dependent. It thus functions as a symporter. NIS is a member of the family of membrane bound transport proteins that also include the sodium dependent glucose cotransporter with which it shares some sequence homology (6), and like other members of this group, it appears to span the plasma membrane of thyroid cells 12 times. Its expression, at least in rat thyroid cells, is dependent upon TSH stimulation (7, 8). Although the original description of NIS was that of the sequence of the rat, the human complementary DNA sequence (9) and location of the human gene on chromosome 19 and its gene structure have also been elucidated (10).
Like Tg, TPO, and TSHR, the iodide transporter is critically important in the biosynthetic mechanism for production of thyroid hormones, so one would expect that genetic alterations of the protein that result in changes in its expression and/or function would cause thyroid dysfunction. A disease process in which one might expect such a mutation is that of iodide transport defect, a congenital disorder of thyroid iodine trapping. In the current issue of JCEM Matsuda and Kosugi (11) (see page 3966) describe exactly such an occurrence. Although another group (12) reported the same mutation during the review process of the current manuscript, this is the first mutation of NIS described as the cause of thyroid disease and may thus represent the next wave of thyroid genetic diagnosis.
The patient in Matsuda and Kosugis report was the product of a consanguineous marriage and was afflicted with a "huge" goiter that was present since early adulthood. Like other described cases of iodide transport defect (ITD), this patients thyroid demonstrated poor ability to trap I131, and iodide concentration in saliva and gastric contents was also reduced. After thyroid biopsy, extraction of messenger RNA, and sequencing of reverse transcriptase derived complementary DNA, the authors found that the patient was homozygous for a sequence alteration of NIS. This mutation resulted in a single amino acid substitution at codon 354, where a threonine residue was replaced by proline. The authors expressed the mutant transporter in vitro and demonstrated that its activity was severely reduced compared with that of normal NIS. The patients daughter was heterozygous for the mutant NIS but had a normal thyroid gland and thyroid function, confirming the recessive nature of the inactivating mutation.
In the current report, the effected patient demonstrated essentially normal concentrations of circulating thyroid hormones, although in the presence of a large goiter. The earlier report of the same mutation indicates that congenital hypothyroidism may also result (12). These discrepancies suggest that the clinical presentation of the same mutation may be somewhat variable and dependent upon other, as yet unknown factors. This variability is consistent with the previous reports of the disease within families referenced by the authors.
The mechanism by which this mutation causes reduced iodine transport remains unknown. Messenger RNA levels for NIS were greatly increased in thyroid derived RNA, but the authors were unable to measure protein expression directly, presumably because they did not have an appropriate antibody for western blotting experiments. Thus, we do not at present know if this mutation causes expression of an inactive protein, if it might not be incorporated into the membrane appropriately, or if some combination of the two might exist. Certainly future experiments by these and other investigators are likely to better delineate the mechanism.
Although the congenital iodide transport defect is the first disease conclusively related to a disorder of NIS, we are likely to recognize several others in the near future. Currently, evidence is accumulating that suggests that NIS, like TPO, Tg, and TSHR is an autoantigen in autoimmune thyroid disease (13, 14, 15). NIS expression in thyroid cancers is likely very important in their ability to trap iodide and thereby be successfully treated with I131. We are thus likely to see measurement of NIS protein and/or mRNA expression in these tumors. Even benign thyroid nodules and multinodular goiter express considerable variability with respect to iodide trapping, and we will surely see investigators characterizing NIS expression in these conditions.
Clearly congenital and acquired thyroid disorders involving the iodide transporter represent the newest wave of thyroid investigation. Although the height of this wave remains to be determined, many thyroidologists and thyroid investigators are likely to ride upon it.
Received October 1, 1997.
Accepted October 2, 1997.
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