Alternative titles; symbols
HGNC Approved Gene Symbol: SLC5A5
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:17,871,945-17,895,174 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.11 | Thyroid dyshormonogenesis 1 | 274400 | Autosomal recessive | 3 |
The sodium-iodide symporter (NIS, or SLC5A5) is a key plasma membrane protein that mediates active I- uptake in thyroid, lactating breast, and other tissues with an electrogenic stoichiometry of 2 Na+ per I-. In thyroid, NIS-mediated I- uptake is the first step in the biosynthesis of iodine-containing thyroid hormones (Dohan et al., 2007).
Dai et al. (1996) cloned the rat symporter and demonstrated its biochemical function in microinjected Xenopus oocytes. Smanik et al. (1996) cloned the human sodium-iodide symporter gene. The gene encodes a 643-amino acid protein with 84% homology to the rat gene.
In a review of sodium/substrate symporter family proteins, Jung (2002) stated that human NIS contains 13 transmembrane domains with the N terminus located on the periplasmic side of the membrane and the C terminus facing the cytoplasm.
Smanik et al. (1997) showed that the coding region of the NIS gene is interrupted by 14 introns. Smanik et al. (1997) reported the nucleotide sequence of each exon-intron junction and identified alternatively spliced forms of the symporter.
By fluorescence in situ hybridization, Smanik et al. (1997) mapped the SLC5A5 gene to 19p13.2-p12.
Smanik et al. (1997) demonstrated that the human sodium-iodide symporter gene is expressed primarily in thyroid tissues, but also in breast, colon, and ovary.
By transfecting NIS promoter-luciferase chimeric plasmids into FRTL-5 cells in the presence or absence of thyroid-stimulating hormone (TSH; see 188540), Ohmori et al. (1998) identified a TSH-responsive element (TRE) between -420 and -370 bp of the 5-prime-flanking region of the NIS gene. Gel mobility shift assays using oligonucleotides specific for thyroid transcription factor-1 (TTF1; 600635), thyroid transcription factor-2 (602617), Pax8 (167415), and the CREB/ATF family (see CREB1, 123810) showed an absence of competition for the TSH-responsive nuclear factor interacting with the NIS TRE in FRTL-5 cells, indicating that it is distinct from these factors. The TRE exists upstream of a TTF1-binding site, -245 to -230 bp. Mutation of the TRE causing a loss of TSH responsiveness also decreased TTF1-induced promoter activity in a transfection experiment. Ohmori et al. (1998) concluded that TSH/cAMP-induced upregulation of the NIS gene requires a novel thyroid transcription factor, which also appears to be involved in TTF-1-mediated thyroid-specific NIS gene expression.
Arturi et al. (1998) studied the expression of SLC5A5 by RT-PCR in a series of 26 primary thyroid carcinomas (19 papillary, 5 follicular, and 2 anaplastic) and 15 follicular adenomas (11 'cold' and 4 'hot'). Five of 19 papillary thyroid cancers did not express SLC5A5 mRNA. In all but 1 follicular cancer, SLC5A5 transcripts were detected. In anaplastic tissue, SLC5A5 mRNA was only barely detected in 1 case. All of the follicular thyroid adenomas except 1 expressed the SLC5A5 gene. In contrast, all tumors studied excluding the anaplastic histotype fully expressed thyroglobulin and thyroid peroxidase mRNA transcripts. The authors concluded that early detection of the loss of SLC5A5 gene expression in the primary cancer, may provide useful information for the management of differentiated thyroid cancer patients.
Lazar et al. (1999) studied the expression of 4 thyroid-specific genes (NIS, thyroid peroxidase (TPO; 606765), thyroglobulin (TG; 188450), and thyroid-stimulating hormone receptor (TSHR; 603372)) as well as the gene encoding glucose transporter-1 (GLUT1, or SLC2A1; 138140) in 90 human thyroid tissues. mRNAs were extracted from 43 thyroid carcinomas (38 papillary and 5 follicular), 24 cold adenomas, 5 Graves thyroid tissues, 8 toxic adenomas, and 5 hyperplastic thyroid tissues; 5 normal thyroid tissues were used as reference. A kinetic quantitative PCR method, based on the fluorescent TaqMan methodology and real-time measurement of fluorescence, was used. NIS expression was decreased in 40 of 43 (93%) thyroid carcinomas and in 20 of 24 (83%) cold adenomas; it was increased in toxic adenomas and Graves thyroid tissues. TPO expression was decreased in thyroid carcinomas but was normal in cold adenomas; it was increased in toxic adenomas and Graves thyroid tissues. TG expression was decreased in thyroid carcinomas but was normal in the other tissues. TSHR expression was normal in most tissues studied and was decreased in only some thyroid carcinomas. In thyroid cancer tissues, a positive relationship was found between the individual levels of expression of NIS, TPO, TG, and TSHR. No relationship was found with the age of the patient. Higher tumor stages (stages greater than I vs stage I) were associated with lower expression of NIS and TPO. Expression of the GLUT1 gene was increased in 1 of 24 (4%) adenomas and in 8 of 43 (19%) thyroid carcinomas. In 6 thyroid carcinoma patients, 131-I uptake was studied in vivo. NIS expression was low in all samples, and 3 patients with normal GLUT1 expression had 131-I uptake in metastases, whereas the other 3 patients with increased GLUT1 gene expression had no detectable 131-I uptake. The authors concluded that: (1) reduced NIS gene expression occurs in most hypofunctioning benign and malignant thyroid tumors; (2) there is differential regulation of the expression of thyroid-specific genes; and (3) an increased expression of GLUT1 in some malignant tumors may suggest a role for glucose-derivative tracers to detect in vivo thyroid cancer metastases by positron-emission tomography scanning.
Venkataraman et al. (1999) hypothesized that SLC5A5 transcriptional failure in thyroid carcinoma could be caused by methylation of DNA in critical regulatory regions and could be reversed with chemical demethylation treatment. In 7 human thyroid carcinoma cell lines lacking SLC5A5 mRNA, treatment with 5-azacytidine or sodium butyrate was able to restore SLC5A5 mRNA expression in 4 cell lines and iodide transport in 2 cell lines. Investigation of methylation patterns in these cell lines revealed that successful restoration of SLC5A5 transcription was associated with demethylation of SLC5A5 DNA in the untranslated region within the first exon. This was also associated with restoration of expression of TTF1. These results suggested a role for DNA methylation in loss of SLC5A5 expression in thyroid carcinomas as well as a potential application for chemical demethylation therapy in restoring responsiveness to therapeutic radioiodide.
Interferon-gamma (IFNG; 147570) had been implicated with contradictory results in the pathogenesis of autoimmune (Hashimoto) thyroiditis (140300). To test whether the local production of IFN-gamma can lead to thyroid dysfunction, Caturegli et al. (2000) generated transgenic mice that express constitutive Ifng in thyroid follicular cells. This expression resulted in severe hypothyroidism, with growth retardation and disruption of the thyroid architecture. The hypothyroidism derived from a profound inhibition of the expression of the sodium-iodide symporter gene.
Cho et al. (2000) showed that both the sodium-iodide symporter (NIS) expression level and radioiodide uptake (RAIU) activity in rat mammary gland are maximal during active lactation compared to those in the mammary glands of virgin and pregnant rats as well as those in the involuting mammary gland. In the lactating mammary gland, NIS is clustered on the basolateral membrane of alveolar cells as a lesser glycosylated form than NIS in thyroid. The RAIU of lactating mammary gland was partially inhibited by treatment with a selective oxytocin antagonist or bromocriptine, an inhibitor of prolactin (PRL; 176760) release. These findings suggested that RAIU and NIS expression in mammary gland are at least in part modulated by oxytocin and PRL. The authors concluded that NIS mRNA level was increased in a dose-dependent manner by oxytocin and PRL in histocultured human breast tumors.
Spitzweg et al. (1999) used both monoclonal and polyclonal antibodies directed against different portions of the SLC5A5 protein together with a highly sensitive immunostaining technique to assess SLC5A5 protein expression in tissue sections derived from normal human salivary and lacrimal glands, pancreas, and gastric and colonic mucosa. Immunohistochemical analysis of normal human salivary and lacrimal glands revealed marked SLC5A5 immunoreactivity in ductal cells and less intense staining of acinar cells. Further, immunostaining of gastric and colonic mucosa showed marked SLC5A5 immunoreactivity confined to chief and parietal cells in gastric mucosa and to epithelial cells lining mucosal crypts in colonic mucosa. In normal human pancreas, SLC5A5 immunoreactivity was located in ductal cells, exocrine parenchymal cells, and Langerhans islet cells. The authors concluded that iodide transport in these glands is a specific property conferred by the expression of SLC5A5 protein, which may serve important functions by concentrating iodine in glandular secretions.
In a review of sodium/substrate symporter family proteins, Jung (2002) stated that human NIS catalyzes uptake of Na+ and iodide with a 2:1 stoichiometry.
Fortunati et al. (2004) evaluated the action of valproic acid, a potent anticonvulsant reported to inhibit histone deacetylase, on cultured thyroid cancer cells. NPA (papillary or poorly differentiated; see 188550) and ARO (anaplastic) cells were treated with increasing valproic acid concentrations. Expression of mRNA and cell localization pattern for the sodium-iodide symporter (NIS), as well as iodine-125 uptake, were evaluated before and after treatment. Valproic acid induced NIS gene expression, NIS membrane localization, and iodide accumulation in NPA cells, and it was effective at clinically safe doses in the therapeutic range. In ARO cells, only induction of NIS mRNA was observed, and was not followed by any change in iodide uptake. The authors concluded that valproic acid is effective at restoring the ability of NPA cells to accumulate iodide.
Perchlorate (ClO(4-)) occurs naturally in the environment and is produced industrially in large quantities. Exposure to ClO(4-) is widespread in the U.S. population, but the potential health impact is unknown. Using canine kidney cells expressing human NIS, Dohan et al. (2007) found that NIS actively transported ClO(4-). However, unlike transport of Na+ and I- by NIS, transport of Na+ and ClO(4-) by NIS was electroneutral, indicating that movement of different substrates by transporters can show different stoichiometries. Nis transported and concentrated radiolabeled ClO(4-) into the milk of lactating rats and reduced uptake of I- in thyroids of both dams and pups. Dohan et al. (2007) concluded that ClO(4-) exposure may be a significant health risk due to its negative effect on thyroid I- levels.
In a patient with an iodide transport defect (274400), Fujiwara et al. (1997) found a homozygous missense mutation (T354P; 601843.0001) in the NIS gene. The parents were consanguineous. The diagnosis of iodide transport defect was based on a failure to concentrate radioiodide by the salivary gland and the clinical and biologic response to potassium iodide treatment. Treatment of the patient's physical findings and serum thyrotropin T4 and T3 levels were maintained. However, mild goiter and multiple mass lesions developed in the thyroid lobes. Histologically, a tumor was found to be follicular adenoma.
In a girl with congenital hypothyroidism and consanguineous parents, an iodide transport defect (TDH1; 274400) was indicated by physiologic studies and response to treatment with potassium iodide. Fujiwara et al. (1997) demonstrated homozygosity for a missense mutation in the sodium-iodide symporter gene: codon 354 was changed from ACA (thr) to CCA (pro). Expressed in HEK293 cells, the mutant gene failed to elicit any detectable iodide transport. According to the predicted protein structure, the mutated thr354 residue lies in the midst of the putative ninth transmembrane segment of the symporter protein. This transmembrane segment is conserved in the sodium/solute symporter family from mammals to bacteria and is a hotspot for the human sodium/glucose cotransporter gene (SGLT1), also symbolized SLC5A1 (182380).
Fujiwara et al. (1998) studied DNA from 3 apparently unrelated families with an iodide transport defect, 1 patient with low thyroid (99m)Tc-pertechnetate uptake, and 52 healthy controls for this mutation. All affected members of the families with the iodide transport defect had the mutation, suggesting that T354P is a recurrent mutation and a major cause of this disorder. The T354P mutation was not detected in the 52 unrelated, normal control samples. Because 2 patients homozygous for the T354P mutation developed multinodular goiters in their second decade of life despite being maintained in the euthyroid state, the authors concluded that homozygosity for the T354P mutation and/or low intrathyroid iodide and high serum thyroid-stimulating hormone levels in early life may account for tumorigenesis.
Matsuda and Kosugi (1997) reported a second Japanese case with the T354P mutation. They found that SLC5A5 mRNA was increased greater than 100-fold of that in the normal thyroid, suggesting possible compensation by overexpression.
Kosugi et al. (1998) identified a homozygous T354P germline mutation in the NIS gene in 7 Japanese patients, including 1 previously reported, from 5 unrelated families. These results suggest a common prevalence of the T354P mutation in Japanese patients. Although these 7 patients had the identical NIS mutation, marked heterogeneity in clinical pictures, especially concerning goiter and hypothyroidism, were noted among them.
Levy et al. (1998) reported that the lack of iodide transport activity in NIS carrying the T354P mutation generated by site-directed mutagenesis is not due to a structural change induced by proline, but rather to the absence of a hydroxyl group at the beta-carbon of the amino acid residue at position 354, indicating that this hydroxyl group is essential for NIS function.
Pohlenz et al. (1997) described a Brazilian kindred with congenital hypothyroidism due to a defect in iodide trapping (TDH1; 274400) caused by a homozygous mutation in the sodium-iodide symporter gene. The mutation was a C-to-A transversion of nucleotide 1163, resulting in a change of codon 272 from TGC (cys) to TGA (stop) (C272X). This nonsense mutation produced a truncated symporter protein with undetectable iodide transport activity when expressed in COS-7 cells. The propositus was homozygous; his unaffected mother, son, and paternal aunt were heterozygous. The propositus was a 39-year-old man who presented with a large goiter. Thyroid gland enlargement had been noted at 3 months of age and treatment with L-thyroxine was begun. Physical and mental development proceeded normally. His heterozygous relatives were clinically euthyroid and had normal or minimally enlarged thyroid glands.
Pohlenz et al. (1998) described a nonsense mutation producing a downstream cryptic 3-prime splice site in a 12-year-old girl with congenital hypothyroidism due to an iodide transport defect (TDH1; 274400). She was diagnosed at birth as athyreotic because her thyroid gland could not be visualized by isotope scanning. Goiter development due to incomplete thyrotropin suppression, a thyroidal radioiodide uptake of less than 1%, and a low saliva to plasma ratio of 2.5 suggested an iodide transport defect. Pohlenz et al. (1998) found that the NIS cDNA contained a C-to-G transversion at nucleotide 1146 in exon 6, resulting in a gln267 (CAG)-to-glu (GAG) substitution (Q267E). This missense mutation produced an NIS with undetectable iodide transport activity when expressed in COS-7 cells. Although only this missense mutation was identified in thyroid and lymphocyte cDNA, genotyping revealed that the proposita and her unaffected brother and father were heterozygous for this mutation. Amplification of cDNA with a primer specific for the wildtype nucleotide 1146 yielded a sequence lacking 67 nucleotides. Genomic DNA showed a C-to-G transversion at nucleotide 1940, producing a stop codon as well as a new downstream cryptic 3-prime splice acceptor site in exon 13, responsible for the 67-bp deletion, frameshift, and premature stop predicting an NIS lacking 129 C-terminal amino acids. This mutation was inherited from the mother and present in the unaffected sister. Thus, although the proposita was a compound heterozygote, because of the very low expression (less than 2.5%) of 1 mutant allele, she was functionally hemizygous for an NIS without detectable bioactivity.
See 601843.0003. The proposita with congenital hypothyroidism due to an iodide transport defect (TDH1; 274400) reported by Pohlenz et al. (1998) was a compound heterozygote for a Q267E mutation inherited from the father (601843.0003) and a tyr531-to-ter (Y531X) mutation inherited from the mother. The nonsense mutation was created by a C-to-G transversion at nucleotide 1940 in exon 13. This nucleotide substitution not only produced a stop (TAG) at codon 531 but also created a new 3-prime splice acceptor site (AC to AG) for intron 12, located downstream of the authentic splice acceptor site. This new cryptic 3-prime splice acceptor site with its corresponding branch site matched the mammalian consensus sequences better and was therefore used preferentially.
In a Japanese patient with iodide transport defect (TDH1; 274400), Kosugi et al. (1998) identified germline mutations in the SLC5A5 gene. The patient was a compound heterozygote for the T354P (601843.0001) mutation and a novel gly93-to-arg (G93R) substitution, located in the third transmembrane domain of the SLC5A5 gene which is encoded by exon 1. When expressed in COS-7 cells, the SLC5A5 constructs carrying these mutations had minimal iodide uptake activity, confirming that the identified mutations are the direct cause of the iodide transport defect in this patient.
In 2 Japanese sibs with iodide transport defect (TDH1; 274400), Kosugi et al. (1998) identified a gly543-to-glu (G543E) substitution in the SLC5A5 gene. The mutation was present in a homozygous state and was located in the twelfth transmembrane domain, which is encoded by exon 13. When expressed in COS-7 cells, the SLC5A5 constructs carrying this mutation had minimal iodide uptake activity, confirming that the identified mutation is the direct cause of the iodide transport defect in these patients.
In a large Hutterite family with extensive consanguinity living in central Canada, Couch et al. (1985) identified 9 children with an autosomal recessive form of congenital hypothyroidism due to an iodide transport defect (TDH1; 274400). By newborn thyroid-stimulating hormone (TSH; see 188540) screening, Kosugi et al. (1999) diagnosed congenital hypothyroidism in 9 additional children (18 total) in the same family. They sequenced the PCR products of each SLC5A5 gene exon with flanking introns amplified from genomic DNA extracted from peripheral blood cells of the patients. In 10 patients, they identified a G-to-A transition at nucleotide 1530 of the SLC5A5 gene, resulting in a gly395-to-arg substitution (G395R). All of the parents tested were heterozygous for the mutation, suggesting that the patients were homozygous. The mutation was located in the tenth transmembrane helix. Expression experiments by transfection of the mutant SLC5A5 cDNA into COS-7 cells showed no perchlorate-sensitive iodide uptake, confirming that the mutation was the direct cause of the iodide transport defect in these patients.
In 2 Spanish sibs with congenital hypothyroidism due to total failure of iodide transport (TDH1; 274400) reported by Albero et al. (1987), Kosugi et al. (2002) identified a homozygous deletion of 6,192 bp spanning from exon 3 to intron 7 and an inverted insertion of a 431-bp fragment spanning from exon 5 to intron 5 of the SLC5A5 gene. The mother was heterozygous for the mutation. The deletion of exons 3-7 predicted an in-frame 182-amino acid deletion from met142 in the fourth transmembrane domain to gln323 in the fourth exoplasmic loop of the protein. Transfection experiments confirmed that the mutation was the direct cause of iodide transport defect in these patients.
Albero, R., Cerdan, A., Sanchez Franco, F. Congenital hypothyroidism from complete iodide transport defect: long-term evolution with iodide treatment. Postgrad. Med. J. 63: 1043-1047, 1987. [PubMed: 3451231] [Full Text: https://doi.org/10.1136/pgmj.63.746.1043]
Arturi, F., Russo, D., Schlumberger, M., du Villard, J.-A., Caillou, B., Vigneri, P., Wicker, R., Chiefari, E., Suarez, H. G., Filetti, S. Iodide symporter gene expression in human thyroid tumors. J. Clin. Endocr. Metab. 83: 2493-2496, 1998. [PubMed: 9661633] [Full Text: https://doi.org/10.1210/jcem.83.7.4974]
Caturegli, P., Hejazi, M., Suzuki, K., Dohan, O., Carrasco, N., Kohn, L. D., Rose, N. R. Hypothyroidism in transgenic mice expressing IFN-gamma in the thyroid. Proc. Nat. Acad. Sci. 97: 1719-1724, 2000. [PubMed: 10677524] [Full Text: https://doi.org/10.1073/pnas.020522597]
Cho, J.-Y., Leveille, R., Kao, R., Rousset, B., Parlow, A. F., Burak, W. E., Jr., Mazzaferri, E. L., Jhiang, S. M. Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands. J. Clin. Endocr. Metab. 85: 2936-2943, 2000. [PubMed: 10946907] [Full Text: https://doi.org/10.1210/jcem.85.8.6727]
Couch, R. M., Dean, H. J., Winter, J. S. Congenital hypothyroidism caused by defective iodide transport. J. Pediat. 106: 950-953, 1985. [PubMed: 3998954] [Full Text: https://doi.org/10.1016/s0022-3476(85)80249-3]
Dai, G., Levy, O., Carrasco, N. Cloning and characterization of the thyroid iodide transporter. Nature 379: 458-460, 1996. [PubMed: 8559252] [Full Text: https://doi.org/10.1038/379458a0]
Dohan, O., Portulano, C., Basquin, C., Reyna-Neyra, A., Amzel, L. M., Carrasco, N. The Na+/I- symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate. Proc. Nat. Acad. Sci. 104: 20250-20255, 2007. [PubMed: 18077370] [Full Text: https://doi.org/10.1073/pnas.0707207104]
Fortunati, N., Catalano, M. G., Arena, K., Brignardello, E., Piovesan, A., Boccuzzi, G. Valproic acid induces the expression of the Na+/I- symporter and iodine uptake in poorly differentiated thyroid cancer cells. J. Clin. Endocr. Metab. 89: 1006-1009, 2004. [PubMed: 14764827] [Full Text: https://doi.org/10.1210/jc.2003-031407]
Fujiwara, H., Tatsumi, K., Miki, K., Harada, T., Miyai, K., Takai, S., Amino, N. Congenital hypothyroidism caused by a mutation in the Na(+)/I(-) symporter. (Letter) Nature Genet. 16: 124-125, 1997. Note: Erratum: Nature Genet. 17: 122 only, 1997. [PubMed: 9171822] [Full Text: https://doi.org/10.1038/ng0697-124]
Fujiwara, H., Tatsumi, K.-I., Miki, K., Harada, T., Okada, S., Nose, O., Kodama, S., Amino, N. Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect. J. Clin. Endocr. Metab. 83: 2940-2943, 1998. [PubMed: 9709973] [Full Text: https://doi.org/10.1210/jcem.83.8.5029]
Jung, H. The sodium/substrate symporter family: structural and functional features. FEBS Lett. 529: 73-77, 2002. [PubMed: 12354616] [Full Text: https://doi.org/10.1016/s0014-5793(02)03184-8]
Kosugi, S., Bhayana, S., Dean, H. J. A novel mutation in the sodium/iodide symporter gene in the largest family with iodide transport defect. J. Clin. Endocr. Metab. 84: 3248-3253, 1999. [PubMed: 10487695] [Full Text: https://doi.org/10.1210/jcem.84.9.5971]
Kosugi, S., Inoue, S., Matsuda, A., Jhiang, S. M. Novel, missense and loss-of-function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients. J. Clin. Endocr. Metab. 83: 3373-3376, 1998. [PubMed: 9745458] [Full Text: https://doi.org/10.1210/jcem.83.9.5245]
Kosugi, S., Okamoto, H., Tamada, A., Sanchez-Franco, F. A novel peculiar mutation in the sodium/iodide symporter gene in Spanish siblings with iodide transport defect. J. Clin. Endocr. Metab. 87: 3830-3836, 2002. [PubMed: 12161518] [Full Text: https://doi.org/10.1210/jcem.87.8.8767]
Kosugi, S., Sato, Y., Matsuda, A., Ohyama, Y., Fujieda, K., Inomata, H., Kameya, T., Isozaki, O., Jhiang, S. M. High prevalence of T354P sodium/iodide symporter gene mutation in Japanese patients with iodide transport defect who have heterogeneous clinical pictures. J. Clin. Endocr. Metab. 83: 4123-4129, 1998. [PubMed: 9814502] [Full Text: https://doi.org/10.1210/jcem.83.11.5229]
Lazar, V., Bidart, J.-M., Caillou, B., Mahe, C., Lacroix, L., Filetti, S., Schlumberger, M. Expression of the Na(+)/I(-) symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J. Clin. Endocr. Metab. 84: 3228-3234, 1999. [PubMed: 10487692] [Full Text: https://doi.org/10.1210/jcem.84.9.5996]
Levy, O., Ginter, C. S., De la Vieja, A., Levy, D., Carrasco, N. Identification of a structural requirement for thyroid Na(+)/I(-) symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism. FEBS Lett. 429: 36-40, 1998. [PubMed: 9657379] [Full Text: https://doi.org/10.1016/s0014-5793(98)00522-5]
Matsuda, A., Kosugi, S. A homozygous missense mutation of the sodium/iodide symporter gene causing iodide transport defect. J. Clin. Endocr. Metab. 82: 3966-3971, 1997. [PubMed: 9398697] [Full Text: https://doi.org/10.1210/jcem.82.12.4425]
Ohmori, M., Endo, T., Harii, N., Onaya, T. A novel thyroid transcription factor is essential for thyrotropin-induced up-regulation of Na+/I- symporter gene expression. Molec. Endocr. 12: 727-736, 1998. [PubMed: 9605935] [Full Text: https://doi.org/10.1210/mend.12.5.0101]
Pohlenz, J., Medeiros-Neto, G., Gross, J. L., Silveiro, S. P., Knobel, M., Refetoff, S. Hypothyroidism in a Brazilian kindred due to iodide trapping defect caused by a homozygous mutation in the sodium/iodide symporter gene. Biochem. Biophys. Res. Commun. 240: 488-491, 1997. [PubMed: 9388506] [Full Text: https://doi.org/10.1006/bbrc.1997.7594]
Pohlenz, J., Rosenthal, I. M., Weiss, R. E., Jhiang, S. M., Burant, C., Refetoff, S. Congenital hypothyroidism due to mutations in the sodium/iodide symporter: identification of a nonsense mutation producing a downstream cryptic 3-prime splice site. J. Clin. Invest. 101: 1028-1035, 1998. [PubMed: 9486973] [Full Text: https://doi.org/10.1172/JCI1504]
Smanik, P. A., Liu, Q., Furminger, T. L., Ryu, K., Xing, S., Mazzaferri, E. L., Jhiang, S. M. Cloning of the human sodium iodide symporter. Biochem. Biophys. Res. Commun. 226: 339-345, 1996. [PubMed: 8806637] [Full Text: https://doi.org/10.1006/bbrc.1996.1358]
Smanik, P. A., Ryu, K.-Y., Theil, K. S., Mazzaferri, E. L., Jhiang, S. M. Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter. Endocrinology 138: 3555-3558, 1997. [PubMed: 9231811] [Full Text: https://doi.org/10.1210/endo.138.8.5262]
Spitzweg, C., Joba, W., Schriever, K., Goellner, J. R., Morris, J. C., Heufelder, A. E. Analysis of human sodium iodide symporter immunoreactivity in human exocrine glands. J. Clin. Endocr. Metab. 84: 4178-4184, 1999. [PubMed: 10566669] [Full Text: https://doi.org/10.1210/jcem.84.11.6117]
Venkataraman, G. M., Yatin, M., Marcinek, R., Ain, K. B. Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na(+)/I(-) symporter gene methylation status. J. Clin. Endocr. Metab. 84: 2449-2457, 1999. [PubMed: 10404820] [Full Text: https://doi.org/10.1210/jcem.84.7.5815]