This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujiwara, H. Articles by Amino, N. Search for Related Content PubMed PubMed Citation Articles by Fujiwara, H. Articles by Amino, N.

Recurrent T354P Mutation of the Na⁺/I^- Symporter in Patients with Iodide Transport Defect¹

Department of Laboratory Medicine, D2 (H.F., K.T., N.A.) and Department of Pediatrics, D5 (K.M., T.H., S.O.), Osaka University Medical School, Osaka 565-0871, Japan; Nose Clinic (O.N.), Osaka 530, Japan; and Department of Pediatrics, Himeji Red Cross Hospital (S.K.), Hyogo 670, Japan

Address all correspondence and requests for reprints to: Tatsumi Ke-ita, Department of Laboratory Medicine, D2, Osaka University Medical School, Suita-shi Yamada-oka 2–2, Osaka 565-0871, Japan. E-mail: tatsumi{at}labo.med.osaka-u.ac.jp

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
Iodide transport defect (ITD) is a rare disorder causing congenital hypothyroidism. We previously reported that homozygous T354P mutation in the sodium/iodide symporter (NIS) gene caused ITD. To clarify the prevalence of this mutation, artificial substitution introducing PCR followed by restriction enzyme analysis was developed as a rapid screening method to detect the T354P mutation. Three apparently unrelated families with ITD, one patient with low thyroidal ^99mTc pertechnetate (^99mTcO₄^-) uptake and 52 healthy controls (104 alleles) were analyzed for this mutation. All families with ITD harbored the mutation, suggesting that T354P is a recurrent mutation and a major cause of ITD. This was not a widespread mutation, because it was not detected in the 52 unrelated normal controls. Because two cases with homozygous T354P mutation developed multinodular goiters within their second decade of life though they had been maintained in euthyroid state, homozygous T354P mutation alone and/or low intrathyroidal iodide and high serum TSH level in early life might account for tumorigenesis. The patient with low thyroidal ^99mTcO₄^- uptake did not harbor the T354P mutation. Because familial hypocalciuric hypercalcemia was also present in this family, a possibility of the combined abnormality of TSH receptor and calcium functions, which includes an abnormality around the G protein, may be examined further.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
IODIDE transport defect (ITD) is a rare disorder caused by the absence or malfunction of iodide transport into the thyroid gland, which is a first and important step in the biosynthesis of the thyroid hormones (1). It is a well-known type of familial goiter with or without cretinism (2).

ITD is usually found by neonatal mass screening as a primary hypothyroidism, and may be misclassified as thyroid agenesis or TSH unresponsiveness because of the low thyroidal uptake of radioiodide. In the thyroid follicle, iodide is concentrated 30–40 times more than plasma levels, enabling the thyroid gland to generate thyroid hormones (2). Iodide is also concentrated at the salivary gland, gastric mucosa, and mammary gland (3), and diffuses from blood into thyroid follicular cells to some extent (2). From this evidence, no concentration of iodide or ^99mTcO₄^- by the salivary gland is required in the diagnostic criteria for ITD (2). In fact, some patients in Japan showed goiter without hypothyroid symptoms even in adulthood because of a high dietary intake of iodine (4, 5). Some other cases developed hypothyroidism after a few months of breast feeding, because iodide is concentrated in breast milk (3).

The sodium/iodide symporter (NIS) (6), a member of the sodium-dependent solute symporter family (7), actively transports iodide from blood into thyroid follicular cells in the presence of the sodium gradient. We previously reported a single nucleotide substitution in the 354th codon converted from ACA (Thr) to CCA (Pro) in the NIS gene of a patient with ITD (8). The substituted threonine lies in the midst of a well-conserved putative transmembrane segment, where threonine itself is well conserved within the sodium/solute symporter family. Expression of NIS with this T354P mutation in cultured cells resulted in a severe loss of iodide transport activity, and showed that this was the direct cause of ITD in the patient. Recently, another homozygous nonsense mutation (C272X) in the NIS gene causing ITD was reported by Pohlenz et al. (9). This mutation also impaired iodide transport activity in cultured cells.

To clarify the significance of the T354P mutation of the NIS gene in some Japanese patients (4), we developed a rapid screening method of the mutation. This method enabled us to analyze the mutation easily without sequencing the gene. Five patients from three unrelated families with ITD were analyzed for the T354P mutation using this method, and all patients harbored the mutation.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
Subjects

Five patients (from three families) with ITD and one patient with low thyroidal ^99mTcO₄^- uptake were examined. Most of the clinical profiles of the patients were reported previously (4, 8, 10). No relationship among these families was found. Clinical and biological data of these cases are summarized in Table 1.

Fifty-two healthy individuals who did not have any thyroid disorder were examined as normal controls.

Case 1: 13-yr-old female with ITD (8)

This patient had consanguineous parents. Her whole blood TSH level was high (>160 mU/L; normal, <20 mU/L) on neonatal screening. At 28 days of age, both her serum thyroid hormones levels and TSH level became normal (T₄, 88 µg/L; T₃, 2.48 µg/L; TSH, 6.5 mU/L), presumably because of high iodide concentration in the breast milk in Japanese population (4, 5). At 3 months of age she showed constipation and poor feeding and was found to have primary hypothyroidism (Table 1). Treatment with levothyroxine was started immediately. At 3 yr of age, she was diagnosed as ITD because she failed to concentrate radioiodide by the salivary gland and responded to potassium iodide treatment. Although she was maintained in euthyroid state with normal serum TSH, free T₄, and free T₃ concentrations, mild goiter developed at 8 yr of age, and multiple mass lesions developed in both thyroid lobes at 11 yr of age. A left hemithyroidectomy was carried out, and pathological diagnosis was follicular adenoma.

We previously showed that this patient had the T354P mutation in the NIS gene (8).

Case 2: 41-yr-old male with ITD (4)

His parents were first cousins and there was no family history of thyroid disorders. At 5 yr of age, he was diagnosed as hypothyroid because of his developmental retardation, and desiccated thyroid powder was supplied. At 13 yr of age, he developed a cervical tumor. It was partially resected, and the histological examination revealed numerous adenomatous nodules. Its diagnosis was adenomatous goiter. Salivary radioiodide/serum trichloroacetic-acid-soluble radioiodide ratios (S/P ratio) of ¹³¹I^- was 0.94, indicating ITD. He maintained in euthyroid state with potassium iodide treatment and was diagnosed ITD.

Cases 3a–3c

Cases 3a, 3b, and 3c are siblings with ITD (4). Their parents were not consanguineous and were healthy without thyroid malfunction.

Case 3a: 31-yr-old male. He was fed on cow’s milk during early infancy. At 3 yr of age, he showed developmental retardation and was diagnosed as hypothyroid. He was treated with desiccated thyroid powder, and his physical development was improved. At 8 yr of age, he was diagnosed as ITD because of loss of concentration of radioiodide by salivary gland. He was mentally retarded. A small goiter was observed after 2 weeks on an iodine-free diet.

Case 3b: 33-yr-old female. She was breastfed and also given cow’s milk during early infancy. Motor activity was slightly sluggish, and she complained of constipation. At 10 yr of age, she developed a small goiter and was short (<2 SD). She was also diagnosed as ITD because of loss of concentration of radioiodide by the salivary gland. Her mental state was borderline.

Case 3c: 36-yr-old female. She was breastfed during early infancy. At 13 yr of age, she was apparently normal except for her slightly short stature (within 2 SD), and a slightly enlarged thyroid was palpable. She was also diagnosed as ITD because of loss of concentration of radioiodide by the salivary gland. Her mental state was normal.

Case 4: 5-yr-old female with low ^99mTcO₄^- uptake (10)

Her TSH level was high on neonatal screening. At 44 days of age, she showed edema, umbilical hernia, and megaloglossia. Laboratory findings showed primary hypothyroidism. Ultrasound imaging indicated a normally sized and sited thyroid gland, but it failed to uptake ^99mTcO₄^-.

At 1 yr of age, she developed multiple cutaneous nodes in her abdomen and legs with hypercalcemia, hypocalciuria, and a normal serum PTH level. Because similar cutaneous nodes, hypercalcemia, and hypocalciuria were also found in her mother, they were diagnosed as familial hypocalciuric hypercalcemia (FHH). The thyroid functions of the mother, however, were within a normal range.

S/P ratio

S/P ratio was determined as described previously (4, 11). In brief, the S/P ratio of iodide was determined 2 or 4 h after iv or oral administration of radioiodide. Blood was withdrawn, and naturally expectorated saliva (mixed) was collected for 5–10 min. The saliva was centrifuged for removal of contaminating solid, and the radioactivity in 1 mL of the supernatant was determined. To the serum was added trichloroacetic acid to 10% followed by centrifugation, and the radioactivity in 1 mL of the supernatant was determined. Saliva/serum ratio was calculated (11). The S/P ratio normally is greater than 10; it is 1 or less in patients with ITD (12).

Screening of the T354P mutation from genomic DNA

Genomic DNA was isolated from peripheral blood by a simple salting out procedure (13).

PCR amplification

PCR was used to amplify genomic DNA fragments containing the T354P mutation and to introduce an artificial substitution (Fig. 1). Cycling conditions were at 94 C for 2 min (one cycle); at 94 C for 30 sec, at 60 C for 1 min, at 72 C for 30 sec (30 cycles); and final extension at 72 C for 5 min with primers phNIS354(-20)U, 5'-CGCTGCCTTCCTCACACGGC-3' and phNIS389L, 5'-CCCCTTGGAGATAATCACGA-3'. The underlined nucleotide in primer phNIS354(-20)U indicates the substituted nucleotide, introducing a HaeIII site in the copies of the mutant allele.

View larger version (21K): [in this window] [in a new window]   Figure 1. Schematic representation of screening method of T354P mutation by HaeIII digestion of artificial substitution introduced PCR-amplified fragments. Exon 9 of NIS gene encompassing T354P mutation is boxed (14 ). Mutation is an A to C transition at 2nd base of exon 9 of NIS gene.

The PCR product containing the codon 354 of the NIS gene was digested at 37 C for 2 h with restriction enzyme HaeIII (Toyobo, Osaka, Japan). Digested products were visualized after electrophoresis in an agarose gel [4% NuSieve 3:1 Agarose (FMC BioProducts, Rockland, ME), 1x TBE buffer] with 100 V for 30 min and staining with ethidium bromide.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
Evaluation of screening method for the T354P mutation in case 1

As previously reported, case 1 was homozygous, and her healthy parents and two siblings were heterozygous for the T354P mutation (8). Genomic DNA from case 1 and her family members were amplified by PCR and produced a 128-bp fragment containing the codon 354 (Fig. 1). The 128-bp fragment from wild-type NIS gene has no HaeIII restriction site. But the adenine to cytosine transition at the first base position of codon 354 makes one HaeIII restriction site in the PCR products and produces fragments of 20- and 108-bp in length after digestion of HaeIII (Fig. 1). The HaeIII digested PCR-amplified fragment from case 1 showed only the 108-bp fragment, whereas those from her family members showed the 108- and 128-bp fragments, and those from normal control showed only the 128-bp fragment (Fig. 2A). These results were completely consistent with our previously reported results obtained by direct sequencing (8).

View larger version (47K): [in this window] [in a new window]   Figure 2. Screening of T354P mutation by HaeIII digestion of artificial substitution introduced PCR-amplified fragments. HaeIII recognized a site created by the T354P mutation and artificial substitution introduced by PCR primer (Fig. 1). Sizes of fragment are indicated at right in base pairs. Marker is pBR322 DNA-MspI digest. Filled circle, homozygous; half-filled box and half-filled circle, heterozygous for T354P mutation. Arrows show probands; double bars, consanguineous marriage.

Screening for T354P mutation in remaining cases

In case 2, HaeIII digested PCR-amplified fragments showed only the 108-bp fragment (Fig. 2B), indicating homozygosity for the T354P mutation.

In cases 3a, 3b, and 3c, HaeIII-digested PCR products yielded 108- and 128-bp fragments in the three patients and their mother, and only the 128-bp fragment in their father (Fig. 2B). Thus the three patients and their mother were heterozygous for the mutation, whereas their father did not harbor the mutation.

In case 4, the PCR product digested by HaeIII yielded fragments of only 128-bp in length (Fig. 2B), showing that the mutation was absent in the genomic DNA from case 4.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
We reported the T354P mutation of the NIS gene in case 1 as a cause of congenital ITD (8). To evaluate the prevalence of this mutation in ITD and in the normal population, we established a rapid screening method for the T354P mutation.

In this study, the T354P mutation was identified in five cases of three unrelated families including case 1. The mutation is recurrent and seems to be a major cause of ITD. Because of the absence of the mutation in the 52 healthy individuals, the frequency of the T354P mutation is assumed to be low in the general population. Although no relationships among these families were discovered, and these families derived from remote districts in Japan, they could have had a common ancestor. Another possibility is that this mutation might be a hot spot and occurred independently. Further analysis is necessary to discriminate between these possibilities.

Cases 3a, 3b, and 3c were heterozygous for the mutation, which derived from their mother (Fig. 2B). Their father did not have the mutation, and the parents were healthy, without any thyroid disorder (4). In case 1, ITD developed only in the patient who was homozygous for the T354P mutation and not in her parents and two siblings, who were heterozygous. T₄, resin T₃ uptake (RT₃U), TSH, and ¹³¹I^- thyroidal uptake in the parents of cases 3a, 3b, and 3c after 2 weeks on an iodine-free diet were mostly in the normal range. The S/P ratios of ¹³¹I^- were 37.5 in their father and 19.4 in their mother (4), which were in the normal range. Therefore, iodide transport ability of thyroid gland in the mother, who was heterozygous for T354P mutation, was considered to be within normal range. Another unknown abnormality, therefore, is probably present in the patients’ and their father’s NIS gene. The genomic structure of the human NIS gene has been published (14), but to analyze the patients’ genomic DNA, further information about the intron sequences adjacent to the intron-exon boundaries is necessary.

Because the T354P mutation was absent in the genomic DNA from case 4 (Fig. 2B), other abnormalities in the NIS gene could have provoked hypothyroidism. Alternatively, because concentrations of radioiodide or ^99mTcO₄^- by the salivary gland was not measured in this case, low thyroidal ^99mTcO₄^- uptake might be caused by TSH unresponsiveness.

Case 4 was also accompanied by FHH. One cause of FHH is the inactivation of the human calcium-sensing receptor (CaR) (15). Because both TSH receptor and CaR are coupled to G protein, which is composed of the three subunits , ß, and (16, 17), an abnormality of a common subunit coupling to both TSHR and CaR may cause both low thyroidal ^99mTcO₄^- uptake and FHH. We need a more precise examination to elucidate this possibility.

Symptoms of hypothyroidism in the three sibling cases (3a, 3b, and 3c) who were heterozygous for the T354P mutation, were relatively mild in contrast to cases 1 and 2, who were homozygous for the mutation (Table 1). Goiters were small in cases 3b and 3c when first seen at 10 and 13 yr of age, respectively, and in case 3a, diffuse goiter was observed only after 2 weeks on an iodine-free diet. But in both cases 1 and 2, who were homozygous for the mutation, their thyroid glands enlarged gradually and developed multinodular goiters. Although they had been maintained in euthyroid state, the multinodular goiters required partial resection at 11 and 14 yr of age, respectively (4, 8). On the other hand, cases 3a, 3b, and 3c did not develop any tumors even after 20 yr of follow-up. Because the clinical course of multinodular goiters in cases 1 and 2 were rapid compared with common multinodular goiters (18), it is interesting to speculate that a homozygous but not heterozygous T354P mutation might be associated with tumorigenesis.

Alternatively, low intrathyroidal iodide and high serum TSH level for a short period in early life may account for tumorigenesis. In the autonomously functioning thyroid nodules, the incidence of activating mutations in TSH receptor was reported to be low in Japan compared with Europe (19). Because Japan is relatively iodide-sufficient area compared with Europe, iodide deficiency alone might increase somatic tumorigenic mutation rate in the subpopulation of thyroid follicular cells with high growth potential, but as observed in cases of endemic goiter with iodide deficiency, diffuse goiter in iodide deficiency commonly develops nodularity in adults (20). In case 1, serum TSH level rose as high as 730 mU/L at 3 months of age with presumably low intrathyroidal iodide. The thyroid stimulating effect of TSH is enhanced by low intrathyroidal iodide concentration, so the extremely high TSH level for a short period in early life in case 1 might greatly enhanced initiation of somatic tumorigenic mutations or focal hyperplasia in multiple thyroid follicular cells and have resulted in multinodular goiter in at a young age.

To understand whether the homozygous T354P mutation or low intrathyroidal iodide and high serum TSH level in early life account for tumorigenesis independently or work in combination, we must wait and see whether other cases of ITD with multinodular goiter in young patients have the same mutation or similar hormonal events.

	Note Added in Proof

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 
Recently, Matsuda et al. reported another case of homozygous T354P mutation in Japan (J Clin Endocrinol Metab. 82: 3966–3971, 1997), and Pohlenz et al. reported a case of novel compound heterozygous recessive mutations (J Clin Invest. 101: 1028–1035, 1998).

	Footnotes

 
¹ This work was supported in part by grants from the Ministry of Education, Science and Culture; the Ministry of Health and Welfare of Japan; the Foundation for Growth Science in Japan; and the Clinical Pathology Research Foundation of Japan.

Received January 23, 1998.

Revised April 29, 1998.

Accepted May 5, 1998.

	References

Top Abstract Introduction Subjects and Methods Results Discussion Note Added in Proof References

 

1. Wolff J. 1983 Congenital goiter with defective iodide transport. Endocr Rev. 4:240–254.[Medline]
2. Stanbury JB. 1972 Familial goiter. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, eds. The metabolic basis of inherited disease. 3rd ed. New York: McGraw-Hill; 223–265.
3. Brown-Grant K. 1961 Extrathyroidal iodide concentrating mechanisms. Physiol Rev. 41:189–214.[Free Full Text]
4. Toyoshima K, Matsumoto Y, Nishida M, et al. 1977 Five cases of absence of iodide concentrating mechanism. Acta Endocrinol (Copenh). 84:527–537.[Medline]
5. Nagataki S, Shizume K, Nakao K. 1967 Thyroid function in chronic excess iodide ingestion: comparison of thyroidal absolute iodine uptake and degradation of thyroxine in euthyroid Japanese subjects. J Clin Endocrinol Metab. 27:638–647.[Medline]
6. Dai G, Levy O, Carrasco N. 1996 Cloning and characterization of the thyroid iodide transporter. Nature. 379:458–460.[CrossRef][Medline]
7. Reizer J, Reizer A, Saier Jr MH. 1994 A functional superfamily of sodium/solute symporters. Biochim Biophys Acta. 1197:133–166.[Medline]
8. Fujiwara H, Tatsumi K, Miki K, et al. 1997 Congenital hypothyroidism caused by a missense mutation in the Na⁺/I^- symporter. Nature Genetics. 16:124–125. [corrections: 1997 Nature Genetics. 17:122.].[CrossRef][Medline]
9. Pohlenz J, Medeiros-Neto G, Gross JL, et al. 1997 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.[CrossRef][Medline]
10. Kodama S, Yoshimura R, Shimizu H, et al. 1994 The diagnostic study of congenital hypothyroidism based on scintigraphy, ultrasound imaging and serum thyroglobulin level. In: Takasugi N, Naruse H, eds. New trends in neonatal screening. Sapporo, Japan: Hokkaido Univ. Press; 213–216.
11. Stanbury JB, Chapman EM. 1960 Congenital hypothyroidism with goiter. Lancet. 1:1162–1165.[Medline]
12. Sarne DH, Refetoff S. 1995 Thyroid function tests. In: DeGroot LJ, eds. Endocrinology, 3rd ed. Philadelphia: WB Saunders; 617–664. vol 1.
13. Miller SA, Dykes DD, Polesky HF. 1988 A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16:1215.[Free Full Text]
14. Smanik PA, Ryu KY, Theil KS, et al. 1997 Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter. Endocrinology. 138:3555–3558.[Abstract/Free Full Text]
15. Pollak MR, Brown EM, Chou YH, et al. 1993 Mutations in the human Ca²⁺ sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 75:1297–1303.[CrossRef][Medline]
16. Patten JL, Johns DR, Valle D, et al. 1990 Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med. 322:1412–1419.[Abstract]
17. Spiegel AM. 1996 Defects in G protein-coupled signal transduction in human disease. Annu Rev Physiol. 58:143–170.[CrossRef][Medline]
18. Yoshida S, Takamatsu J, Kuma K, et al. 1996 A variant of adenomatous goiter with characteristic histology and possible hereditary thyroglobulin abnormality. J Clin Endocrinol Metab. 81:1961–1966.[Abstract]
19. Takeshita A, Nagayama Y, Yokoyama N, et al. 1995 Rarity of oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in Japan. J Clin Endocrinol Metab. 80:2607–2611.[Abstract]
20. Studer H, Gerber H. 1995 Multinodular Goiter. In: DeGroot LJ, eds. Endocrinology, 3rd ed. Philadelphia: WB Saunders; 769–782. vol 1.

This article has been cited by other articles:

				M. D. Reed-Tsur, A. De la Vieja, C. S. Ginter, and N. Carrasco Molecular Characterization of V59E NIS, a Na+/I- Symporter Mutant that Causes Congenital I- Transport Defect Endocrinology, June 1, 2008; 149(6): 3077 - 3084. [Abstract] [Full Text] [PDF]

				G. Riesco-Eizaguirre and P. Santisteban A perspective view of sodium iodide symporter research and its clinical implications. Eur. J. Endocrinol., October 1, 2006; 155(4): 495 - 512. [Abstract] [Full Text] [PDF]

				G. Szinnai, S. Kosugi, C. Derrien, N. Lucidarme, V. David, P. Czernichow, and M. Polak Extending the Clinical Heterogeneity of Iodide Transport Defect (ITD): A Novel Mutation R124H of the Sodium/Iodide Symporter Gene and Review of Genotype-Phenotype Correlations in ITD J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1199 - 1204. [Abstract] [Full Text] [PDF]

				A. De la Vieja, C. S. Ginter, and N. Carrasco Molecular Analysis of a Congenital Iodide Transport Defect: G543E Impairs Maturation and Trafficking of the Na+/I- Symporter Mol. Endocrinol., November 1, 2005; 19(11): 2847 - 2858. [Abstract] [Full Text] [PDF]

				Z. Zhang, Y.-Y. Liu, and S. M. Jhiang Cell Surface Targeting Accounts for the Difference in Iodide Uptake Activity between Human Na+/I- Symporter and Rat Na+/I- Symporter J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6131 - 6140. [Abstract] [Full Text] [PDF]

				K. Krohn, D. Fuhrer, Y. Bayer, M. Eszlinger, V. Brauer, S. Neumann, and R. Paschke Molecular Pathogenesis of Euthyroid and Toxic Multinodular Goiter Endocr. Rev., June 1, 2005; 26(4): 504 - 524. [Abstract] [Full Text] [PDF]

				A. De la Vieja, C. S. Ginter, and N. Carrasco The Q267E mutation in the sodium/iodide symporter (NIS) causes congenital iodide transport defect (ITD) by decreasing the NIS turnover number J. Cell Sci., February 15, 2004; 117(5): 677 - 687. [Abstract] [Full Text] [PDF]

				O. Dohan, A. De la Vieja, V. Paroder, C. Riedel, M. Artani, M. Reed, C. S. Ginter, and N. Carrasco The Sodium/Iodide Symporter (NIS): Characterization, Regulation, and Medical Significance Endocr. Rev., February 1, 2003; 24(1): 48 - 77. [Abstract] [Full Text] [PDF]

				D.-M. Niu, B. Hwang, Y.-K. Chu, C.-J. Liao, P.-L. Wang, and C.-Y. Lin High Prevalence of a Novel Mutation (2268 insT) of the Thyroid Peroxidase Gene in Taiwanese Patients with Total Iodide Organification Defect, and Evidence for a Founder Effect J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4208 - 4212. [Abstract] [Full Text] [PDF]

				S. Kosugi, H. Okamoto, A. Tamada, and F. Sanchez-Franco A Novel Peculiar Mutation in the Sodium/Iodide Symporter Gene in Spanish Siblings with Iodide Transport Defect J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3830 - 3836. [Abstract] [Full Text] [PDF]

				O. Dohan, M. V. Gavrielides, C. Ginter, L. M. Amzel, and N. Carrasco Na+/I- Symporter Activity Requires a Small and Uncharged Amino Acid Residue at Position 395 Mol. Endocrinol., August 1, 2002; 16(8): 1893 - 1902. [Abstract] [Full Text] [PDF]

				A. De la Vieja, O. Dohan, O. Levy, and N. Carrasco Molecular Analysis of the Sodium/Iodide Symporter: Impact on Thyroid and Extrathyroid Pathophysiology Physiol Rev, July 1, 2000; 80(3): 1083 - 1105. [Abstract] [Full Text] [PDF]

				S. Kosugi, S. Bhayana, and H. J. Dean A Novel Mutation in the Sodium/Iodide Symporter Gene in the Largest Family with Iodide Transport Defect J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3248 - 3253. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujiwara, H. Articles by Amino, N. Search for Related Content PubMed PubMed Citation Articles by Fujiwara, H. Articles by Amino, N.