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Expression of Pendrin and the Pendred Syndrome (PDS) Gene in Human Thyroid Tissues¹

Departments of Clinical Biology (J.M.B., V.L.), Pathology (B.C.), and Nuclear Medicine (C.M., M.S.), Institut Gustave-Roussy, 94805 Villejuif, France; and Dipartimento di Medicina Sperimentale e Clinica, Policlinico Mater Domini (D.R., S.F.), 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Prof. J. M. Bidart, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. E-mail: bidart{at}igr.fr

	Abstract

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The gene recently cloned that is responsible for the Pendred syndrome (PDS), an autosomal recessive disease characterized by goiter and congenital sensorineural deafness, is mainly expressed in the thyroid gland. Its product, designated pendrin, was shown to transport chloride and iodide. To investigate whether the PDS gene is altered during thyroid tumorigenesis, PDS gene expression and pendrin expression were studied using real-time kinetic quantitative PCR and antipeptide antibodies, respectively, in normal, benign, and malignant human thyroid tissues. The results were then compared to those observed for sodium/iodide symporter (NIS) expression.

In normal tissue, pendrin is localized at the apical pole of thyrocytes, and this in contrast to the basolateral location of NIS. Immunostaining for pendrin was heterogeneous both inside and among follicles. In hyperfunctioning adenomas, the PDS messenger ribonucleic acid level was in the normal range, although immunohistochemical analysis showed strong staining in the majority of follicular cells. In hypofunctioning adenomas, mean PDS gene expression was similar to that detected in normal thyroid tissues, but pendrin immunostaining was highly variable. In thyroid carcinomas, PDS gene expression was dramatically decreased, and pendrin immunostaining was low and was positive only in rare tumor cells. This expression profile was similar to that observed for the NIS gene and its protein product. In conclusion, our study demonstrates that pendrin is located at the apical membrane of thyrocytes and that PDS gene expression is decreased in thyroid carcinomas.

	Introduction

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THE GENE responsible for Pendred syndrome (PDS), an autosomal recessive disease characterized by goiter and congenital sensorineural deafness, has recently been identified (1). The PDS gene is located on chromosome 7q31 and encodes a 5-kb transcript that is mainly expressed in the thyroid gland (2, 3). The PDS gene product, pendrin, is a highly hydrophobic transmembrane protein composed of 780 amino acids. On the basis of sequence homology, it was first suggested that pendrin might belong to the sulfate anion transporter family, composed of the human diastrophic dysplasia sulfate transporter (4) and the human sulfate transporter down-regulated in adenoma (5). More recently, pendrin was shown to transport chloride and iodide, but not sulfate, thereby emphasizing a potential critical role for this protein in thyroid physiology (6, 7). This is in agreement with previous in vitro and in vivo findings showing that iodine organification was altered in thyroid cells obtained from a patient with PDS (8).

The iodine pathway comprises several steps in thyroid cells that involve an iodide transport mechanism via the sodium/iodide symporter (NIS) (9), iodide organification into the thyroglobulin (Tg) molecule at the apical pole that is mediated by the thyroid peroxidase (TPO), and thyroid hormone synthesis and secretion (10, 11). Biochemical abnormalities that affect the complex process of thyroid hormone synthesis have been demonstrated in differentiated thyroid cancers (DTC) (12, 13). In vivo, DTC usually appear as hypofunctioning cold nodules on the thyroid scintiscan, indicating impaired radioiodine trapping ability, but they retain the capacity to synthesize Tg and to respond to TSH stimulation (14). In vitro studies of tumor cells revealed a low concentration of intracellular iodine, reduced Tg iodination, decreased TPO activity, and a low rate of thyroid hormone synthesis (15).

A defective iodide-trapping mechanism appears to be an early and constant feature during oncogenic transformation of thyroid cells (16). Recent reports have shown that this defect is due to reduced NIS gene expression detected in both malignant and benign hypofunctioning thyroid tumors (17, 18, 19, 20, 21). Other changes in the expression of thyroid-specific genes (TPO, Tg, and TSH receptor) are associated with neoplastic transformation, but are present in only some thyroid tumor phenotypes (21, 22). In this respect, the demonstration that pendrin serves as an iodide transporter prompted us to investigate whether PDS gene expression may be altered during thyroid tumorigenesis.

We analyzed PDS gene expression using real-time kinetic quantitative PCR (23) and pendrin expression using an immunohistochemical method based on antipeptide antibodies in a series of normal, benign, and malignant human thyroid tissues, in which we recently studied Tg, TPO, TSH receptor, and NIS gene expression (21).The results of PDS gene expression were then compared to those observed for NIS gene expression, which have been previously reported (21).

	Materials and Methods

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Tissue samples

Thyroid tissue samples were selected after histological examination and classified according to WHO recommendations (24). Tissue samples selected for real-time quantitative PCR were as follows (21): hyperfunctioning tissues, including Graves’ thyroid tissues (n = 5) and toxic adenomas (n = 8), benign hypofunctioning thyroid follicular adenomas (n = 24), and differentiated thyroid carcinomas (n = 43), including papillary carcinomas (n = 38) and poorly differentiated and widely invasive follicular carcinomas (n = 5). To obtain calibrator materials for real-time PCR analysis, normal tissue counterparts (n = 5) were carefully microdissected from thyroid glands obtained from five patients with papillary carcinoma. For immunohistochemical analysis, normal thyroid samples (n = 4) and pathological thyroid tissue specimens were selected from the above series, including Graves’ thyroid tissues (n = 3), benign hypofunctioning adenomas (n = 5), and papillary carcinomas (n = 8). Specimens were frozen at -80 C in isopentane and stored in liquid nitrogen before use. Except for the patients with Graves’ disease or toxic adenoma, in whom serum TSH was undetectable, thyroid samples were obtained from euthyroid subjects whose serum TSH concentrations were in the normal range at the time of surgery. This study was performed in accordance with protocols previously approved by the local human studies committee.

Peptide synthesis, production, and characterization of antipeptide antiserum to pendrin

A composite peptide spanning the N-terminal (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) and the C-terminal (765–780) regions of pendrin was synthesized by a conventional solid phase method using a PE Applied Biosystems model 431A peptide synthesizer (Foster City, CA). The identity and purity of the 1–16/765–780 peptide were verified as previously described (18). The synthetic peptide was conjugated to keyhole limpet hemocyanin using benzidine as the coupling agent on the ⁷⁶⁵Tyr residue. Two rabbits were immunized by intradermal injections of the synthetic peptide-carrier conjugate. After two boosts at 3-week intervals, animals were bled, and their serum specimens were tested in an enzyme-linked immunosorbent assay. Antisera at various dilutions were verified for their capacity to react with the pendrin synthetic peptide coated on microtiter plates. Antibody binding was then revealed by peroxidase-labeled goat antirabbit antibody (Nordic, Tilburg, The Netherlands). The production and characteristics of the antihuman NIS antiserum have been described previously (18).

Immunohistochemistry

Serial frozen cryostat tissue sections (5 µm) were cut and fixed in acetone for 10 min. These sections were then incubated for 30 min with either the antipendrin or anti-NIS antiserum, diluted at 1:75 and 1:500, respectively. Sections were then washed three times in Tris-HCl buffer for 5 min each time and incubated with a biotinylated antibody (K4017, EnVision Labeled Polymer, DAKO Corp., Carpinteria, CA). They were washed again three times and incubated with alkaline phosphatase-labeled streptavidin (DAKO-K674) for 10 min. After three additional washes, staining was completed after incubation with a substrate chromogen solution (DAKO-K699 Fast red). Negative controls were obtained by studying nonthyroid tissues and incubating thyroid sections with preimmune antiserum and immune antiserum preabsorbed with excess corresponding peptide.

Determination of messenger RNA (mRNA) level using real-time PCR

Total RNA was isolated from tissue samples using the DNA/RNA extraction Midi kit according to the manufacturer’s instructions (QIAGEN, Hilden, Germany). The quality of RNA was assessed by conventional gel electrophoresis. One microgram of total RNA from each sample was reverse transcribed in a 20-µL volume reaction using 50 U Moloney murine leukemia virus reverse transcriptase, 20 U ribonuclease inhibitor (Perkin-Elmer Corp./PE Applied Biosystems, Foster City, CA), 1 mmol/L dA/T/C/G (Amersham-Pharmacia Biotech, Uppsala, Sweden), 5 mmol/L MgCl₂, 10 mmol/L Tris-HCl (pH 8.3), 10 mmol/L KCl, and 50 pmol/L of random hexamers (Perkin-Elmer Corp./PE Applied Biosystems). The complementary DNAs were then diluted 1:20 in nuclease-free H₂O (Promega Corp., Madison, WI).

Oligonucleotide primers and TaqMan (PE Applied Biosystems) probes were designed to be intron spanning, using the computer program Primer Express (Perkin-Elmer Corp./PE Applied Biosystems). They were purchased from Perkin-Elmer Corp./PE Applied Biosystems, and their sequences are presented in Table 1. PCR reaction was carried out to produce amplicons that were subsequently analyzed by gel electrophoresis and sequencing. Real-time quantitative PCR was achieved in 96 sample tubes/assay using a complementary DNA equivalent of 20 ng/total RNA·50 µL/tube with the TaqMan PCR core reagent kit according to the manufacturer’s instructions: 1 x buffer A, 5 mmol/L MgCl₂, 200 µmol/L dA/C/G, 400 µmol/L dU, 1.25 U AmpliTaq Gold DNA polymerase, 2.5 U uracyl N-glycosylase, 100 mmol/L TaqMan probe, and 200 mmol/L of each primer. PCR was developed on the ABI Prism 7700 Sequence Detector (Perkin-Elmer Corp./PE Applied Biosystems). To normalize for differences in the amount of total RNA added to the reaction, amplification of 18S ribosomal RNA was performed as an endogenous control. Primers and probes for 18S RNA were purchased from Perkin-Elmer Corp./PE Applied Biosystems. The mRNA content of each target gene was simultaneously determined in the 85 samples, including the 5 paired normal/tumor samples, in a 1-run assay.

The expression of PDS and NIS genes detected in each histological type was compared with that in normal samples. mRNA expression patterns were compared using the t test, and the correlation between these expression profiles was studied using Spearman’s rank order correlation coefficient for each histological type. The level of significance chosen was fixed at 5%.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Production and characterization of antipeptide antiserum to pendrin

Rabbit antiserum titers obtained after immunization with the composite pendrin (1–16/765–780) synthetic peptide-carrier conjugate were determined by enzyme-linked immunosorbent assay. Both animals produced antisera, and competitive inhibition experiments (data not shown) indicated that the affinity of these antisera for the synthetic peptide ranged from 10^-6 to 5 x 10^-7 mol/L. The characteristics of the antiserum directed against human NIS have been described previously (18).

Determination of the mRNA level

To validate the real-time PCR method, standard curves for the PDS gene and 18S ribosomal RNA were constructed from PCR products that were serially diluted in nuclease-free H₂O. Figure 1 shows the amplification plots for the PDS and NIS mRNAs and control 18S RNA. The efficiency of the standard curve, as determined by its slope, allowed us to quantify the PDS gene expression profile in each thyroid specimen by using the comparative threshold cycle (Ct) method according to the manufacturer’s instructions. The characteristics of the assay for NIS gene expression have been reported previously (21). The calibrator was constituted from one sample of normal tissue: it was used as the 1 x sample, and all other levels were expressed as an n-fold difference relative to the calibrator. The intraassay coefficient of variation was less than 1%.

View larger version (42K): [in this window] [in a new window]   Figure 1. Amplification plots of the PDS and NIS mRNAs plus ribosomal 18S RNA. Twenty nanograms of total RNA extracted from a paired normal/papillary carcinoma were used in the TaqMan PCR assay. N, Normal tissue; T, tumor tissue.

Among the five specimens of normal thyroid tissue, mean and median PDS gene expression levels were similar (Fig. 2 and Table 2). Mean and median NIS gene expression levels were also similar in normal thyroid specimens (21).

View larger version (14K): [in this window] [in a new window]   Figure 2. Box plots for PDS and NIS markers according to the histological diagnosis (0, normal tissues; 1, hyperfunctioning tissues; 2, hypofunctioning adenomas; 3, carcinomas). The gray box shows the limits of the middle half of the data (the bold line inside the box represents the median). Whiskers are drawn to the nearest value not exceeding a standard span (1.5 x interquartile range) from the quartiles. Extreme points (outliers) are highlighted by a cross.

View larger version (120K): [in this window] [in a new window]   Figure 3. Expression and localization of pendrin and NIS proteins in human normal thyroid tissue. A, Location of pendrin at the apical membrane of thyrocytes; B, basolateral distribution of NIS protein. Magnification, x1000.

View larger version (162K): [in this window] [in a new window]   Figure 4. Expression and localization of pendrin (A, C, and E) and NIS (B, D, and F) proteins in human thyroid tissues. a and b, Normal tissue: the distributions of pendrin and NIS proteins are heterogeneous (magnification, x250). C and D, Hyperfunctioning tissue from Graves’ disease (magnification, x250); the great majority of follicular cells are strongly immunostained with both antibodies. E and F, Papillary carcinoma; low staining with both antibodies (magnification: pendrin, x250; NIS, x200).

In tissue obtained from thyroid glands affected by Graves’ disease and toxic adenomas, PDS mRNA levels were in the normal range, whereas NIS mRNA levels were significantly increased. However, immunohistochemistry showed strong staining in the majority of follicular cells with both antipendrin and anti-NIS antisera (Fig. 4, C and D).

PDS gene and pendrin expression in hypofunctioning thyroid adenomas

In hypofunctioning adenomas, the mean and median PDS gene expression levels were similar to those detected in normal thyroid tissues. A more than 3-fold decrease was observed in only 5 of 24 hypofunctioning nodules. In contrast, 20 of 24 of these tissue specimens displayed reduced NIS mRNA levels. Pendrin immunostaining was highly variable among these adenomas, ranging from very weak staining to staining similar to that observed in normal thyroid tissues.

PDS gene and pendrin expression in thyroid carcinomas

Profound alterations were detected in the expression of the two target genes in neoplastic thyroid tissues. PDS mRNA expression was 2- to 1000-fold lower (median, 100-fold) than that in normal thyroid tissues. NIS gene expression was decreased to a similar extent. Pendrin immunostaining was weak and was positive in only a small minority of tumor cells (Fig. 4, E and F). The same pattern of weak staining was observed for NIS.

In contrast to mean NIS expression, which was decreased to the same extent in both hypofunctioning adenomas and differentiated thyroid carcinomas (P = 0.72), mean PDS gene expression was significantly lower in thyroid cancer tissues than in hypofunctioning adenomas (P < 0.001). In hypofunctioning adenomas, PDS gene expression was not related to that of the NIS gene (P = 0.19), whereas a close relationship was found in malignant thyroid tissues (P < 0.001).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Intrathyroidal iodine metabolism is profoundly altered in thyroid cancer tissues. Previously identified biochemical and molecular defects hamper radioiodine concentration in most neoplastic thyroid tumors and account for its absence in approximately a third of thyroid cancer metastases (25). Our study demonstrates that the pendrin-PDS gene pathway is also impaired in thyroid cancer tissues, and this is consistent with the defective iodine organification found in these tissues (26).

Pendrin, the predicted protein, was demonstrated to accelerate the transport of chloride and iodide (6). Defective iodine organification due to an inactivating mutation of the PDS gene is observed in patients with PDS. This results in a goiter, with various degrees of hypothyroidism; an alteration in iodine organification is attested to by a positive perchlorate discharge test and the presence of Tg molecules displaying a normal monomer size but a low hormone and iodine content (27).

More interestingly, our immunohistochemical study, based on an antipeptide antibody, demonstrated that pendrin is located at the apical pole of thyrocytes. Together with the above-mentioned data, this observation suggests that pendrin is the apical iodide transporter that permits the organification of Tg.

In Graves’ thyroid tissues and in toxic adenomas, PDS gene expression was not significantly increased, in contrast to that of NIS and TPO (21). This suggests that, like Tg mRNA expression, PDS gene expression is less sensitive to the stimulatory effects of the TSH pathway. However, immunohistochemistry showed stronger staining in these tissue specimens than in normal tissues, indicating that pendrin expression is regulated at the transcription level, and that this is increased in these tissues. This finding is in accordance with the increased rate of thyroid hormone synthesis.

In contrast to NIS mRNA and protein levels, which were decreased in both benign and malignant hypofunctioning thyroid tumors, PDS gene and pendrin expression levels appeared to be normal in most hypofunctioning adenomas and were significantly decreased only in differentiated thyroid carcinomas. A highly significant correlation was found between pendrin and NIS gene expression in differentiated thyroid carcinomas. Although the mechanism of this alteration remains to be investigated, these data suggest that the expression of these two genes is regulated by different pathways. These data also suggest that the limited degree of iodination of Tg found in differentiated thyroid carcinoma is related to defects not only in the iodine-trapping ability and in the iodination process through low TPO biochemical activity, but also to low expression of apical pendrin.

In conclusion, our study demonstrates that pendrin is located at the apical membrane of thyrocytes and suggests that it is probably the apical iodide transporter. PDS gene expression is dramatically decreased in DTC, but not in hypofunctioning adenomas. It remains to be established whether and to what extent PDS gene expression constitutes a critical alteration in thyroid tumors.

	Acknowledgments

 
We acknowledge Jean-Pierre Levillain for expert technical assistance with peptide synthesis, and Lorna Saint-Ange for editing the manuscript.

	Footnotes

 
¹ This work was supported by grants from the Comité du Val de Marne de la Ligue Nationale Contre le Cancer, the Electricité de France, the FEGEFLUC, LIPHA Santé, and the Associazione Italiana per la Ricerca sul Cancro.

Received July 19, 1999.

Revised November 30, 1999.

Accepted December 20, 1999.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Billerbeck AE, Cavaliere H, Goldberg AC, Kalil J, Medeiros-Neto G. 1994 Clinical and molecular genetics studies in Pendred’s syndrome. Thyroid. 4:279–284.[Medline]
2. Everett LA, Glaser B, Beck JC, et al. 1997 Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 17:411–422.[CrossRef][Medline]
3. Coyle B, Reardon W, Herbrick JA, et al. 1998 Molecular analysis of the PDS gene in Pendred syndrome. Hum Mol Genet. 7:1105–1112.[Abstract/Free Full Text]
4. Hastbacka J, de la Chapelle A, Mahtani MM, et al. 1994 The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell. 78:1073–1087.[CrossRef][Medline]
5. Schweinfest CW, Henderson KW, Suster S, Kondoh N, Papas TS. 1993 Identification of a colon mucosa gene that is down-regulated in colon adenomas and adenocarcinomas. Proc Natl Acad Sci. 90:4166–4170.[Abstract/Free Full Text]
6. Scott DA, Wang R, Kreman TM, Sheffield VC, Karnishki LP. 1999 The Pendred syndrome gene encodes a chloride-iodide transport protein. Nat Genet. 21:440–443.[CrossRef][Medline]
7. Kraiem Z, Heinrich R, Sadeh O, Shiloni E, Nassir E, Hazani E, Glaser B. 1999 Sulfate transport is not impaired in Pendred syndrome thyrocytes. J Clin Endocrinol Metab. 84:2574–2576.[Abstract/Free Full Text]
8. Sheffield VC, Kraiem Z, Beck JC, et al. 1996 Pendred syndrome maps to chromosome 7q21–34 and is caused by an intrinsic defect in thyroid iodine organification. Nat Genet. 12:424–426.[CrossRef][Medline]
9. Smanik PA, Liu Q, Furminger L, Ryu K, Xing S, Mazzaferri EL, Jhiang SM. 1996 Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun. 226:339–345.[CrossRef][Medline]
10. Carrasco N. 1993 Iodide transport in the thyroid gland. Biochim Biophys Acta. 1154:65–82.[Medline]
11. Cavalieri RR. 1997 Iodine metabolism and thyroid physiology: current concepts. Thyroid. 7:177–181.[Medline]
12. Brabant G, Maenhaut C, Kohrle J, et al. 1991 Human thyrotropin receptor gene: expression in thyroid tumors and correlation to markers of thyroid differentiation and dedifferentiation. Mol Cell Endocrinol. 82:7–12.
13. Hoang-Vu C, Dralle H, Scheumann G, Maenhaut C, Horn R, von zur Muhlen A, Brabant G. 1992 Gene expression of differentiation- and dedifferentiation markers in normal and malignant human thyroid tissues. Exp Clin Endocrinol. 100:51–56.[Medline]
14. Schlumberger M, Charbord P, Fragu P, Lumbroso J, Parmentier C, Tubiana M. 1980 Circulating thyroglobulin and thyroid hormones in patients with metastases of differentiated thyroid carcinoma: relationship to serum thyrotropin levels. J Clin Endocrinol Metab. 51:513–519.[Medline]
15. Thomas-Morvan C, Nataf B, Tubiana M. 1974 Thyroid proteins and hormone synthesis in human thyroid cancer. Acta Endocrinol (Copenh). 76:651–669.[Medline]
16. Trapasso F, Iuliano R, Chiefari E, et al. 1999 Iodide symporter gene expression in normal and transformed rat thyroid cells. Eur J Endocrinol. 140:447–451.[Abstract]
17. Jhiang SM, Cho JY, Ryu KY, et al. 1998 An immunohistochemical study of Na⁺/I^- symporter in human thyroid tissues and salivary gland tissues. Endocrinology. 139:4416–4419.[Abstract/Free Full Text]
18. Caillou B, Troalen F, Baudin E, Talbot M, Filetti S, Schlumberger M, Bidart JM. 1998 Na⁺/I^- symporter in human thyroid tissues: an immunohistochemical study. J Clin Endocrinol Metab. 83:4102–4106.[Abstract/Free Full Text]
19. Arturi F, Russo D, Schlumberger M, et al. 1998 Iodide symporter gene expression in human thyroid tumors. J Clin Endocrinol Metab. 83:2493–2496.[Abstract/Free Full Text]
20. Ryu KY, Senokozlieff ME, Smanik PA, et al. 1999 Development of reverse transcription-competitive polymerase chain reaction method to quantitate the expression levels of human sodium iodide symporter. Thyroid. 4:405–409.
21. Lazar V, Bidart JM, Caillou B, Mahé C, Lacroix L, Filetti S, Schlumberger M. 1999 Expression of the Na⁺/I^- symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J Clin Endocrinol Metab. 84:3228–3234.[Abstract/Free Full Text]
22. Natali PG, Berlingieri MT, Nicotra MR, Fusco A, Santoro E, Bigotti A, Vecchio G. 1995 Transformation of thyroid epithelium is associated with loss of c-Kit receptor. Cancer Res. 55:1787–1791.[Abstract/Free Full Text]
23. Gibson UE, Heid CA, Williams P. 1996 A novel method for real time quantitative RT-PCR. Genome Res. 6:995–1001.[Abstract/Free Full Text]
24. Hedinger C, Williams ED, Sobin LH. 1988 Histological typing of thyroid tumours, 2nd Ed, vol 11. Berlin: Springer-Verlag.
25. Schlumberger M, Challeton C, De Vathaire F, et al. 1996 Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med. 37:598–605.[Abstract/Free Full Text]
26. Cooper DS, Axelrod L, DeGroot LJ, Vickery Jr AL, Maloof F. 1981 Congenital goiter and the development of metastatic follicular carcinoma with evidence for a leak of nonhormonal iodide: clinical, pathological, kinetic, and biochemical studies and a review of the literature. J Clin Endocrinol Metab. 52:294–306.[Abstract]
27. Mason ME, Dunn AD, Wortsman J, et al. 1995 Thyroids from siblings with Pendred’s syndrome contain thyroglobulin messenger ribonucleic acid variants. J Clin Endocrinol Metab. 80:497–503.[Abstract]

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				V. Porra, F. Bernier-Valentin, S. Trouttet-Masson, N. Berger-Dutrieux, J.-L. Peix, A. Perrin, S. Selmi-Ruby, and B. Rousset Characterization and Semiquantitative Analyses of Pendrin Expressed in Normal and Tumoral Human Thyroid Tissues J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1700 - 1707. [Abstract] [Full Text] [PDF]

				J. P. Taylor, R. A. Metcalfe, P. F. Watson, A. P. Weetman, and R. C. Trembath Mutations of the PDS Gene, Encoding Pendrin, Are Associated with Protein Mislocalization and Loss of Iodide Efflux: Implications for Thyroid Dysfunction in Pendred Syndrome J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1778 - 1784. [Abstract] [Full Text] [PDF]

				A.-C. Gerard, M.-C. Many, C. Daumerie, S. Costagliola, F. Miot, J. J. M. DeVijlder, I. M. Colin, and J.-F. Denef Structural Changes in the Angiofollicular Units between Active and Hypofunctioning Follicles Align with Differences in the Epithelial Expression of Newly Discovered Proteins Involved in Iodine Transport and Organification J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1291 - 1299. [Abstract] [Full Text] [PDF]

				M. D. L. Figueiredo, L. C. Cardoso, A. C. F. Ferreira, D. V. B. Campos, M. da Cruz Domingos, R. Corbo, L. E. Nasciutti, M. Vaisman, and D. P. Carvalho Goiter and Hypothyroidism in Two Siblings due to Impaired Ca+2/NAD(P)H-Dependent H2O2-Generating Activity J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4843 - 4848. [Abstract] [Full Text] [PDF]

				D. Cauvi, M.-C. Nlend, N. Venot, and O. Chabaud Sulfate transport in porcine thyroid cells. Effects of thyrotropin and iodide Am J Physiol Endocrinol Metab, September 1, 2001; 281(3): E440 - E448. [Abstract] [Full Text] [PDF]

				W. E. Winter and M. R. Signorino Molecular Thyroidology Ann. Clin. Lab. Sci., July 1, 2001; 31(3): 221 - 244. [Abstract] [Full Text] [PDF]

				C. Spitzweg, K. J. Harrington, L. A. Pinke, R. G. Vile, and J. C. Morris The Sodium Iodide Symporter and Its Potential Role in Cancer Therapy J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3327 - 3335. [Full Text] [PDF]

				I. E. Royaux, S. M. Wall, L. P. Karniski, L. A. Everett, K. Suzuki, M. A. Knepper, and E. D. Green Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion PNAS, March 27, 2001; 98(7): 4221 - 4226. [Abstract] [Full Text] [PDF]

				J.-M. Bidart, L. Lacroix, D. Evain-Brion, B. Caillou, V. Lazar, R. Frydman, D. Bellet, S. Filetti, and M. Schlumberger Expression of Na+/I- Symporter and Pendred Syndrome Genes in Trophoblast Cells J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4367 - 4372. [Abstract] [Full Text]

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