Human Molecular Genetics, 2000, Vol. 9, No. 11 1709-1715
© 2000 Oxford University Press
Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4)
Howard Hughes Medical Institute and the Department of Pediatrics, 1Department of Internal Medicine and the University of Iowa Hospitals and Clinics and Iowa City Veterans Affairs and 2Molecular Otolaryngology Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
Received 30 March 2000; Revised and Accepted 28 April 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The PDS gene encodes a transmembrane protein, known as pendrin, which functions as a transporter of iodide and chloride. Mutations in this gene are responsible for Pendred syndrome and autosomal recessive non-syndromic hearing loss at the DFNB4 locus on chromosome 7q31. A screen of 20 individuals from the midwestern USA with non-syndromic hearing loss and dilated vestibular aqueducts identified three people (15%) with PDS mutations. To determine whether PDS mutations in individuals with Pendred syndrome differ functionally from PDS mutations in individuals with non-syndromic hearing loss, we compared three common Pendred syndrome allele variants (L236P, T416P and E384G), with three PDS mutations reported only in individuals with non-syndromic hearing loss (V480D, V653A and I490L/G497S). The mutations associated with Pendred syndrome have complete loss of pendrin-induced chloride and iodide transport, while alleles unique to people with DFNB4 are able to transport both iodide and chloride, albeit at a much lower level than wild-type pendrin. We hypothesize that this residual level of anion transport is sufficient to eliminate or postpone the onset of goiter in individuals with DFNB4. We propose a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the colloid space.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss and goiter. The severity of the hearing loss is variable, ranging from 40 to 100 dB, and is typically associated with an inner ear malformation in which the upper coils of the cochlea form a common cavity (Mondini dysplasia) and the vestibular aqueducts are dilated (DVA) (1–3). The majority of people with Pendred syndrome develop a goiter before puberty as a consequence of a partial organification defect in which thyrocyte-mediated iodide uptake is normal but binding to thyroglobulin (Tg) is inefficient (4). This defect can be demonstrated by a perchlorate discharge test. The normal discharge of previously infused radiolabeled iodide is <10% after administration of perchlorate; however, in people with Pendred syndrome the discharge is >15% and can be as high as 80% (4–6).
One-hundred years after Pendred syndrome was described, the gene responsible for this disorder was linked by two groups to chromosome 7q22–q31.1 (7–9). Linkage was quickly followed by the discovery of the Pendred syndrome gene (PDS) and the subsequent identification of more than 25 different PDS mutations in people with classic Pendred syndrome (10–12). However, two reports described PDS mutations in individuals with sensorineural hearing loss and DVA in the absence of goiter (13,14). These individuals were reported to have non-syndromic hearing loss (DFNB4). It is unclear whether the mutations segregating in these people are functionally distinct from those associated with Pendred syndrome or if the phenotypic difference reflects variation in genetic background or environmental factors.
The PDS gene encodes a transmembrane protein, known as pendrin, which is expressed in the thyroid, inner ear and kidney. Although pendrin was hypothesized originally to be a sulfate transporter, sulfate transport is not impaired in thyrocytes from patients with Pendred syndrome (15). Functional studies in Xenopus laevis oocytes and Sf9 cells have demonstrated that pendrin is not a transporter of sulfate but acts to transport iodide and chloride (16). Additional experiments have shown that human pendrin expressed in Xenopus oocytes also mediates chloride/formate exchange (17).
In this work, we have screened the PDS gene in 20 individuals from the midwestern USA with DVA and non-syndromic hearing loss to determine the prevalence of PDS mutations in this population. We also have compared the effects of common Pendred syndrome and DFNB4 mutations on pendrin iodide and chloride transport. Based on these results, and previously published findings, we propose a model for Pendrin function in the thyroid.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mutation analysis of individuals with DVA and non-syndromic hearing loss
DVA is a common radiological finding in people with Pendred syndrome and has been seen in all reported families with non-syndromic hearing loss due to PDS mutations. To estimate the percentage of people with DVA-associated non-syndromic hearing loss caused by mutations in the PDS gene, we screened the PDS coding sequence of 20 individuals from midwestern USA with apparent non-syndromic sensorineural hearing loss and DVA.
As summarized in Table 1, three individuals (15%) carry one or more PDS coding sequence mutations. Two of these individuals are heterozygous for the L236P or T416P mutation, alleles commonly seen in individuals with Pendred syndrome. Individual 8050 carries a novel V480D allele opposite the L236P allele, but a second PDS mutation was not discovered in individual 8080 (T416P/wt). Individual 5140 carries a novel V653A allele but a second PDS mutation has not been discovered (V653A/wt). Interestingly, this individual also carries the GJB2 35delG mutation, which is the most common mutation seen with non-syndromic hearing loss at the DFNB1 locus.
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Functional analysis of Pendred syndrome alleles
At least 25 different mutations of the PDS gene have been identified, which cause Pendred syndrome. For functional analysis, we selected the two most common PDS mutations, T416P and L236P, and a third mutation, E384G, which has been reported in several families (11,12,18). The E384G mutation was of particular interest since its effect on pendrin function may be due to a single amino acid substitution, disruption of normal splicing or a combination of both (18).
The uptake of iodide and chloride was significantly stimulated in Xenopus oocytes injected with wild-type PDS cRNA (Fig. 1), consistent with the known role of pendrin as a transporter of these anions. In contrast, the uptake of iodide and chloride in oocytes injected with equal quantities of PDS cRNA containing the L236P, T416P or E384G mutations was not significantly different from water-injected controls (Fig. 1). At 2 and 3 h time-points, oocytes injected with wild-type PDS cRNA demonstrated increasing amounts of anion transport, whereas iodide and chloride uptake in oocytes injected with L236P, T416P and E384G cRNA continued to approximate that seen in water-injected controls (data not shown). These data suggest that the L236P, T416P and E384G mutations cause complete loss of pendrin-induced iodide and chloride transport. These data also suggest that the substitution of a glycine residue for glutamic acid at position 384 is sufficient to cause loss of pendrin function in the absence of splicing defects.
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To determine whether PDS alleles associated with non-syndromic hearing loss differ functionally from alleles seen with classic Pendred syndrome, we analyzed the iodide and chloride transport of the V480D and V653A alleles, which were identified in our screen of individuals with non-syndromic hearing loss and DVA. Oocytes injected with cRNA containing the V480D and V653A mutations showed significantly lower levels of iodide and chloride transport when compared with oocytes injected with wild-type PDS; however, uptake remained significantly higher than that seen in water-injected controls (Fig. 1). Increasing the amount of injected cRNA of the Pendred syndrome mutation, L236P, failed to increase anion transport above water-injected controls (Fig. 2). In contrast, enhancement of anion transport activity is observed with increasing amounts of cRNA with the DVA mutations V480D and V653A. These results demonstrate that the V480D and V653A alleles retain the ability to transport anions, and that their level of transport can be amplified with increased expression of the mutated pendrin protein.
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In addition to the V480D and V653A alleles identified in this report, several families have been described with non-syndromic hearing loss due to mutations in the PDS gene (13,14) the largest being an inbred family from India described by Li et al. (13). A screen of PDS in this family showed that all affected individuals are homozygous for two single amino acid changes: I409L and G497S. To determine pendrin transport activity with these mutations, three PDS cRNA variants were constructed; one carrying the I490L mutation, one with the G497S mutation and the third containing both mutations (I/G). As shown in Figure 3, the uptake of both chloride and iodide was significantly greater in oocytes injected with I490L cRNA compared with water-injected controls, with chloride and iodide uptake 67 and 68% respectively of that observed in oocytes injected with wild-type PDS. Anion transport in oocytes injected with G497S cRNA and I490L/G497S cRNA was also greater than in water-injected controls; however, transport was markedly reduced compared with both wild-type PDS and the I490L mutation. Increasing the amount of injected G497S and I490L/G497S cRNA resulted in a further stimulation of transport activity (Fig. 4). The high level of transport activity with the I490L mutation and the low level of pendrin activity with the G497S and I490L/G497S mutations suggest that the reduction of pendrin function in the Indian family with non-syndromic DVA described by Li et al. (13) is caused primarily by the G497S mutation. In addition, the G497S mutation retains residual pendrin anion transport activity, similar to what we observed with the non-syndromic PDS DVA mutations, V480D and V653A.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Individuals with disease-causing mutations in PDS can present with at least two distinct phenotypes. Most commonly, individuals have a ‘classic’ Pendred syndrome phenotype of sensorineural hearing loss and goiter. Other individuals, however, have sensorineural hearing loss in the absence of goiter (DFNB4). Variation is also seen in the extent of the inner ear malformation, with some individuals having Mondini dysplasia and DVA whereas others have only DVA. Although this variation could reflect differences in genetic background or environmental factors, our results suggest that differences in pendrin-mediated anion transport also play an important role in determining phenotype.
The T416P, L236P and E384G alleles are found in individuals with a classic Pendred syndrome phenotype and result in complete loss of pendrin-induced iodide and chloride transport. In contrast, the I490L/G497S, V653A and V480D alleles, which have been found only in individuals with DFNB4, show residual pendrin-induced iodide and chloride transport. Although residual anion transport may be sufficient to prevent or postpone the onset of goiter in these individuals, it is less than the level required to maintain hearing or ensure normal development of the inner ear. The differential sensitivity of these organs to the same mutation may be due to a second transport system in the thyroid that can compensate, in part, for the decrease in pendrin function. Alternatively, it may be possible for PDS expression to be amplified to a greater extent in the thyroid than in the inner ear, allowing the thyroid gland to maintain a higher level of pendrin-mediated anion transport than the inner ear in the face of decreased pendrin function.
In the normal thyroid gland, iodide is taken up by the Na+/I– cotransporter on the basolateral side of the thyrocyte, and transported quickly across the apical membrane into the colloid space where it is bound to Tg in a process known as organification (18,19). In Pendred syndrome, iodide is taken up normally by the thyroid but is not efficiently bound to Tg (4). We hypothesize that pendrin transports iodide across the apical membrane of the thyrocyte and into the colloid space (Fig. 5). In this model, disruption of pendrin transport results in decreased iodide flux into the colloid and pooling of unbound iodide within the thyrocyte. Consistent with this model is the fact that pendrin has recently been immunolocalized to the apical membrane of thyrocytes (20).
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In the absence of pendrin function, a low level of iodide flux into the colloid space may still occur through a second transporter system, such as an iodide channel (21,22). Although this low level of iodide flux appears to be insufficient to prevent the onset of goiter in most individuals, it can explain why individuals with Pendred syndrome have a partial instead of a complete defect in organification, as would be predicted if all iodide flux was abolished. If this ‘basal’ level of iodide flux is augmented, even by residual levels of pendrin function as with the DFNB4 alleles, sufficient iodide is transported across the apical membrane to maintain thyroid function and prevent or postpone the onset of goiter.
PDS mutations were found in three out of 20 individuals (15%) from the midwestern USA with sensorineural hearing loss and DVA in the absence of goiter. Although two PDS mutations were identified in individual 8080 (L236P/V480D), a screen of the PDS coding region in individuals 5140 and 8050 failed to identify a second PDS mutation. It is possible that these individuals carry unidentified mutations in the regulatory/non-coding regions of the PDS. The identification of a GJB2 35delG null allele in individual 5140 also raises the intriguing possibility that a combination of defects in two distinct genes can give rise to a hearing-loss phenotype.
The ability to measure the function of various PDS alleles in a Xenopus oocyte expression system can distinguish disease-causing mutations from common polymorphisms. In the case of the DFNB4 family reported by Li et al. (13), our results suggest that the G497S allele represents a disease-causing mutation that significantly reduces pendrin anion transport. In contrast, the I490L allele is unlikely to cause hearing loss in the homozygous state, since the level of pendrin function would not drop below the 50% level seen in the asymptomatic carriers of L236P, T416P or E384G alleles. However, decreased function of the I490L allele might result in a clinical phenotype when inherited opposite a PDS null allele.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Patient identification
Patients with DVA were sequentially accrued from hearing loss referrals to an otolaryngology clinic in the midwestern USA. Their evaluation included a complete history and physical examination, audiometry and temporal bone computed tomography. To be classified as DVA, enlargement of the vestibular aqueduct had to be >1.5 mm at a point midway between the endolymphatic sac and the vestibule, although in nearly all cases, the enlargement was much greater, making it possible to trace the vestibular aqueduct directly into the vestibule. All patients also had progressive hearing loss. Excluded from this study were people from consanguineous populations and those with syndromic, mild, unilateral, acquired or dominant types of hearing loss. All procedures were approved by the University of Iowa Human Subjects Committee.
Individuals 5140 and 8080 were both 6 years old, and individual 8050 was 21 years old.
PDS mutation screening
After extracting DNA from whole blood using standard procedures, mutation screening was completed by single-strand conformation polymorphism (SSCP) and direct sequencing of the PDS coding region. In brief, PCR was performed with 40 ng of genomic DNA in a 10 µl reaction containing 1 µl buffer [160 mM (NH4)2SO4, 670 mM Tris–HCl pH 8.8, 0.1% Tween-20], 1.65 mM MgCl2, 0.4 µl of 2.5 mM each dATP, dCTP, dTTP and dGTP, 1 pmol each forward and reverse primer, 5% w/v glycerol and 0.25 U Taq polymerase (Table 2). Amplification conditions were 94°C for 1 min, followed by three sets of 13 cycles each of 94°C for 30 s, 56°C (55°C, set 2; 54°C, set 3) for 30 s and 72°C for 30 s, ending with an extension cycle of 72°C for 10 min. Reaction products were resolved on either MDE (FMC Bioproducts, Rockland, ME) or 6% non-denaturing polyacrylamide, 10% w/v glycerol gels and visualized by silver staining. Sequencing was completed on an Applied Biosystems (ABI, Foster City, CA) model 373 automated sequencer. Sequence data were compared with published sequence for PDS using the Sequencher 3.1 software program package (Gene Codes, Ann Arbor, MI).
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Preparation of altered PDS plasmids
The PDS coding sequence, spanning nucleotides 207–2564, was amplified by PCR from a human thyroid gland Quick-Clone cDNA library (Clontech, Palo Alto, CA). The generation of the PCR product and its cloning into a modified pGEM vector have been described previously (16).
To determine the effect of various amino acid substitutions on pendrin function, plasmids containing modifications in the PDS coding sequence were constructed using a QuikChange Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA), according to the manufacturer’s instructions. Briefly, two complementary primers of 30–45 bp were synthesized which contained the desired mutation flanked by unmodified nucleotide sequence. These primers were used in primer extension reactions using PfuTurbo DNA polymerase with cesium chloride-purified plasmid DNA acting as template. After 12–18 extension cycles, the original plasmid DNA (non-mutant) was digested with the methylation-dependant restriction enzyme DpnI. The complementary, non-methylated, mutated strands, which were resistant to DpnI digestion, hybridized to form circular, double-stranded plasmids containing staggered nicks. These mutated plasmids were transformed into XL2-Blue supercompetent cells using a standard heat-shock protocol.
Colonies containing plasmids were selected using a blue/white color screen on antibiotic plates containing IPTG and X-gal. Plasmid DNA was extracted from overnight cultures of individual colonies and screened for the desired mutations by direct sequencing. The complete coding sequence of selected mutant clones was determined to insure that random errors had not been introduced into the coding portion of the plasmid.
cRNA was quantified by measurement of the optical density at 260 nm wavelength. In addition, 1 µl of each transcription reaction was separated on a 20% formaldehyde/agarose gel, together with 5 µg of an RNA standard (0.24–9.5 kb ladder; Gibco BRL). The RNA was separated by electrophoresis, immediately photographed, then scanned into Microsoft PhotoEditor. Quantification was by the ‘Kodak Digital Science 1D’ program. The relative amounts of the different RNA samples generated in a single preparation were within 20% by the two methods. To avoid variability resulting from storage, the different cRNAs used in any experimental condition were generated at the same time.
The ability of each mutant cRNA to be translated into an appropriately sized product was checked in vitro using a rabbit reticulocyte lysate system (Promega, Madison, WI). Two micrograms of capped cRNA were added to 35 µl of rabbit reticulocyte lysate, 0.5 µl (1 mM) amino acid mixture without leucine, 0.5 µl (1 mM) amino acid mixture without methionine, and 40 U RNAsin ribonuclease inhibitor, and brought to a final volume of 50 µl with nuclease-free water. This mixture was incubated for 90 min at 30°C. The resulting products were separated by SDS–PAGE on a 6–13% gradient gel, then transferred to a nitrocellulose membrane using a Semi-Dry Electroblotter at 1.1 mA/cm2 for 75 min. After transfer, the membrane was blocked with 5% non-fat dry milk (10 mM phosphate, 137 mM NaCl pH 7.4, 0.1% Tween-20) for 30 min and incubated at room temperature for 1 h with the primary antibody (Penta-His antibody; Quiagen, Valencia, CA) in PDS/Tween. After washing, the protein bands were visualized by cheimluminescence. In each case, a product of predicted size was identified.
Anion transport assays in Xenopus oocytes
Lobes of Xenopus oocytes were incubated with gentle shaking in 7–10 ml of a 1 mg/ml collagenase solution prepared in normal frog Ringer (NFR: 115 mM NaCl, 2.5 KCl, 1.8 mM CaCl2, 10 mM HEPES, 5 mM sodium pyruvate, made to pH 7.35 with NaOH) for ~1 h. Oocytes were washed once in calcium-free NFR (115 mM NaCl, 2.5 KCl, 10 mM HEPES, 5 mM sodium pyruvate, made to pH 7.35 with NaOH), twice in NFR and incubated at 16°C. Oocytes were injected with water or various concentrations cRNA in a 50 nl volume using a Drummond ‘NANOJECT’ microinjector (Drummond Scientific Co., Broomall, PA) and returned to 16°C for ~72 h. For uptakes, oocytes were washed at room temperature in chloride-free buffer [115 mM sodium gluconate, 2.5 mM potassium gluconate, 2.0 mM Ca(OH)2, 11.0 mM HEPES pH 7.35] and incubated in 300–600 µl isotopic uptake solution. The isotope uptake solution contained either chloride-free buffer plus 100 µM [125I]tetramethylammonium iodide or chloride-free buffer plus 4 mM [36Cl]tetramethylammonium chloride. After incubation, oocytes were washed three times with ice-cold chloride-free buffer to remove unincorporated isotope, solubilized in 200 µl of 10% SDS and added to 2 ml of 3a70B complete counting cocktail (Research Products International Corp., Mount Prospect, IL). The uptake of radioisotope was determined by scintillation spectroscopy.
Each reported value represents the mean ± SEM from at least three different frogs. Two-tailed Student’s t-test was used for the calculation of P-values.
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ACKNOWLEDGEMENTS |
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L.K. was supported by the Office of Research and Development, Department of Veterans Affairs, and by grants from the NIH (DK47881) and the March of Dimes Birth Defects Foundation (507). R.J.H.S. was supported in part by grant RO1-DC02842. V.C.S. is an associate investigator of the Howard Hughes Medical Institute.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 319 335 6898; Fax: +1 319 335 7588; Email: val-sheffield@uiowa.edu
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REFERENCES |
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 U. Napiontek, G. Borck, W. Muller-Forell, N. Pfarr, A. Bohnert, A. Keilmann, and J. Pohlenz Intrafamilial Variability of the Deafness and Goiter Phenotype in Pendred Syndrome Caused by a T416P Mutation in the SLC26A4 Gene J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5347 - 5351. [Abstract] [Full Text] [PDF]
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H-J Park, S Shaukat, X-Z Liu, S H Hahn, S Naz, M Ghosh, H-N Kim, S-K Moon, S Abe, K Tukamoto, et al. Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness J. Med. Genet., April 1, 2003; 40(4): 242 - 248. [Abstract] [Full Text] [PDF]
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 L. P. Karniski, T. Wang, L. A. Everett, E. D. Green, G. Giebisch, and P. S. Aronson Formate-stimulated NaCl absorption in the proximal tubule is independent of the pendrin protein Am J Physiol Renal Physiol, November 1, 2002; 283(5): F952 - F956. [Abstract] [Full Text] [PDF]
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 P. Rotman-Pikielny, K. Hirschberg, P. Maruvada, K. Suzuki, I. E. Royaux, E. D. Green, L. D. Kohn, J. Lippincott-Schwartz, and P. M. Yen Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome Hum. Mol. Genet., October 2, 2002; 11(21): 2625 - 2633. [Abstract] [Full Text] [PDF]
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 M. Bitner-Glindzicz Hereditary deafness and phenotyping in humans Br. Med. Bull., October 1, 2002; 63(1): 73 - 94. [Abstract] [Full Text] [PDF]
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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]
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L. Ng, A. Rusch, L. L. Amma, K. Nordstrom, L. C. Erway, B. Vennstrom, and D. Forrest Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor {alpha} gene Hum. Mol. Genet., November 1, 2001; 10(23): 2701 - 2708. [Abstract] [Full Text] [PDF]
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L. P. Karniski Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype Hum. Mol. Genet., July 1, 2001; 10(14): 1485 - 1490. [Abstract] [Full Text] [PDF]
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L. A. Everett, I. A. Belyantseva, K. Noben-Trauth, R. Cantos, A. Chen, S. I. Thakkar, S. L. Hoogstraten-Miller, B. Kachar, D. K. Wu, and E. D. Green Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome Hum. Mol. Genet., January 1, 2001; 10(2): 153 - 161. [Abstract] [Full Text] [PDF]
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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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