Original Article
Inactivating Mutations in the Gene for Thyroid Oxidase 2 (THOX2) and Congenital Hypothyroidism
N Engl J Med 2002; 347:95-102July 11, 2002
- Abstract
Background
Several genetic defects are associated with permanent congenital hypothyroidism. Immunologic, environmental, and iatrogenic (but not genetic) factors are known to induce transient congenital hypothyroidism, which spontaneously resolves within the first months of life. We hypothesized that molecular defects in the thyroid oxidase system, which is composed of at least two proteins, might be involved in the pathogenesis of permanent or transient congenital hypothyroidism in babies with defects in iodide organification, for which the oxidase system is required.
Methods
Nine patients were recruited who had idiopathic congenital hypothyroidism (one with permanent and eight with transient hypothyroidism) and an iodide-organification defect and who had been identified by the screening program for congenital hypothyroidism. The DNA of the patients and their relatives was analyzed for mutations in the genes for thyroid oxidase 1 (THOX1 ) and 2 (THOX2 ).
Results
The one patient with permanent and severe thyroid hormone deficiency and a complete iodide-organification defect had a homozygous nonsense mutation in the THOX2 gene that eliminates all functional domains of the protein. Three of the eight patients with mild transient congenital hypothyroidism and a partial iodide-organification defect had heterozygous mutations in the THOX2 gene that prematurely truncate the protein, thus abolishing its functional domains.
Conclusions
Biallelic inactivating mutations in the THOX2 gene result in complete disruption of thyroid-hormone synthesis and are associated with severe and permanent congenital hypothyroidism. Monoallelic mutations are associated with milder, transient hypothyroidism caused by insufficient thyroidal production of hydrogen peroxide, which prevents the synthesis of sufficient quantities of thyroid hormones to meet the large requirement for thyroid hormones at the beginning of life.
Media in This Article
Figure 1
Mutations in the Thyroid Oxidase 2 Gene (THOX2 ) in Patients with Permanent and Transient Congenital Hypothyroidism.Figure 3
Segregation Analysis of Mutations in the Thyroid Oxidase 2 Gene (THOX2 ) in Three Families with Permanent or Transient Congenital Hypothyroidism.Article Activity
- Article
Congenital hypothyroidism is the most common congenital endocrine disorder, affecting 1 in every 3000 to 4000 newborns. Neonatal screening programs allow its early detection and treatment, thus preventing the cognitive and motor impairment caused by lack of thyroid hormone during the early postnatal phase of brain development.1 The need for thyroid hormone supplementation can be permanent or transient.2,3
The cause of permanent congenital hypothyroidism of primary origin has been linked to defects in proteins involved in the synthesis of thyroid hormones4 and to defects in transcription factors involved in the development of the thyroid gland.5-7 Overall, these cases represent a small percentage of the population with congenital hypothyroidism, and the cause of the vast majority of cases remains unknown.8,9
Transient congenital hypothyroidism can be caused by iodine deficiency, exposure to excess iodine in the perinatal period (e.g., from the use of iodinated disinfectants or contrast agents), or fetal exposure to either maternally derived thyroid-blocking antibodies or antithyroid drugs taken by pregnant women with thyroid autoimmune disease.10-13 Congenital thyroid dysfunction can also be a consequence of premature birth14,15 or, in rare cases, of protein-losing nephrosis.16 However, in about 20 percent of patients with transient disease, the cause remains elusive.17-20 Sporadic reports have suggested that transient congenital hypothyroidism might be related to mild thyroid dyshormonogenesis.21
The generation of hydrogen peroxide is a critical step in the synthesis of thyroid hormones.22 Hydrogen peroxide is used as a substrate by thyroid peroxidase in the incorporation of iodine into thyroglobulin, an essential step of thyroid hormonogenesis known as organification. The thyroid oxidase 1 (THOX1) and 2 (THOX2) proteins have recently been identified as components of the hydrogen peroxide generation system of the thyroid.23,24 The level of expression of the THOX2 gene, as determined by serial analysis of gene expression, is at least five times as high as that of THOX1.25 The THOX1 and THOX2 genes encode two very similar proteins that are inserted in the apical membrane of the thyroid follicular cell. The structure of these proteins includes seven putative transmembrane domains, four NADPH-binding sites and one flavine adenine dinucleotide (FAD)–binding site, and (unlike other human oxidases) two EF-hand motifs (so termed because helixes E and F resemble an outstretched index finger and thumb, respectively) that putatively control enzymatic activity through calcium binding.26
Most inborn errors of thyroid hormone synthesis are caused by defects in iodide organification. To date, patients with thyroid-organification defects have been shown to harbor mutations in the genes encoding thyroid peroxidase, thyroglobulin, and pendrin.27-29 We tested the hypothesis that mutations in the thyroid oxidase system are the molecular basis for apparently idiopathic cases of congenital hypothyroidism with an iodide-organification defect.
Methods
Selection of Patients
Patients with congenital hypothyroidism were selected for genetic screening after written informed consent had been obtained from the parent or guardian. The inclusion criterion was the presence of an iodide-organification defect, as determined by a positive intravenous perchlorate test (discharge, 10 percent or more) in the neonatal period. Patients who had iodide-organification defects of known cause were excluded. The causes included complete iodide-organification defects with mutations in the thyroid peroxidase gene27; Pendred's syndrome or mutations in the PDS gene, which encodes the iodide transporter pendrin30; and biochemical indicators of thyroglobulin-synthesis defects or mutations in the thyroglobulin gene.31 Patients who had transient congenital hypothyroidism of known cause were also excluded. The causes included maternal thyroid autoimmune disease, maternal use of antithyroid drugs during pregnancy, an excess or shortage of iodine, and premature birth.
Evaluation of Clinical Data
Data on gestational age, mode of delivery, birth weight, and documented use of iodinated products were collected from clinical files. In the Dutch screening program for congenital hypothyroidism, the total thyroxine in a filter-paper blood spot is determined, normally within the first week of life. When thyroxine values are less than or equal to –0.8 SD of the mean value on the standard daily distribution curve, thyrotropin is measured. When the screening results are abnormal, plasma thyrotropin, total thyroxine, free thyroxine, total triiodothyronine, thyroxine-binding globulin, and thyroglobulin are determined. Urinary excretion of iodine is determined within the first three weeks of life.32 Before the start of thyroxine treatment, when dyshormonogenesis is suspected, the uptake of iodine-123 by the thyroid is measured, followed by the administration of sodium perchlorate. Thyroid hormone therapy is monitored by periodic determinations of plasma thyrotropin and free thyroxine levels, and the thyroxine dose is adjusted accordingly. Therapy is stopped in patients with suspected transient hypothyroidism when they reach the age of three years. Four weeks later, thyrotropin, thyroxine, and triiodothyronine are measured. All these measurements obtained from the study patients were compared with those of 44 patients with congenital hypothyroidism who had a complete iodide-organification defect due to mutations in the thyroid peroxidase gene.
Perchlorate-Discharge Test
The perchlorate challenge was performed according to a protocol adapted for neonates.19 After intravenous administration of 0.9 MBq (25 μCi) [123I]sodium iodide, thyroidal uptake of the isotope was monitored every 30 minutes with a gamma camera and a pinhole collimator. At 120 minutes, 100 mg of sodium perchlorate was given intravenously, and the decrease in radioactivity in the thyroid was determined at 150 and 180 minutes. The percent discharge of iodine from the thyroid gland was calculated as the ratio between the uptake 60 minutes after perchlorate administration and the uptake just before perchlorate administration, multiplied by 100. A discharge value above 10 percent indicates failure to retain the administered radioiodine, usually because of a defect in organification.
Identification of the Genomic Organization of the THOX1 and THOX2 Genes
The GenBank data base was screened with the THOX1 and THOX2 complementary DNA sequences (AF230495 and AF230496, respectively). From three human genomic clones (contigs) on chromosome 15 (AC009700.4, AC12255.4, and AC051619), the intron–exon boundaries of the THOX genes were analyzed, and the number of coding exons was determined.
Detection of Mutations
After written informed consent had been obtained, genomic DNA was isolated from the venous blood of patients and first-degree relatives, together with 100 control subjects of white, black, and Asian origin. The complete coding region of the human THOX1 and THOX2 genes, including intron–exon boundaries, was amplified from genomic DNA with use of the polymerase chain reaction (PCR) and sense and antisense primers designed on the basis of the genetic sequences. The PCR fragments were analyzed on an Agilent 1100-DHPLC system, equipped with a Zorbax double-stranded DNA temperature-controlled column and a Diode array detector.33,34 The oligonucleotide sequences, PCR-amplification process, and conditions used in chromatography are described in Supplementary Appendix 1. Samples showing an aberrant chromatographic pattern were directly sequenced with fluorescent dideoxynucleotide primers (Big Dye, Perkin Elmer Applied Biosystems) on an automated DNA sequencer (ABI 3100, Perkin Elmer Applied Biosystems).
The relatives of the patients and the 100 controls underwent genotyping by heteroduplex analysis, sequencing, or digestion of the respective DNA-amplified PCR products with appropriate restriction enzymes, according to the specifications of the manufacturers.
The sponsors of this study had no involvement in the design of the study; in the collection, analysis, and interpretation of data; or in the writing of the report.
Results
Pattern of Congenital Hypothyroidism in Selected Patients
From an original cohort of 45 patients with severe congenital hypothyroidism at screening and a complete iodide-organification defect, 44 patients were excluded because of mutations in the thyroid peroxidase gene, leaving 1 patient of this group in the study (Patient 1 in Table 1Table 1
Thyroid Function in Patients with Iodide-Organification Defects and Mutations in the THOX2 Gene.). From an original cohort of 15 patients who had mild hypothyroidism at screening that proved to be transient during follow-up and a partial iodide-organification defect, 4 were excluded because of iodine intoxication (1 patient), putative thyroglobulin-synthesis defects (2 patients), or Pendred's syndrome (1 patient). Another three of these patients were not available for genetic testing. Thus, eight patients in this group were studied (Patients 2, 3, and 4 and the five patients with a partial organification defect). Table 1 shows the clinical data from these patients and their status with respect to mutations in the THOX1 and THOX2 genes.At screening, Patient 1 had thyroxine levels below the limit of detection and very high thyrotropin levels. Subsequent diagnostic procedures showed a properly located gland with a high uptake of iodine-123 and complete discharge of iodide in the perchlorate test. This patient requires continued thyroid hormone therapy.
At screening, Patient 2 had mildly decreased thyroxine and elevated thyrotropin levels, whereas Patients 3 and 4 had thyroxine values in the low-normal range (0.8 and 1.1 SD below the mean value of the daily distribution curve, respectively) and hyperthyrotropinemia. Routine determination of thyrotropin in blood spots at thyroxine levels below 0.8 SD of the mean value of the daily distribution curve allowed the detection of hyperthyrotropinemia and subsequent referral of Patients 3 and 4. Iodine-123–uptake studies in each case showed a properly located gland with a partial (40 to 66 percent) discharge of iodide in the perchlorate test. After several adjustments in dosage, these three patients were given very low doses of thyroxine (mean, 1.3 μg per kilogram of body weight per day), and after they reached the age of three years, therapy was stopped for diagnostic purposes. All of them remained euthyroid during the follow-up period of 12 months.
The same mild and transient phenotype of congenital hypothyroidism was present in the other five patients with a partial iodide-organification defect in whom no mutations in the THOX genes were identified. The phenotype of this subgroup clearly differed from that of patients who had severe congenital hypothyroidism with complete iodide-organification defects due to mutations in the gene for thyroid peroxidase (Table 1).
Screening for Mutations of the THOX1 and THOX2 Genes
The open reading frames of the THOX1 and THOX2 genes are divided among 33 exons, spanning 36 and 22 kb, respectively, on the long arm of chromosome 15. All 33 coding exons for both genes were PCR-amplified from genomic DNA of the patients. Analysis of PCR products by denaturing high-performance liquid chromatography showed multiple aberrant patterns. Most of them were also present in normal control alleles and are considered nonfunctional polymorphisms. The samples corresponding to the aberrant chromatographic patterns of exon 11 (Patient 1), exon 16 (Patients 2 and 3), and exon 21 (Patient 4) of the THOX2 gene were directly sequenced, revealing three different single-nucleotide changes and a 4-bp deletion. Patient 1 was homozygous for the mutation, and Patients 2, 3, and 4 were heterozygous (Figure 1Figure 1
Mutations in the Thyroid Oxidase 2 Gene (THOX2 ) in Patients with Permanent and Transient Congenital Hypothyroidism.). These changes were absent in 100 control alleles. In Patient 1, exon 11 of THOX2 had a homozygous substitution of thymine for cytosine at position 1300 (C1300T) that generates a premature termination signal (R434X). Patient 2 was heterozygous for the C2056T mutation in exon 16 of THOX2, which also generates a premature stop codon instead of the incorporation of a glutamine (Q686X). Patient 3 was heterozygous for the C2101T nonsense mutation in exon 16 of THOX2, which changes arginine 701 into a premature termination signal (R701X). Patient 4 had a monoallelic deletion of GTTC at position 2895 (2895–2898del) in exon 21 of THOX2 that introduces a frame shift generating a termination signal in exon 22 (S965fsX994). Southern blotting found no evidence of chromosomal deletions in the THOX genes (data not shown).All four THOX2 mutations should induce premature stop codons that delete the predicted functional hydrogen peroxide–generating domains and are considered inactivating mutations (Figure 2Figure 2
Functional Domains and Mutations of the Thyroid Oxidase 2 (THOX2) Protein.).Pedigree Analysis
The parents of Families 1 and 2 (from Turkey) and Family 3 (from Surinam) settled in the Netherlands before the 1980s, and most of their descendants participated in the Dutch screening program for congenital hypothyroidism. Family 4 has a white Dutch background. The parents were all born before the screening program was instituted. A total of 17 persons from two generations were available for hormonal and genetic testing. The levels of thyrotropin, thyroxine, free thyroxine, triiodothyronine, and thyroglobulin and the thyroid size were normal in every member of the four families except for the patients (data not shown). The genotypes of the available family members were determined by direct sequencing, restriction-site analysis, or heteroduplex analysis (Figure 3Figure 3
Segregation Analysis of Mutations in the Thyroid Oxidase 2 Gene (THOX2 ) in Three Families with Permanent or Transient Congenital Hypothyroidism.).In Family 1, the index patient (Subject II-1 in Figure 3), the product of a consanguineous marriage, was homozygous for the C1300T mutation in THOX2. Her father (Subject I-1), mother (Subject I-2), and brother (Subject II-2) were heterozygous and had normal thyroid function.
In Family 2, the index patient (Subject II-3 in Figure 3) and her father (Subject I-1) were heterozygous for the C2056T THOX2 mutant allele, whereas the mother (Subject I-2) was homozygous for the wild-type allele. The patient's older brother (Subject II-1) did not carry the mutation and had normal screening values. Subject II-2 was born in Turkey and was not available for screening.
In Family 3, the index patient (Subject II-2 in Figure 3), her brother (Subject II-1), and her mother (Subject I-2) had the THOX2 C2101T mutation. The results of screening of the patient's brother (Subject II-1) for congenital hypothyroidism were reported to be normal. Retrieval of these results after 10 years showed a blood-spot thyroxine value of 12 μg per deciliter (154 nmol per liter), corresponding to –0.6 SD of the mean value of the daily thyroxine-distribution curve, just above the cutoff level for thyrotropin determination in the Dutch screening program. This borderline blood-spot thyroxine value might have caused a false negative screening result. At 10 years of age, Subject II-1 was euthyroid and performed normally at school. His target height was 173.5 cm, and he was growing at –2.0 SD of the mean value on the Dutch standard growth curve, whereas his sister (Subject II-2), with a target height of 159 cm, was growing at –0.8 SD of the standard curve.
In Family 4, the index patient (Subject II-2 in Figure 3) inherited the THOX2 2895–2898del mutation from her father (Subject II-1). Her older brother, who had normal screening results, did not carry the deletion.
Discussion
The generation of hydrogen peroxide is an essential step in the synthesis of thyroid hormones. Over the past three decades, a few cases of thyroidal hydrogen peroxide deficiency have been described, but the molecular basis of these defects has not been investigated.39-41
We studied the genomic organization and screened the THOX1 and THOX2 genes for mutations in patients with congenital hypothyroidism and iodide-organification defects. Mutations in the THOX2 gene were present in one patient with a complete iodide-organification defect and permanent congenital hypothyroidism and in three of eight patients with partial iodide-organification defects and transient congenital hypothyroidism. All mutations resulted in premature stop codons that delete the NADPH- and FAD-binding sites of the THOX2 protein. Functional studies of gp91phox, a protein of the phagocyte oxidase system that is homologous with the THOX proteins, show that truncation of these sites leads to complete loss of activity.42
The patient with severe and permanent congenital hypothyroidism was homozygous for a THOX2 inactivating mutation. This finding proves that abolishing functional THOX2 protein completely blocks thyroid hormone synthesis.
The three patients with a milder and transient form of the disease were heterozygous for three other inactivating mutations, suggesting that insufficiency of the THOX2 protein within the thyroid oxidase complex was the underlying mechanism of disease. However, the neonatal euthyroid profile of Subject II-2 in Family 1, who was heterozygous for the C1300T mutation, might indicate the existence of dominant negative properties in mutant proteins 2, 3, and 4 that are not present in mutant protein 1. In contrast to mutant 1, mutants 2, 3, and 4 retain the hydrophobic stretch of the first transmembrane domain of the THOX2 protein, which might allow the insertion of the protein in the membrane and aberrant interactions with other components of the oxidase system.43 It is tempting to speculate that these putative other components are involved in the molecular basis of the transient congenital hypothyroidism of the patients in our study who did not have THOX1 or THOX2 mutations.
Partial insufficiency of the THOX2 protein, resulting in diminished hydrogen peroxide production, is present only during the first weeks or months of postnatal life, when the requirement for thyroid hormones is large. On the basis of evidence that transient congenital hypothyroidism and hyperthyrotropinemia are associated with impaired intellectual development in children,44 we advise treatment of these patients as soon as possible after birth, as well as thyroid-function tests in newborn siblings of children with transient congenital hypothyroidism. Furthermore, it is important to follow these patients for subclinical or overt hypothyroidism, goiter, or both in adolescence and adulthood, especially during pregnancy, when the need for thyroxine increases. If the expression of this genetic disorder recurs during pregnancy, the neurologic development of the offspring can be hampered.45,46
In conclusion, biallelic and monoallelic inactivating mutations in the THOX2 gene are associated with permanent and transient congenital hypothyroidism, respectively. These findings prove that the THOX2 protein is an essential component of the thyroidal system of hydrogen peroxide generation. Furthermore, they represent to our knowledge the first demonstration that transient congenital hypothyroidism can be genetically determined and show that thyroid dyshormonogenesis is involved in the transient form of congenital hypothyroidism.
Supported by a European Society for Pediatric Endocrinology Fellowship sponsored by Novo Nordisk (to Dr. Moreno), and a grant from the Dr. Ludgardine Bouwman Foundation (to Dr. de Vijlder).
We are indebted to the patients (and to their parents) for their collaboration, to Janine de Randamie for her assistance in DNA diagnostics, to Brenda Wiedijk for assistance in the collection of data, to Dr. P. Harmsen and Dr. R. van Andel for clinical follow-up of some patients, and to Professor Dirk Roos for critical reading of the manuscript.
Source Information
From the Department of Pediatric Endocrinology, Emma Children's Hospital (J.C.M., H.B., M.J.E.K., A.S.P.T., J.J.M.V., T.V., C.R.-S.), and the Neurozintuigen Laboratory (F.B.), Academic Medical Center, University of Amsterdam, Amsterdam.
Address reprint requests to Dr. Moreno at P.O. Box 22700, 1100 DE Amsterdam, the Netherlands, or at j.c.moreno@amc.uva.nl.
- References
References
1
New England Congenital Hypothyroidism Collaborative 2
Fisher DA ,Klein AH . Thyroid development and disorders of thyroid function in the newborn. N Engl J Med 1981;304:702-712
Full Text | Web of Science | Medline3
Delange F ,Dodion J ,Wolter R , et al. Transient hypothyroidism in the newborn infant. J Pediatr 1978;92:974-976
CrossRef | Web of Science | Medline4
de Vijlder JJM, Vulsma T. Hereditary metabolic disorders causing hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner & Ingbar's the thyroid: a fundamental and clinical text. 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:733-42.
5
Devriendt K ,Vanhole C ,Matthijs G ,De Zegher F . Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med 1998;338:1317-1318
Full Text | Web of Science | Medline6
Clifton-Bligh RJ ,Wentworth JM ,Heinz P , et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 1998;19:399-401
CrossRef | Web of Science | Medline7
Macchia PE ,Lapi P ,Krude H , et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 1998;19:83-86
CrossRef | Web of Science | Medline8
Lapi P ,Macchia P ,Chiovato L , et al. Mutations in the gene encoding thyroid transcription factor-1 (TTF-1) are not a frequent cause of congenital hypothyroidism (CH) with thyroid dysgenesis. Thyroid 1997;7:383-387
CrossRef | Web of Science | Medline9
Perna M ,Civitareale D ,De Filipis V ,Sacco M ,Cisternino C ,Tassi V . Absence of mutations in the gene encoding thyroid transcription factor-1 (TTF-1) in patients with thyroid dysgenesis. Thyroid 1997;7:377-381
CrossRef | Web of Science | Medline10
Sava L ,Delange F ,Belfiore A , et al. Transient impairment of thyroid function in newborn from an area of endemic goiter. J Clin Endocrinol Metab 1984;59:90-95
CrossRef | Web of Science | Medline11
l'Alemand D ,Gruters A ,Heidemann P ,Schurbrand P . Iodine-induced alterations of thyroid function in newborn infants after prenatal and perinatal exposure to povidone iodine. J Pediatr 1984;102:935-938
Web of Science12
Stubbe P ,Heidemann P ,Schurnbrand P ,Ulbrich R . Transient congenital hypothyroidism after amniofetography. Eur J Pediatr 1980;135:97-99
CrossRef | Web of Science | Medline13
Matsuura N ,Yamada Y ,Nohara Y , et al. Familial neonatal transient hypothyroidism due to maternal TSH-binding inhibitor immunoglobulins. N Engl J Med 1980;303:738-741
Full Text | Web of Science | Medline14
Frank JE ,Faix JD ,Hermos RJ , et al. Thyroid function in very low birth weight infants: effects on neonatal hypothyroidism screening. J Pediatr 1996;128:548-554
CrossRef | Web of Science | Medline15
van Wassenaer AG ,Kok JH ,de Vijlder JJM , et al. Effects of thyroxine supplementation on neurological development in infants born at less than 30 weeks' gestation. N Engl J Med 1997;336:21-26
Full Text | Web of Science | Medline16
Trimarchi F ,Gemelli M ,Benvenga S , et al. Transient congenital hypothyroidism in an infant with congenital nephrosis of the Finnish type. Acta Paediatr Scand 1983;72:145-147
CrossRef | Web of Science | Medline17
Coakley JC ,Francis I ,Gold H ,Mathur K ,Connelly JF . Transient primary hypothyroidism in the newborn: experience of the Victorian Neonatal Thyroid Screening Programme. Aust Paediatr J 1989;25:25-30
Medline18
Leger J ,Czernichow P . Hyperthyrothropinémie néonatal transitoire. Arch Fr Pediatr 1988;45:783-786
Medline19
Vulsma T. Etiology and pathogenesis of congenital hypothyroidism. (Ph.D. thesis. Amsterdam: University of Amsterdam, 1991.)
20
Fisher DA ,Dussault JH ,Foley TP , et al. Screening for congenital hypothyroidism: results of screening one million North American infants. J Pediatr 1979;94:700-705
CrossRef | Web of Science | Medline21
Nose O ,Harada T ,Miyai K , et al. Transient neonatal hypothyroidism probably related to immaturity of thyroidal iodine organification. J Pediatr 1986;108:573-576
CrossRef | Web of Science | Medline22
Corvilain B ,Van Sande J ,Laurent E ,Dumont JE . The H2O2-generating system modulates protein iodination and the activity of the pentose phosphate pathway in dog. Endocrinology 1991;128:779-785
CrossRef | Web of Science | Medline23
Dupuy C ,Ohayon R ,Valent A ,Noel-Hudson MS ,Deme D ,Virion Q . Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. J Biol Chem 1999;274:37265-37269
CrossRef | Web of Science | Medline24
De Deken X ,Wang D ,Costagliola S , et al. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem 2000;275:23227-23233
CrossRef | Web of Science | Medline25
Moreno JC ,Pauws E ,van Kampen AHC ,Jedlickova M ,de Vijlder JJM ,Ris-Stalpers C . Cloning of tissue-specific genes using serial analysis of gene expression and a novel computational substraction approach. Genomics 2001;75:70-76
CrossRef | Web of Science | Medline26
Keller T ,Damude HG ,Werner D ,Doerner P ,Dixon RA ,Lamb C . A plant homolog of the neutrophil NADPH oxidase gp91phox subunit gene encodes a plasma membrane protein with Ca2+ binding motifs. Plant Cell 1998;10:255-266
CrossRef | Web of Science | Medline27
Bakker B ,Bikker H ,Vulsma T ,de Randamie JSE ,Wiedijk BM ,de Vijlder JJM . Two decades of screening for congenital hypothyroidism in the Netherlands: TPO gene mutations in total iodide organification defects (an update). J Clin Endocrinol Metab 2000;85:3708-3712
CrossRef | Web of Science | Medline28
Hishinuma A ,Takamatsu J ,Ohyama Y , et al. Two novel cysteine substitutions (C1263R and C1995S) of thyroglobulin cause a defect in intracellular transport of thyroglobulin in patients with congenital goiter and the variant type of adenomatous goiter. J Clin Endocrinol Metab 1999;84:1438-1444
CrossRef | Web of Science | Medline29
Everett LA ,Glaser B ,Beck JC , et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997;17:411-422
CrossRef | Web of Science | Medline30
Van Hauwe P ,Everett LA ,Coucke P , et al. Two frequent missense mutations in Pendred syndrome. Hum Mol Genet 1998;7:1099-1104
CrossRef | Web of Science | Medline31
Van de Graaf SAR ,Cammenga M ,Ponne NJ , et al. The screening for mutations in the thyroglobulin cDNA from six patients with congenital hypothyroidism. Biochimie 1999;81:425-432
CrossRef | Web of Science | Medline32
Bakker B ,Vulsma T ,de Randamie J , et al. A negative iodine balance is found in healthy neonates compared with neonates with thyroid agenesis. J Endocrinol 1999;161:115-120
CrossRef | Web of Science | Medline33
Jones AC ,Austin J ,Hansen N , et al. Optimal temperature selection for mutation detection by denaturing HPLC and comparison to single-stranded conformation polymorphism and heteroduplex analysis. Clin Chem 1999;45:1133-1140
Web of Science | Medline34
Xiao W ,Oefner PJ . Denaturing high-performance liquid chromatography: a review. Hum Mutat 2001;17:439-474
CrossRef | Web of Science | Medline35
Fisher DA . Management of congenital hypothyroidism. J Clin Endocrinol Metab 1991;72:523-529
CrossRef | Web of Science | Medline36
Nelson JC ,Clark SJ ,Borut DL , et al. Age-related changes in serum free thyroxine during childhood and adolescence. J Pediatr 1993;123:899-905
CrossRef | Web of Science | Medline37
Vulsma T ,Gons MH ,de Vijlder JJM . Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989;321:13-16
Full Text | Web of Science | Medline38
McDougall IR, Cavalieri RR. In vivo radionuclide tests and imaging. In: Braverman LE, Utiger RD, eds. Werner & Ingbar's the thyroid: a fundamental and clinical text. 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:355-75.
39
Kusakabe T . Deficient cytochrome b5 reductase activity in nontoxic goiter with iodide organification defect. Metabolism 1975;24:1103-1113
CrossRef | Web of Science | Medline40
Niepomniszcze H ,Targovnik HM ,Gluzman BE ,Curuchet P . Abnormal H2O2 supply in the thyroid of a patient with goiter and iodine organification defect. J Clin Endocrinol Metab 1987;65:344-348
CrossRef | Web of Science | Medline41
Figueiredo MDL ,Cardoso LC ,Ferreira ACF , et al. Goiter and hypothyroidism in two siblings due to impaired Ca2+/NAD(P)H-dependent H2O2-generating activity. J Clin Endocrinol Metab 2001;86:4843-4848
CrossRef | Web of Science | Medline42
Yu L ,Cross AR ,Zhen L ,Dinauer MC . Functional analysis of the NADPH oxidase in granulocytic cells expressing a delta488-497 gp91(phox) deletion mutant. Blood 1999;94:2497-2504
Web of Science | Medline43
De Deken X ,Wang D ,Dumont JE ,Miot F . Characterization of ThOX proteins as components of the thyroid H2O2-generating system. Exp Cell Res 2002;273:187-196
CrossRef | Web of Science | Medline44
Calaciura F ,Mendorla G ,Distefano M , et al. Childhood IQ measurements in infants with transient congenital hypothyroidism. Clin Endocrinol (Oxf) 1995;43:473-477
CrossRef | Web of Science | Medline45
Haddow JE ,Palomaki GE ,Allan WC , et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-555
Full Text | Web of Science | Medline46
Pop V ,Kuipens JL ,van Baar AL , et al. Low normal maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50:149-155
CrossRef | Web of Science | Medline
- Citing Articles (83)
Citing Articles
1
Sureka Bollepalli, Susan R. Rose. 2012. Disorders of the Thyroid Gland. , 1307-1319.
CrossRef2
P. Fong. (2011) Thyroid iodide efflux: a team effort?. The Journal of Physiology 589:24, 5929-5939
CrossRef3
Yun Soo Bae, Hyunjin Oh, Sue Goo Rhee, Young Do Yoo. (2011) Regulation of reactive oxygen species generation in cell signaling. Molecules and Cells 32:6, 491-509
CrossRef4
Jung-Hee Joo, Ji-Hwan Ryu, Chang-Hoon Kim, Hyun Jik Kim, Mi-Sun Suh, Jin-Oh Kim, Seung Yeun Chung, Sang Nam Lee, Hwan Mook Kim, Yun Soo Bae, Joo-Heon Yoon. (2011) Dual Oxidase 2 is Essential for the Toll-Like Receptor 5-Mediated Inflammatory Response in Airway Mucosa. Antioxidants & Redox Signaling110808133547000
CrossRef5
Jennifer L. Meitzler, Paul R. Ortiz de Montellano. (2011) Structural stability and heme binding potential of the truncated human dual oxidase 2 (DUOX2) peroxidase domain. Archives of Biochemistry and Biophysics 512:2, 197-203
CrossRef6
C. Massart, C. Hoste, A. Virion, J. Ruf, J.E. Dumont, J. Van Sande. (2011) Cell biology of H2O2 generation in the thyroid: Investigation of the control of dual oxidases (DUOX) activity in intact ex vivo thyroid tissue and cell lines. Molecular and Cellular Endocrinology 343:1-2, 32-44
CrossRef7
Helmut Grasberger, Samuel Refetoff. (2011) Genetic causes of congenital hypothyroidism due to dyshormonogenesis. Current Opinion in Pediatrics 23:4, 421-428
CrossRef8
Eun-Young Yun, Jae-Sam Hwang, Young-Il Yoon, Mi-Young Ahn, Nam-Jung Kim, O-Yu Kwon, Won-Jae Lee, Tae-Won Goo. (2011) Microarray expression profiling of Spodoptera litura in response to oxidative stress. Archives of Insect Biochemistry and Physiology 77:3, 145-162
CrossRef9
Domenico Del Principe, Luciana Avigliano, Isabella Savini, Maria Valeria Catani. (2011) Trans-Plasma Membrane Electron Transport in Mammals: Functional Significance in Health and Disease. Antioxidants & Redox Signaling 14:11, 2289-2318
CrossRef10
L. Fugazzola, M. Muzza, G. Weber, P. Beck-Peccoz, L. Persani. (2011) DUOXS defects: Genotype-phenotype correlations. Annales d'Endocrinologie 72:2, 82-86
CrossRef11
Klaudia Brix, Dagmar Führer, Heike Biebermann. (2011) Molecules important for thyroid hormone synthesis and action - known facts and future perspectives. Thyroid Research 4:Suppl 1, S9
CrossRef12
Masato Katsuyama, Kuniharu Matsuno, Chihiro Yabe-Nishimura. (2011) Physiological roles of NOX/NADPH oxidase, the superoxide-generating enzyme. Journal of Clinical Biochemistry and Nutrition
CrossRef13
Ana Chiesa, Carina M. Rivolta, Héctor M. Targovnik, Laura Gruñeiro-Papendieck. (2010) Clinical, biochemical, and molecular findings in Argentinean patients with goitrous congenital hypothyroidism. Endocrine 38:3, 377-385
CrossRef14
Ágnes Donkó, Éva Ruisanchez, Anna Orient, Balázs Enyedi, Réka Kapui, Zalán Péterfi, Xavier de Deken, Zoltán Benyó, Miklós Geiszt. (2010) Urothelial cells produce hydrogen peroxide through the activation of Duox1. Free Radical Biology and Medicine 49:12, 2040-2048
CrossRef15
Chunbo Liu, Fengjun Wang, Changjun Wu, Min Zhou. (2010) TPO and DIO1 Mutations in Patients With the Coexistence of Hashimoto Thyroiditis and Papillary Thyroid Carcinoma. The Endocrinologist 20:5, 254-258
CrossRef16
Robert Rapaport, Gidon Akler, Molly O. Regelmann, Fenella Greig. (2010) Time for Thyrotropin Releasing Hormone to Return to the United States of America. Thyroid 20:9, 947-948
CrossRef17
Andreas Petry, Michael Weitnauer, Agnes Görlach. (2010) Receptor Activation of NADPH Oxidases. Antioxidants & Redox Signaling 13:4, 467-487
CrossRef18
Yun Soo Bae, Myoung Kwon Choi, Won-Jae Lee. (2010) Dual oxidase in mucosal immunity and host–microbe homeostasis. Trends in Immunology 31:7, 278-287
CrossRef19
Gijs B. Afink, Geertruda Veenboer, Janine de Randamie, Remco Keijser, Christof Meischl, Hans Niessen, Carrie Ris-Stalpers. (2010) Initial Characterization of C16orf89 , A Novel Thyroid-Specific Gene. Thyroid 20:7, 811-821
CrossRef20
Peter Kovacic, Corey Edwards. (2010) Integrated approach to the mechanisms of thyroid toxins: electron transfer, reactive oxygen species, oxidative stress, cell signaling, receptors, and antioxidants. Journal of Receptors and Signal Transduction 30:3, 133-142
CrossRef21
Thomas Hill, Changhong Xu, Richart W. Harper. (2010) IFNγ mediates DUOX2 expression via a STAT-independent signaling pathway. Biochemical and Biophysical Research Communications 395:2, 270-274
CrossRef22
Ji-Hwan Ryu, Eun-Mi Ha, Won-Jae Lee. (2010) Innate immunity and gut–microbe mutualism in Drosophila. Developmental & Comparative Immunology 34:4, 369-376
CrossRef23
Ya Zhang, Shaolin Mu, Baolin Deng, Jianzhong Zheng. (2010) Electrochemical removal and release of perchlorate using poly(aniline-co-o-aminophenol). Journal of Electroanalytical Chemistry 641:1-2, 1-6
CrossRef24
Doga Turkkahraman, Ozgul M. Alper, Suray Pehlivanoglu, Funda Aydin, Akin Yildiz, Guven Luleci, Sema Akcurin, Iffet Bircan. (2010) Analysis of TPO gene in Turkish children with iodide organification defect: identification of a novel mutation. Endocrine 37:1, 124-128
CrossRef25
Satoshi Okano, Lingyun Zhou, Toshimasa Kusaka, Kazuhide Shibata, Kazuhiro Shimizu, Xu Gao, Yuko Kikuchi, Yoshiyuki Togashi, Tomonori Hosoya, Satoru Takahashi, Osamu Nakajima, Masayuki Yamamoto. (2010) Indispensable function for embryogenesis, expression and regulation of the nonspecific form of the 5-aminolevulinate synthase gene in mouse. Genes to Cells 15:1, 77-89
CrossRef26
Masato Katsuyama. (2010) NOX/NADPH Oxidase, the Superoxide-Generating Enzyme: Its Transcriptional Regulation and Physiological Roles. Journal of Pharmacological Sciences 114:2, 134-146
CrossRef27
K. Eder, R. Ringseis. 2010. 7 Health aspects of oxidized dietary fats. , 143-180.
CrossRef28
Helmut Grasberger, Samuel Refetoff. 2010. Congenital Defects of Thyroid Hormone Synthesis. , 87-327.
CrossRef29
Abdelmounaaïm Allaoui, Anne Botteaux, Jacques E. Dumont, Candice Hoste, Xavier De Deken. (2009) Dual oxidases and hydrogen peroxide in a complex dialogue between host mucosae and bacteria. Trends in Molecular Medicine 15:12, 571-579
CrossRef30
David I. Brown, Kathy K. Griendling. (2009) Nox proteins in signal transduction. Free Radical Biology and Medicine 47:9, 1239-1253
CrossRef31
Carlo Corbetta, Giovanna Weber, Francesca Cortinovis, Davide Calebiro, Arianna Passoni, Maria C. Vigone, Paolo Beck-Peccoz, Giuseppe Chiumello, Luca Persani. (2009) A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH). Clinical Endocrinology 71:5, 739-745
CrossRef32
Thomas L. Leto, Stanislas Morand, Darrell Hurt, Takehiko Ueyama. (2009) Targeting and Regulation of Reactive Oxygen Species Generation by Nox Family NADPH Oxidases. Antioxidants & Redox Signaling 11:10, 2607-2619
CrossRef33
D. Turkkahraman,, O.M. Alper,, F. Aydin,, A. Yildiz,, S. Pehlivanoglu,, G. Luleci,, S. Akcurin,, I. Bircan,. (2009) Final Diagnosis in Children with Subclinical Hypothyroidism and Mutation Analysis of the Thyroid Peroxidase Gene (TPO). Journal of Pediatric Endocrinology and Metabolism 22:9, 845-852
CrossRef34
Tohru Kamata. (2009) Roles of Nox1 and other Nox isoforms in cancer development. Cancer Science 100:8, 1382-1388
CrossRef35
Rosalind S. Brown. 2009. The Thyroid. , 250-282.
CrossRef36
Guangjie Cheng, John C. Salerno, Zehong Cao, Patrick J. Pagano, J. David Lambeth. (2008) Identification and characterization of VPO1, a new animal heme-containing peroxidase. Free Radical Biology and Medicine 45:12, 1682-1694
CrossRef37
Ralf P Brandes, Katrin Schröder. (2008) Differential vascular functions of Nox family NADPH oxidases. Current Opinion in Lipidology 19:5, 513-518
CrossRef38
William M. Nauseef. (2008) Nox enzymes in immune cells. Seminars in Immunopathology 30:3, 195-208
CrossRef39
Hideki Sumimoto. (2008) Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species. FEBS Journal 275:13, 3249-3277
CrossRef40
Sebastián A. Esperante, Carina M. Rivolta, Lucrecia Miravalle, Viviana Herzovich, Sonia Iorcansky, Marco Baralle, Héctor M. Targovnik. (2008) Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands. Clinical Endocrinology 68:5, 828-835
CrossRef41
Hidemi Ohye, Shuji Fukata, Akira Hishinuma, Takumi Kudo, Eijun Nishihara, Mitsuru Ito, Sumihisa Kubota, Nobuyuki Amino, Tamio Ieiri, Kanji Kuma, Akira Miyauchi. (2008) A Novel Homozygous Missense Mutation of the Dual Oxidase 2 (DUOX2) Gene in an Adult Patient with Large Goiter. Thyroid 18:5, 561-566
CrossRef42
Moreno, José C., Klootwijk, Willem, van Toor, Hans, Pinto, Graziella, D'Alessandro, Mariella, Lèger, Aubène, Goudie, David, Polak, Michel, Grüters, Annette, Visser, Theo J., . (2008) Mutations in the Iodotyrosine Deiodinase Gene and Hypothyroidism. New England Journal of Medicine 358:17, 1811-1818
Full Text43
Albert van der Vliet. (2008) NADPH oxidases in lung biology and pathology: Host defense enzymes, and more. Free Radical Biology and Medicine 44:6, 938-955
CrossRef44
DELBERT A. FISHER, ANNETTE GRUETERS. 2008. Disorders of the Thyroid in the Newborn and Infant. , 198-226.
CrossRef45
Sabrina Rigutto, Candice Hoste, Jacques E. Dumont, Bernard Corvilain, Françoise Miot, Xavier De Deken. (2007) Duox1 is the main source of hydrogen peroxide in the rat thyroid cell line PCCl3. Experimental Cell Research 313:18, 3892-3901
CrossRef46
Kyra A. Gelderman, Malin Hultqvist, Lina M. Olsson, Kristin Bauer, Angela Pizzolla, Peter Olofsson, Rikard Holmdahl. (2007) Rheumatoid Arthritis: The Role of Reactive Oxygen Species in Disease Development and Therapeutic Strategies. Antioxidants & Redox Signaling 9:10, 1541-1568
CrossRef47
Yan-Hong Gu, Tadaaki Kato, Shohei Harada, Hiroaki Inomata, Tomohiro Saito, Kikumaro Aoki. (2007) Seasonality in the Incidence of Congenital Hypothyroidism in Japan: Gender-Specific Patterns and Correlation with Temperature. Thyroid 17:9, 869-874
CrossRef48
Mariela Caputo, Carina M. Rivolta, Sebastían A. Esperante, Laura Gruñeiro-Papendieck, Ana Chiesa, Claudia G. Pellizas, Rogelio González-Sarmiento, Héctor M. Targovnik. (2007) Congenital hypothyroidism with goitre caused by new mutations in the thyroglobulin gene. Clinical Endocrinology 67:3, 351-357
CrossRef49
Shinya Toyokuni, Shinya Akatsuka. (2007) Pathological investigation of oxidative stress in the post-genomic era. Pathology International 57:8, 461-473
CrossRef50
Carina M. Rivolta, Mariana Louis-Tisserand, Viviana Varela, Laura Gruñeiro-Papendieck, Ana Chiesa, Rogelio González-Sarmiento, Héctor M. Targovnik. (2007) Two compound heterozygous mutations (c.215delA/c.2422T?C and c.387delC/c.1159G?A) in the thyroid peroxidase gene responsible for congenital goitre and iodide organification defect. Clinical Endocrinology 67:2, 238-246
CrossRef51
Yardena Tenenbaum-Rakover, Sunee Mamanasiri, Carrie Ris-Stalpers, Alina German, Joseph Sack, Stavit Allon-Shalev, Joachim Pohlenz, Samuel Refetoff. (2007) Clinical and genetic characteristics of congenital hypothyroidism due to mutations in the thyroid peroxidase (TPO) gene in Israelis. Clinical Endocrinology 66:5, 695-702
CrossRef52
Karl-Heinz Krause. (2007) Aging: A revisited theory based on free radicals generated by NOX family NADPH oxidases. Experimental Gerontology 42:4, 256-262
CrossRef53
Christiane Christophe-Hobertus, Daniel Christophe. (2007) Human Thyroid Oxidases genes promoter activity in thyrocytes does not appear to be functionally dependent on Thyroid Transcription Factor-1 or Pax8. Molecular and Cellular Endocrinology 264:1-2, 157-163
CrossRef54
Hiroyuki NUNOI. (2007) Two breakthroughs in CGD studies. Japanese Journal of Clinical Immunology 30:1, 1-10
CrossRef55
Nicole Pfarr, Eckhard Korsch, Stefan Kaspers, Antje Herbst, Armin Stach, Claudia Zimmer, Joachim Pohlenz. (2006) Congenital hypothyroidism caused by new mutations in the thyroid oxidase
2 (THOX2) gene. Clinical Endocrinology 65:6, 810-815
CrossRef56
Carina M. Rivolta, Héctor M. Targovnik. (2006) Molecular advances in thyroglobulin disorders. Clinica Chimica Acta 374:1-2, 8-24
CrossRef57
Thomas L. Leto, Miklos Geiszt. (2006) Role of Nox Family NADPH Oxidases in Host Defense. Antioxidants & Redox Signaling 8:9-10, 1549-1561
CrossRef58
Carrie Ris-Stalpers. (2006) Physiology and Pathophysiology of the DUOXes. Antioxidants & Redox Signaling 8:9-10, 1563-1572
CrossRef59
Kazuhito Rokutan, Tsukasa Kawahara, Yuki Kuwano, Kumiko Tominaga, Atsuo Sekiyama, Shigetada Teshima-Kondo. (2006) NADPH Oxidases in the Gastrointestinal Tract: A Potential Role of Nox1 in Innate Immune Response and Carcinogenesis. Antioxidants & Redox Signaling 8:9-10, 1573-1582
CrossRef60
D. Carranza, G. Van Vliet, M. Polak. (2006) Hypothyroïdie congénitale. Annales d'Endocrinologie 67:4, 295-302
CrossRef61
Nicole Pfarr, Thomas J. Musholt, Petra B. Musholt, Rita Brzezinska, Joachim Pohlenz. (2006) Congenital primary hypothyroidism with subsequent adenomatous goiter in a Turkish patient caused by a homozygous 10-bp deletion in the thyroid peroxidase (TPO) gene. Clinical Endocrinology 64:5, 514-518
CrossRef62
Anissa Djemli, Guy Van Vliet, Edgard E. Delvin. (2006) Congenital hypothyroidism: From paracelsus to molecular diagnosis. Clinical Biochemistry 39:5, 511-518
CrossRef63
Sachiko Kitanaka, Ayaka Takeda, Utako Sato, Yuko Miki, Akira Hishinuma, Tamio Ieiri, Takashi Igarashi. (2006) A novel compound heterozygous mutation in the thyroglobulin gene resulting in congenital goitrous hypothyroidism with high serum triiodothyronine levels. Journal of Human Genetics 51:4, 379-382
CrossRef64
John S Fuqua. (2006) Genetics, clinical management and natural history of congenital hypothyroidism. Expert Review of Endocrinology & Metabolism 1:2, 265-279
CrossRef65
A. Donko, Z. Peterfi, A. Sum, T. Leto, M. Geiszt. (2005) Dual oxidases. Philosophical Transactions of the Royal Society B: Biological Sciences 360:1464, 2301-2308
CrossRef66
Hideki Sumimoto, Kei Miyano, Ryu Takeya. (2005) Molecular composition and regulation of the Nox family NAD(P)H oxidases. Biochemical and Biophysical Research Communications 338:1, 677-686
CrossRef67
Yvonne Böttcher, Markus Eszlinger, Anke Tönjes, Ralf Paschke. (2005) The genetics of euthyroid familial goiter. Trends in Endocrinology & Metabolism 16:7, 314-319
CrossRef68
Laura Fugazzola, Deborah Mannavola, Maria Cristina Vigone, Valentina Cirello, Giovanna Weber, Paolo Beck-Peccoz, Luca Persani. (2005) Total Iodide Organification Defect: Clinical and Molecular Characterization of an Italian Family. Thyroid 15:9, 1085-1088
CrossRef69
Yuuki Inoue, Michio Ogasawara, Takuma Moroi, Masanobu Satake, Kaoru Azumi, Tadaaki Moritomo, Teruyuki Nakanishi. (2005) Characteristics of NADPH oxidase genes (Nox2, p22, p47, and p67) and Nox4 gene expressed in blood cells of juvenile Ciona intestinalis. Immunogenetics 57:7, 520-534
CrossRef70
Huiling He, Katie Olesnanik, Rebecca Nagy, Sandya Liyanarachchi, Manju L. Prasad, Constantine A. Stratakis, Richard T. Kloos, Albert de la Chapelle. (2005) Allelic Variation in Gene Expression in Thyroid Tissue. Thyroid 15:7, 660-667
CrossRef71
Franco Scinicariello, H. Edward Murray, Lester Smith, Sharon Wilbur, Bruce A. Fowler. (2005) Genetic Factors That Might Lead to Different Responses in Individuals Exposed to Perchlorate. Environmental Health Perspectives 113:11, 1479-1484
CrossRef72
Rossella Gaudino, Catherine Garel, Paul Czernichow, Juliane Leger. (2005) Proportion of various types of thyroid disorders among newborns with congenital hypothyroidism and normally located gland: a regional cohort study. Clinical Endocrinology 62:4, 444-448
CrossRef73
Erwin Pauws, Gwendolyn G. Sijmons, Cigdem Yaka, Carrie Ris-Stalpers. (2004) A Novel Homeobox Gene Overexpressed in Thyroid Carcinoma. Thyroid 14:7, 500-505
CrossRef74
Andrew R Cross, Anthony W Segal. (2004) The NADPH oxidase of professional phagocytes—prototype of the NOX electron transport chain systems. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1657:1, 1-22
CrossRef75
J. David Lambeth. (2004) NOX enzymes and the biology of reactive oxygen. Nature Reviews Immunology 4:3, 181-189
CrossRef76
J. Pachucki, D. Wang, D. Christophe, F. Miot. (2004) Structural and functional characterization of the two human ThOX/Duox genes and their 5′-flanking regions. Molecular and Cellular Endocrinology 214:1-2, 53-62
CrossRef77
Antonio C. Nascimento, Dulce R. Guedes, Cecilia S. Santos, Meyer Knobel, Ileana G.S. Rubio, Geraldo Medeiros-Neto. (2003) Thyroperoxidase Gene Mutations in Congenital Goitrous Hypothyroidism with Total and Partial Iodide Organification Defect. Thyroid 13:12, 1145-1151
CrossRef78
Teresa Lara-Ortíz, Héctor Riveros-Rosas, Jesús Aguirre. (2003) Reactive oxygen species generated by microbial NADPH oxidase NoxA regulate sexual development in Aspergillus nidulans. Molecular Microbiology 50:4, 1241-1255
CrossRef79
Massimo Tonacchera, Patrizia Agretti, Giuseppina De Marco, Rossella Elisei, Anna Perri, Elena Ambrogini, Melissa De Servi, Claudia Ceccarelli, Paolo Viacava, Samuel Refetoff, Claudio Panunzi, Maria Luisa Manca Bitti, Paolo Vitti, Luca Chiovato, Aldo Pinchera. (2003) Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein. Clinical Endocrinology 59:4, 500-506
CrossRef80
José C Moreno, Jan J.M de Vijlder, Thomas Vulsma, Carrie Ris-Stalpers. (2003) Genetic basis of hypothyroidism: recent advances, gaps and strategies for future research. Trends in Endocrinology & Metabolism 14:7, 318-326
CrossRef81
Meyer Knobel, Geraldo Medeiros-Neto. (2003) An Outline of Inherited Disorders of the Thyroid Hormone Generating System. Thyroid 13:8, 771-801
CrossRef82
John C. Fyfe, Kit Kampschmidt, Van Dang, Brian A. Poteet, Qianchuan He, Charles Lowrie, Peter A. Graham, Virginia M. Fetro. (2003) Congenital Hypothyroidism with Goiter in Toy Fox Terriers. Journal of Veterinary Internal Medicine 17:1, 50-57
CrossRef83
Joanne Rovet, Denis Daneman. (2003) Congenital Hypothyroidism. Pediatric Drugs 5:3, 141-149
CrossRef
