Original Article
Brief Report
Mutations in the Iodotyrosine Deiodinase Gene and Hypothyroidism
N Engl J Med 2008; 358:1811-1818April 24, 2008
- Abstract
DEHAL1
has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of iodotyrosine deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in iodotyrosine deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.
Media in This Article
Figure 1
Mutations in DEHAL1 Associated with Iodotyrosine Deiodinase Deficiency.Figure 2
Functional Characterization of Wild-Type and DEHAL1 Mutations.Article Activity
- Article
Iodine is an essential component of thyroid hormone. To ensure that iodine is available for thyroid hormone biosynthesis, two highly specialized systems evolved in the thyroid gland. One, the sodium–iodide symporter, accumulates iodide in thyroid cells by active membrane transport.1 The other recycles iodide through the deiodination of monoiodotyrosine and diiodotyrosine, the main iodinated by-products of the synthesis of thyroid hormone.2-4 This enzyme activity is known to exist in the thyroid, liver, and kidneys.5 Three decades ago, the partial purification of a flavoprotein from bovine thyroid was reported and found to deiodinate iodotyrosines.6 However, the molecular nature of this enzyme remained unknown. The use of serial analysis of gene expression on human thyroid tissue led to the identification of DEHAL1,7,8 which encodes a nitroreductase-related enzyme capable of deiodinating iodotyrosines.8,9 Nitroreductases are proteins that can reduce a wide range of nitroaromatic compounds with the use of flavin mononucleotide as a cofactor.10
Hypothyroidism is the most common congenital endocrine disorder, occurring in 1 of 3000 newborns because of complete or partial failure of thyroid development or thyroid hormone production.11 Thyroid hormones (triiodothyronine and its precursor, thyroxine) are essential for the correct development and maturation of the brain, a process that starts in utero but that extends into postnatal life.12
Several genetic defects are known to be associated with both permanent and transient congenital hypothyroidism.13 In many countries, newborns are screened for congenital hypothyroidism, and detected cases are immediately treated, which safely prevents the development of mental retardation.14 Here we report the identification of defects in DEHAL1 that produce a phenotype of severe hypothyroidism, goiter, excessive levels of iodotyrosine in serum and urine, and variable mental deficits derived from unrecognized hypothyroidism.
Methods
Patients
We selected patients for screening for DEHAL1 mutations on the basis of the presence of hypothyroidism and goiter with additional features consistent with iodotyrosine deiodinase deficiency, including elevated serum diiodotyrosine levels (in Patients 1 and 4), a distinct iodide uptake profile by the thyroid gland (in Patient 4), and a documented family background (in Patients 2 and 3). Genetic screening was performed after written informed consent was obtained from the patients or their parents.
Screening for Mutations
The six coding exons of DEHAL1 (National Center for Biotechnology Information accession number, AY259176.1) were amplified by polymerase-chain-reaction (PCR) assay from genomic DNA with the use of primers flanking intron–exon junctions. (Primer sequences are listed in the Supplementary Appendix, available with the full text of this article at www.nejm.org.) The PCR products were purified with the use of a PCR purification kit (Roche) and were directly sequenced with the use of the BigDye Terminator V1.1 cycle sequencing kit and an automated ABI 3100 sequencer (PerkinElmer).
Functional Analysis of Mutants
Wild-type DEHAL1 complementary DNA was subcloned in the pcDNA3.1 expression vector and subsequently underwent site-directed mutagenesis (Stratagene) for the three changes identified in patients. Wild-type and mutant alleles were expressed in mammalian cells, which were homogenized and subjected to an iodotyrosine deiodinase assay for both monoiodotyrosine and diiodotyrosine substrates with the use of cation-exchange chromatography.
To test the responsiveness of mutants to flavin mononucleotide, increasing concentrations of the flavin were added to the cell-culture medium after transfection, and the homogenates were analyzed for their monoiodotyrosine deiodination capacity after 24 hours. The protein stability of mutants was studied by quantification of protein signals in Western blots with the use of polyclonal peptide antibodies against DEHAL1 (Eurogentec). To investigate the effect of local amino acid changes that were identified, different artificial mutants were generated at amino acid positions that had mutations in the patients and were functionally tested in the iodotyrosine deiodinase assay. (For further details concerning the experimental procedures, see the Methods section of the Supplementary Appendix.)
Results
Phenotypes of Patients
Patient 1, a 26-year-old woman who had been born in Germany to consanguineous parents of Turkish origin, had a normal thyrotropin level during neonatal screening.15 However, she presented at 18 months of age with typical signs of hypothyroidism, including an enlarged tongue, puffy and dry skin, and a coarse cry. She had short stature (<3rd percentile for her age) and a delayed bone age of 9 months. On the Denver Developmental Scale for infants, she had a delay of 6 to 8 months. Thyroid function tests were consistent with profound primary hypothyroidism, and an enlarged thyroid gland was evident clinically and on ultrasonography (Table 1Table 1
Characteristics of the Patients.). Thyroid uptake of iodide-123 was rapid and high, and administration of perchlorate did not release radioiodine from the gland, which ruled out the existence of an iodide organification defect. The serum diiodotyrosine level was elevated. Despite immediate treatment and strict hormonal control during childhood, the patient had psychomotor retardation, with a low IQ (85 at 9 years of age) and poor school performance. Her parents were euthyroid and without goiter.Patients 2 and 3, who were 47 and 43 years of age, respectively, were sisters who had received the diagnosis of hypothyroidism during infancy and had been born before the era of routine screening for congenital hypothyroidism (Table 1). Their parents, who were first cousins, were members of a group of Scottish traveling families who had a high incidence of consanguinity and in whom iodotyrosine deiodinase deficiency was clinically described in pioneering reports by Hutchison and McGirr and by Murray et al.18-20 As a consequence of the family's itinerant lifestyle, their early medical records were not available. Adherence to thyroxine treatment may have been erratic. Patient 2 had undergone thyroidectomy for compressive symptoms from goiter and had a history of moderate learning disability. Patient 3 had a goiter but no history of learning disability. Their ancestry, history of hypothyroidism since infancy, and goiter made them candidates for the presence of an iodotyrosine deiodinase defect and prompted the molecular screening of DEHAL1.
Patient 4 was a 9-year-old boy who had been born in France to parents of Moroccan descent who were first cousins. The results of screening for congenital hypothyroidism were normal (Table 1). His infancy and childhood were unremarkable, with good physical growth and psychomotor development. At the age of 8 years, he presented with asthenia and an enlargement in neck volume, and his condition was diagnosed as nonautoimmune hypothyroidism and goiter. Ultrasonography of the thyroid showed homogeneous and hypervascularized goiter, and scintigraphy showed a very rapid and high uptake of iodide-123 (74% at both 20 and 50 minutes after administration), which suggested increased iodide turnover in the gland.21 The patient's serum diiodotyrosine level was elevated. His parents were euthyroid and did not have goiter.
Identification of DEHAL1 Mutations
The complete open reading frame of DEHAL1 was amplified and sequenced in all four patients. Patient 1 had a homozygous C→T mutation in exon 2 of DEHAL1 (Figure 1A and 1BFigure 1
Mutations in DEHAL1 Associated with Iodotyrosine Deiodinase Deficiency.), resulting in the replacement of arginine with tryptophan at position 101 (designated Arg101Trp) at the 10th position of the catalytic nitroreductase domain of the DEHAL1 protein, between two predicted flavin mononucleotide–binding amino acids22 (Figure 1C).Patients 2 and 3 were both homozygous for a three-base-pair in-frame CAT deletion in exon 2 of the gene, causing the replacement of both phenylalanine at position 105 and isoleucine at position 106 by leucine (designated Phe105–Ile106Leu) (Figure 1A and 1B). The change was localized within the nitroreductase domain in close vicinity to another putative flavin mononucleotide–binding amino acid (Figure 1C).
Patient 4 was homozygous for a T→C mutation in DEHAL1 that resulted in a substitution of threonine for isoleucine at position 116 (Ile116Thr), located in the nitroreductase domain but outside the flavin mononucleotide–binding pocket (Figure 1).
For controls, we analyzed 118 chromosomes in DNA from healthy white subjects, since all four patients were also white.
DEHAL1 Mutations In Vitro
To evaluate the functional consequences of the mutations that were identified, we introduced each mutation into the DEHAL1 complementary DNA. Wild-type and mutant proteins were transiently expressed in mammalian cells and subjected to an in vitro iodotyrosine deiodination assay. All three mutations dramatically reduced the capacity of DEHAL1 for deiodination of monoiodotyrosine and diiodotyrosine (Figure 2A and 2BFigure 2
Functional Characterization of Wild-Type and DEHAL1 Mutations.). Although the Arg101Trp and Phe105–Ile106Leu mutations virtually abolished monoiodotyrosine and diiodotyrosine deiodination, Ile116Thr showed some residual activity (4% for monoiodotyrosine and 2.5% for diiodotyrosine).We examined the deiodinating capacity of the protein product of these mutations in response to the addition of increasing concentrations of flavin mononucleotide in the cell-culture medium. In agreement with the nitroreductase nature of the DEHAL1 protein, wild-type–transfected cells showed an increase in the rate of monoiodotyrosine deiodination that was dependent on the flavin mononucleotide concentration (Figure 2C). In contrast, Arg101Trp and Phe105–Ile106Leu mutants showed no response, and a partial increase was observed for Ile116Thr with maximal induction by a factor of 7 at 0.5 mM of flavin mononucleotide (Figure 2C).
We also analyzed the protein abundance of mutants, as compared with that of wild-type DEHAL1, in 24-hour transfected cells. As detected by an antibody against carboxy-terminal epitopes of DEHAL1, the Arg101Trp and Phe105–Ile106Leu mutants showed protein levels similar to those of wild-type DEHAL1, whereas the protein signal for Ile116Thr was decreased by a factor of approximately 10 (Figure 2D). In the absence of significant differences between messenger RNA levels for wild-type and Ile116Thr alleles on semiquantitative reverse-transcriptase PCR experiments, this finding suggested accelerated protein degradation of the Ile116Thr mutant (Figure 2 of the Supplementary Appendix).
Finally, we examined the effect of the introduction of various amino acids with varied hydropathic profiles, size, and structural characteristics on substrate deiodination at the three mutated sites found in the patients. Replacement of the basic arginine at position 101 by a small and neutral alanine showed the same deleterious effect as the original Arg101Trp mutation (0.9% monoiodotyrosine deiodination) (Figure 2E). In contrast, the introduction of histidine at this position, an amino acid more similar to the wild-type arginine in charge and size, partially rescued the activity (15%). Similarly, introduction of a nonpolar valine at position 116, a hydrophobic amino acid similar to the natural isoleucine at this position, completely recovered the normal deiodinase activity of DEHAL1 (Figure 2E). However, even when the loss of the aromatic phenylalanine at position 105 seemed the most relevant change in the Phe105–Ile106Leu mutation, we showed that the introduction of either tyrosine (aromatic) or alanine (nonaromatic) at position 105 inferred no reduction in DEHAL1 enzyme activity (Figure 2E). These results suggest that strong changes in hydrophobicity are involved in the pathogenic effect of the two missense mutations, even though they are not essential in the inactivation of DEHAL1 by the three-base-pair deletion.
Discussion
We screened four patients who had hypothyroidism with biochemical features or a clinical history suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. We identified three different mutations in exon 2; these mutations were in close vicinity to one another and were localized within the nitroreductase, catalytic domain of the protein. The mutations dramatically disrupt the capacity of DEHAL1 to deiodinate each of its natural substrates, monoiodotyrosine and diiodotyrosine.
The patients presented striking phenotypic variability with regard to the time of expression of the disease. Although hypothyroidism was already present during infancy in Patients 1, 2, and 3, as judged both by clinical records and evident intellectual deficits in two patients, clinical disease presented much later in childhood in Patient 4. One might speculate that differences in iodine intake in the geographic areas where the patients were born or later lived may have influenced the phenotypic expression of DEHAL1 defects. For example, Patient 1 was exposed to high iodine levels at birth through maternal disinfection with povidone iodine, which might have masked the genetic defect.
The prevalence of iodotyrosine deiodinase defects among persons with hereditary hypothyroidism is currently unknown. We speculate that borderline expression during the neonatal period and a possible masking of this defect as a nonautoimmune goiter (the cause of which is usually not investigated in detail) might lead to underdiagnosis of the DEHAL1 defect. Furthermore, the general lack of sensitive assays for diiodotyrosine and monoiodotyrosine to determine these levels in urine or serum and a lack of awareness of this type of hypothyroidism may also contribute to overlooking the diagnosis. Development of alternative diagnostic means (e.g., iodotyrosine detection in urine by mass spectrometry) might facilitate the study of neonatal populations to estimate the prevalence and degree of expression of DEHAL1 defects in various communities. Better and earlier diagnosis might prevent the mental deficits related to delayed diagnosis and treatment of hypothyroidism when the disease is expressed in infancy, at a time when the brain is still very sensitive to a lack of thyroid hormone.
We identified three different defects in DEHAL1, two missense mutations (Arg101Trp and Ile116Thr) and one in-frame three-base-pair deletion (Phe105–Ile106Leu). Although Arg101Trp and Phe105–Ile106Leu virtually abolish the activity of DEHAL1 protein, the Ile116Thr mutant showed significant residual iodotyrosine deiodinase activity. This finding might partially explain the more favorable phenotype of Patient 4. However, functional differences among the mutants, along with environmental factors (e.g., iodine intake), may well be involved in the phenotypic variability of the disease.
Functional analysis of DEHAL1 mutations suggests that each mutation may lead to disease through varied pathogenic pathways. The two missense mutations involved amino acid changes that caused strong local changes in hydrophobicity. However, the characteristics of the amino acid changes that were introduced by the three-base-pair deletion were not responsible for the deleterious effect of the Phe105–Ile106Leu mutation on DEHAL1 function but rather the deletion of one amino acid at position 105 of the protein. The flavin mononucleotide–dependent increase in iodotyrosine deiodinase activity was absent in the Arg101Trp and Phe105–Ile106Leu mutants, whereas the Ile116Thr mutant retained this capacity. It is tempting to speculate that localization of mutations within or outside putative pockets of flavin mononucleotide binding of the enzyme could be involved in this distinct effect. Finally, the Ile116Thr mutant was specifically subjected to rapid protein degradation, which did not affect the other two mutants. The rapid degradation of this mutant may have contributed to its low iodotyrosine deiodinase activity more than a decrease in catalytic efficiency. Further studies are required to elucidate the intrinsic pathway implicated in degradation of this particular genetic mutant.
In conclusion, we showed that homozygous mutations in DEHAL1 appear to cause human iodotyrosine deiodinase deficiency, leading to hereditary hypothyroidism and goiter. There was substantial variability in the time of onset of hypothyroidism in the patients. This variability is of critical importance for the development of mental retardation, since unrecognized hypothyroidism with onset during the first years of life, but not later, will lead to disturbed maturation of the central nervous system and psychomotor retardation. Factors that can influence this phenotypic variability may be environmental (e.g., variations in intake of iodine) but also genetic, since each individual type of DEHAL1 defect determines the functional capacity for iodotyrosine deiodination. Our work reveals a crucial role for the DEHAL1 protein in human iodide metabolism23 and emphasizes the importance of worldwide efforts to eradicate iodine deficiency,24 including in industrialized countries in which mild-to-moderate iodine deficiency still exists.
Supported by a VENI grant from the Dutch Organization for Scientific Research (to Dr. Moreno).
No potential conflict of interest relevant to this article was reported.
This article is dedicated to the memory of F. Delange, who devoted his professional life to the study of iodine deficiency and led international efforts toward its eradication worldwide.
We thank the patients and their families for their willingness to participate in the study; Dr. G. Kuiper for his contribution with respect to the iodotyrosine deiodination assay; Dr. H. Meinhold and Dr. A. Baumgartner for providing the diiodotyrosine antibody; and R. van der Wal, T. Nooteboom, and C. van der Hout for providing technical help.
Source Information
From the Erasmus Medical Center, Erasmus University, Rotterdam, the Netherlands (J.C.M., W.K., H.T., T.J.V.); Paris Descartes–INSERM Unité 845, Necker Enfants Malades Hospital (G.P., M.P.), and Groupe Hospitalier Pitié–Salpêtrière (A.L.) — all in Paris; Cancer Research UK Cell Structure Research Group, Dundee University (M.D.), and Tayside University Hospitals National Health Service Trust, Ninewells Hospital and Medical School (D.G.) — all in Dundee, United Kingdom; and Charité Hospital, Humboldt University, Berlin (A.G.).
Address reprint requests to Dr. Moreno at the Department of Internal Medicine, Room Ee 593, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands, or at j.morenonavarro@erasmusmc.nl.
- References
References
1
Dai G ,Levy O ,Carrasco N . Cloning and characterization of the thyroid iodide transporter. Nature 1996;379:458-460
CrossRef | Web of Science | Medline2
Roche J ,Michel O ,Lissitzky S . Enzymatic dehalogenation of iodotyrosine by thyroid tissue; on its physiological role. Biochim Biophys Acta 1952;9:161-169
CrossRef | Web of Science | Medline3
Stanbury JB ,Kasenaar AAH ,Meijer JWA . The metabolism of iodotyrosines. I. The fate of mono- and di-iodo tyrosine in normal subjects and in patients with various diseases. J Clin Endocrinol Metab 1956;16:735-746
CrossRef | Web of Science | Medline4
Querido A ,Stanbury JB ,Kassenaar AA ,Mejier JW . The metabolism of iodotyrosines. III. Di-iodotyrosine deshalogenating activity of human thyroid tissue. J Clin Endocrinol Metab 1956;16:1096-1101
CrossRef | Web of Science | Medline5
Choufur JC ,Kassenaar AAH ,Querido A . The syndrome of congenital hypothyroidism with defective dehalogenation of iodotyrosines: further observations and a discussion on the pathophysiology. J Clin Endocrinol Metab 1960;20:983-989
CrossRef | Web of Science | Medline6
Rosenberg IN ,Goswami A . Purification and characterization of a flavoprotein from bovine thyroid with iodotyrosine deiodinase activity. J Biol Chem 1979;254:12318-12325
Web of Science | Medline7
Moreno JC ,Pauws E ,van Kampen AH ,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 | Medline8
Moreno JC . Identification of novel genes involved in congenital hypothyroidism using serial analysis of gene expression. Horm Res 2003;60:Suppl 3:96-102
CrossRef | Web of Science | Medline9
Gnidehou S ,Caillou B ,Talbot M , et al. Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site. FASEB J 2004;18:1574-1576
Web of Science | Medline10
Haynes CA ,Koder RL ,Miller A-F ,Rogers DW . Structures of nitroreductase in three states: effect of inhibitor binding and reduction. J Biol Chem 2002;277:11513-11520
CrossRef | Web of Science | Medline11
Park SM ,Chatterjee VKK . Genetics of congenital hypothyroidism. J Med Genet 2005;42:379-389
CrossRef | Web of Science | Medline12
Lavado-Autric R ,Auso E ,Garcia-Velasco JV , et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 2003;111:1073-1082
CrossRef | Web of Science | Medline13
Moreno JC ,Bikker H ,Kempers MJ , et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 2002;347:95-102
Full Text | Web of Science | Medline14
Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestationsNew England Congenital Hypothyroidism Collaborative. Lancet 1981;14:1095-1098
15
Gruters A ,Finke R ,Krude H ,Meinhold H . Etiological grouping of permanent congenital hypothyroidism with a thyroid gland in situ. Horm Res 1994;41:3-9
Web of Science | Medline16
McDougall TR, 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.
17
Meinhold H ,Gramm H-J ,Meisner W , et al. Elevated serum diiodotyrosine (DIT) in severe infections and sepsis: DIT, a possible new marker of leukocyte activity. J Clin Endocrinol Metab 1991;72:945-995
CrossRef | Web of Science | Medline18
Hutchison JH ,McGirr EM . Hypothyroidism as an inborn error of metabolism. J Clin Endocrinol Metab 1954;14:869-886
CrossRef | Web of Science | Medline19
Hutchison JH ,McGirr EM . Sporadic non-endemic goitrous cretinism. Hereditary transmission. Lancet 1956;270:1035-1037
CrossRef | Web of Science | Medline20
Murray P ,Thomson JA ,McGirr EM ,Wallace TJ ,Macdonald EM ,Maccabe HM . Absent and defective iodotyrosine deiodination in a family some of whose members are goitrous cretins. Lancet 1965;1:183-185
CrossRef | Web of Science | Medline21
de Vijlder JJM . Primary congenital hypothyroidism: defects in iodine pathways. Eur J Endocrinol 2003;149:247-256
CrossRef | Web of Science | Medline22
Hecht HJ ,Erdmann H ,Park HJ ,Sprinzl M ,Schmid RD . Crystal structure of NADH oxidase from Thermus thermofilus. Nat Struct Biol 1995;2:1109-1114
CrossRef | Medline23
Pedraza PE ,Obregon M-J ,Escobar-Morreale HF ,Escobar del Rey F ,Morreale de Escobar G . Mechanisms of adaptation to iodine deficiency in rats: thyroid status is tissue specific. Its relevance for man. Endocrinology 2006;147:2098-2108
CrossRef | Web of Science | Medline24
Andersson M ,Takkouche B ,Egli E ,Allen HE ,de Benoist B . Current global iodine status and progress over the last decade towards the elimination of iodine deficiency. Bull World Health Organ 2005;83:518-525
Web of Science | Medline
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A. Grüters, H. Krude. (2008) Angeborene Hypothyreose. Monatsschrift Kinderheilkunde 156:10, 951-960
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Kopp, Peter A., . (2008) Reduce, Recycle, Reuse — Iodotyrosine Deiodinase in Thyroid Iodide Metabolism. New England Journal of Medicine 358:17, 1856-1859
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