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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1199-1204
Copyright © 2006 by The Endocrine Society

CLINICAL CASE SEMINAR

Extending the Clinical Heterogeneity of Iodide Transport Defect (ITD): A Novel Mutation R124H of the Sodium/Iodide Symporter Gene and Review of Genotype-Phenotype Correlations in ITD

Gabor Szinnai, Shinji Kosugi, Christèle Derrien, Nadine Lucidarme, Véronique David, Paul Czernichow and Michel Polak

Pediatric Endocrine Unit, and Institut National de la Santé et de la Recherche Médicale, Equipe mixte INSERM 0363, Hôpital Necker Enfants-Malades (G.S., M.P.), 75743 Paris, France; Departments of Clinical Genetics and Medical Ethics, Kyoto University Graduate School of Medicine (S.K.), Kyoto 606-8501, Japan; Department of Endocrinology and Diabetes, Molecular Laboratory, Centre Hospitalier Universitaire (C.D., V.D.), 35043 Rennes, France; and Pediatric Endocrine and Diabetes Unit, Hôpital Robert Debré (N.L., P.C.), 75019 Paris, France

Address all correspondence and requests for reprints to: Dr. Michel Polak, Service d’Endocrinologie Pédiatrique and Institut National de la Santé et de la Recherche Médicale, Equipe Mixte INSERM 0363, Hôpital Necker Enfants Malades, 149 rue de Sèvres, F-75743 Paris Cedex 15, France. E-mail: michel.polak{at}nck.ap-hop-paris.fr.


   Abstract
Top
 Abstract
Introduction
 Patient and Methods
 Results
 Discussion
 References
 
Context: Iodide transport defect (ITD) is an autosomal recessive disorder resulting in varying degrees of congenital hypothyroidism (CH) with goiter and low or absent radioiodide uptake (RIUT), as determined by thyroid scintigraphy, and low iodide saliva to plasma ratio. Defects of the sodium/iodide symporter gene (NIS) have been shown to cause ITD.

Objective: We describe molecular studies of NIS in a patient with ITD and genotype-phenotype correlation analysis in 31 patients with NIS defects reported worldwide.

Design: NIS sequencing and functional studies of the new NIS mutation in vitro were performed.

Results: In a newborn with symptomatic CH and a large goiter, thyroid scintigraphy showed no RIUT (0%). NIS sequencing identified the new homozygous mutation, R124H, in exon 2. This mutation was associated with abolition of iodide uptake in vitro when transfected in COS-7 cells. Immunocytochemical studies documented correct targeting of the mutated protein to the plasma membrane of transfected cells. Genotype-phenotype correlation analysis showed that the onset of hypothyroidism occurred during the neonatal period with four NIS mutations (neonatal onset of hypothyroidism genotype), during infancy with three NIS mutations (infancy onset of hypothyroidism genotype), and during childhood with three NIS mutations (childhood onset of hypothyroidism genotype). RIUT is a direct measure of residual NIS activity in vivo. Mean RIUT was lower in patients with the neonatal onset of hypothyroidism genotype (0.88 ± 0.2%) than in the infancy onset of hypothyroidism (1.9 ± 0.4%; P < 0.05) and childhood onset of hypothyroidism (2.6 ± 0.7%; P < 0.05) genotypes.

Conclusions: We identified a new NIS mutation, R124H, in a newborn with the complete clinical ITD phenotype. Genotype-phenotype correlations suggest that age at hypothyroidism onset may be genotype specific and may depend on genotype-specific residual NIS activity.


   Introduction
Top
 Abstract
 Introduction
Patient and Methods
 Results
 Discussion
 References
 
IODIDE TRANSPORT DEFECT (ITD; Online Mendelian Inheritance in Man, OMIM 274400) is an uncommon form of dyshormonogenetic congenital hypothyroidism (CH) caused by sodium/iodide symporter gene (NIS) mutations transmitted according to an autosomal recessive pattern (1, 2, 3, 4, 5). Diagnostic criteria for ITD include a variable degree of CH and goiter, low or absent radioiodide uptake (RIUT) by the thyroid and other NIS-expressing organs (e.g. the salivary glands and gastric mucosa), and a low iodide saliva to plasma ratio (1, 2).

NIS is a specialized plasma membrane glycoprotein that mediates active iodide transport. In thyrocytes, NIS is located at the basolateral membrane and is responsible for active iodide trapping from the bloodstream (6). Rat and human NIS genes were cloned in 1996 (7, 8). Human NIS is located on chromosome 19, consists of 15 exons, and encodes a protein of 643 amino acids. The first NIS mutation causing ITD was described in 1997 (3). Nine mutations (V59E, G93R, Q267E, C272X, T354P, G395R, frame-shift 515X, Y531X, and G543E) and two deletions (DelM143-Q323 and DelA439-P443) have been described to date (3, 4, 9, 10, 11, 12, 13, 14, 15, 16, 17).

We identified a new NIS mutation in a patient with the complete clinical picture of ITD at birth. Furthermore, we investigated genotype-phenotype correlations in all the reported patients with NIS defects to look for genotype-specific differences in age at hypothyroidism onset and in residual RIUT.


   Patient and Methods
Top
 Abstract
 Introduction
 Patient and Methods
Results
 Discussion
 References
 
Molecular analysis

The molecular study was approved by our institutional review board and performed with the informed consent of the parents. A standard procedure was used to extract genomic DNA from peripheral blood cells of the patient and parents. NIS was examined by sequencing DNA segments amplified by PCR. Exons 1–7, 9, 10, and 14 were amplified using a pair of primers derived from the flanking introns. Exons 2 and 3, 6 and 7, and 9 and 10 were coamplified with the intervening introns. Nucleotide sequences of all amplified exons were determined in both orientations by direct sequencing with an Applied Biosystems 373A sequencer (Foster City, CA).

Construction of expression vectors, transfection, iodide uptake assays, and immunocytochemical studies

A wild-type human NIS construct was obtained by TA cloning of full-length (nucleotide –59 to +1975) human NIS cDNA in the pCR3.1 vector (Invitrogen Life Technologies, San Diego, CA) under control of the cytomegalovirus promoter (4, 11, 14, 16). An R124H construct was generated by site-directed mutagenesis. COS-7 cells were transfected with 25 µg mutant or wild-type NIS DNA or with control vector DNA (pCR3-CAT; Invitrogen Life Technologies) by electroporation. COS-7 cells were transfected with 12.5 µg of each of two kinds of constructs to mimic the parents with the heterozygous R124 mutation. To monitor transfection efficiency, 0.1 µg pSVGH was cotransfected with mutant or wild-type NIS plasmid cDNA or control vector. Cells were aliquoted into 24-well plates (105 cells/well). Forty-eight hours after transfection, the medium was harvested for RIA of human GH, and the cells were evaluated for iodide uptake, as previously described (4, 11, 14, 16). Immunocytochemical staining of transfected cells was performed as previously described (12, 16).

Genotype-phenotype correlation analysis

All cases with identified NIS molecular defects reported in the literature were reviewed. Clinical features (age at onset of hypothyroidism and goiter and evidence of developmental delay at diagnosis), data on laboratory and imaging investigations (result of neonatal screening, TSH, T4, T3, RIUT measurements, and iodide saliva to plasma ratio), and the iodine status of the country of origin (18) were entered in a database. Three groups of NIS defects were defined according to age at the onset of hypothyroidism: neonatal onset of hypothyroidism (NOH genotypes), infancy onset of hypothyroidism (IOH genotypes), and childhood onset of hypothyroidism (COH genotypes).

The Mann-Whitney U test was used to analyze RIUT differences across the three genotypes. In the four patients with RIUT values less than 1%, the value of 0.99% was used for statistical analysis. The {chi}2 test was used to compare detection rates by neonatal screening. Results are presented as the mean ± SE.


   Results
Top
 Abstract
 Introduction
 Patient and Methods
 Results
Discussion
 References
 
Case report

The patient was a full-term, 3620-g boy born to healthy nonconsanguineous parents from Cameroon. A large posterior fontanel and mild axial hypotonia were noted at birth. Prolonged jaundice developed. TSH elevation was detected by neonatal screening. On d 14, clinical goiter was present, and serum measurements of TSH and free T4 were obtained. The results confirmed the diagnosis of severe congenital hypothyroidism [TSH, 234 mU/liter; free T4, 0.27 ng/dl (3.5 pmol/liter)]. Ultrasound showed marked enlargement of the thyroid (calculated thyroid volume, 3.8 ml; normal, 1 ml), which was in the normal pretracheal position. A radionuclide scan revealed the absence of 123I uptake by the thyroid after 6 and 24 h. Salivary and gastric tissues also failed to concentrate 123I from the bloodstream, suggesting a diagnosis of ITD. The parents were euthyroid and had normal thyroid volume by ultrasound (father, 20.5 ml; mother, 20.6 ml). Tests in the mother found no antibodies to thyroglobulin or peroxidase and ruled out low urinary iodide excretion. No other family members had a known history of hypothyroidism. Thyroid hormone supplementation was started on d 15, with a dose of 8 µg/kg·d. The patient’s growth and development were normal at follow-up, and thyroid size returned to normal during thyroid hormone replacement therapy. At 5 yr of age, the patient was still receiving hormone replacement therapy and had no goiter.

Molecular evaluation

Our patient was homozygous for a single G to A nucleotide change at base 718 in exon 2, resulting in the missense mutation R124H (arginine 124 changed to histidine). Both parents were heterozygous for this mutation (Fig. 1Go).


Figure 1
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  		FIG. 1. Detection of the R124H mutation. Chromatograms showing part of the NIS exon 2 sequence from a normal subject, from the index patient (homozygous for the R124H mutation), and from the patient’s mother (heterozygous for the R124H mutation).

 
COS-7 cells transfected with mutant R124H NIS cDNA showed no perchlorate-sensitive iodide uptake, confirming that the mutation was the direct cause of ITD in our patient (Fig. 2AGo). Cells cotransfected with wild-type/R124H showed an approximately 50% reduction in iodide uptake activity compared with cells transfected with 25 µg wild-type NIS cDNA. This reduced uptake was very similar to that in cells transfected with half-doses of two kinds of cDNA constructs: wild-type NIS and control vector cDNAs. Cotransfection with pSVGH and measurement of GH concentrations in culture medium showed no differences in transfection efficiencies among transfectants.


Figure 2
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  		FIG. 2. A, Iodide uptake activity in COS7 cells transfected with wild-type (WT) or mutant (R124H) NIS cDNA or with the control vector pCR3-CAT (Control). WT/R124H and WT/control indicate cells cotransfected with a half dose (12.5 µg) of two kinds of DNA constructs. {blacksquare}, Nonspecific iodide transport or binding in the presence of 1 mmol/liter ClO4–. The error bars indicate SE values (n = 6). B, Immunostaining of mutant transfectant with anti-NIS-antibody. COS-7 cells transfected with WT (WT and WT Absorbed) and mutant (R124H) NIS expression vector.

 
Immunostaining of cells transfected with the mutation construct revealed that the mutant NIS protein was properly expressed and targeted to the cell membrane (Fig. 2BGo).

Genotype-phenotype correlation analysis

We identified 31 patients, including the patient described in this report, with 10 different NIS molecular defects reported worldwide. The onset of hypothyroidism was detected during the neonatal period in patients with R124H, G395R, Q267E/Y531X, or DelM143-Q323 (NOH genotypes); during infancy in patients with C272X, DelA439-P443, or T354P (IOH genotypes); and during childhood in patients with G543E, V59E/T354P, or G93R/T354P (COH genotypes). The phenotype of the homozygous T354P mutation (n = 9) varied considerably; hypothyroidism occurred during infancy in three patients and during childhood in four patients, whereas euthyroid goiter developed in two siblings. In contrast, of the 10 G395R patients, six experienced hypothyroidism during the neonatal period, and four did so between 1 and 3 months of age (Table 1GoGo).


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  		TABLE 1. Genotype-phenotype correlation analysis in 31 patients with NIS defects

 

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  		TABLE 1A.
 
Mean (±SE) residual RIUT values were compared across the NOH, IOH, and COH genotypes. Patients with NOH genotypes showed significantly lower mean residual RIUT (0.88 ± 0.2%) compared with those with IOH (1.9 ± 0.4%; P < 0.05) or COH (2.6 ± 0.7%; P < 0.05) genotypes (Fig. 3Go).


Figure 3
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  		FIG. 3. Genotype-specific residual RIUT. NOH, NIS defects with neonatal onset of hypothyroidism; IOH, NIS defects with onset of hypothyroidism during infancy; COH, NIS defects with onset of hypothyroidism during childhood. Box-whisker plots represent mean, upper and lower quartile, and minimal and maximal values. *, P < 0.05.

 
Neonatal screening detected all tested NOH patients (n = 8), but missed all four tested IOH and COH patients. The detection rate was significantly different between NOH vs. IOH and COH patients (P < 0.05). Some degree of developmental delay was present in seven of 11 IOH and in four of six COH patients at diagnosis of ITD.

No correlation with genotype or genotype-specific residual RIUT was observed for goiter onset; severity of hypothyroidism based on TSH, T4, and T3 values; or iodide saliva to plasma ratio (Table 1GoGo). Goiter was diagnosed at a median age of 11 yr in 18 of 21 patients with NIS defects other than G395R. In contrast, goiter did not develop in any of the 10 G395R patients during a follow-up of 191 patient years. Goiter occurred before hypothyroidism (n = 3), concomitantly with hypothyroidism (n = 6), or after hypothyroidism despite replacement therapy (n = 9).


   Discussion
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
References
 
We identified a novel homozygous mutation in the NIS gene of a patient with ITD. In agreement with the autosomal recessive inheritance pattern of ITD, both parents were heterozygous for the mutation. Our in vitro expression studies confirmed that the R124H mutation was associated with the absence of perchlorate-sensitive iodide uptake, and no dominant negative effect of the mutant protein was observed. The mutated NIS protein was shown to be correctly targeted to the plasma membrane, but the mechanism underlying the complete loss of NIS protein activity was not elucidated. Detailed molecular studies have shown that the T354P, G395R, and Q267E NIS proteins are all properly located in the cell membrane, but that their structural abnormalities interfere with NIS activity in a variety of ways (19, 20, 21). In contrast, the G543E mutation impairs NIS protein maturation and trafficking to the cell surface (22). According to the current model for the secondary structure of NIS, with 13 transmembrane segments, the R124H mutation is located within the intracellular loop between transmembrane segments III and IV. The functional roles of Arg124 and the adjacent Phe in the NIS protein are unknown. These residues may be involved in Na+ binding, because they are highly conserved in the sodium/solute symporter family from mammals to bacteria (data not shown), in analogy with T354P (3).

Our patient exhibited clinical manifestations of CH, including an open posterior fontanel, prolonged jaundice, and mild axial hypotonia, which were present in only one of 30 other patients with NIS defects (16) and in fewer than 10% of newborns with CH detected by neonatal screening (23). The presence of a large goiter in the orthotopic position suggested thyroid dyshormonogenesis or transient CH. The latter was excluded on the basis of normal thyroid function and iodide excretion and negative antithyroid antibodies in the mother. Large dyshormonogenetic goiters have been found in fetuses and newborns with thyroglobulin synthesis defects (24, 25), but not in any of the 30 previous reported cases of NIS mutations. In our patient with a large goiter, thyroid scintigraphy revealed complete lack of RIUT and suggested ITD as the cause of CH. Molecular and functional studies confirmed the presence of a new loss of function NIS mutation. In summary, our case report extends the clinical variability of ITD due to NIS mutations to the complete phenotype with clinically patent hypothyroidism and a large goiter in the neonatal period, and it suggests that age at onset and disease severity may be genotype specific.

To elucidate genotype-phenotype correlations in ITD, we compared clinical and laboratory parameters of our patient with those of 30 patients from 15 families with nine NIS defects reported worldwide. Our results are biased by the fact that the study is based on a retrospective review of cases reported in the literature and by the small number of reported cases for most of the NIS defects. Nevertheless, our data show that the age at hypothyroidism onset was genotype specific for the 10 reported NIS defects. Some overlap occurred between NOH and IOH in G395R patients. However, the four patients whose hypothyroidism was detected on clinical grounds during infancy (postnatal age, 35, 35, 42, and 112 d, respectively) would perhaps have been identified by neonatal screening. In contrast, the reasons underlying the wide variability in age at onset and the severity of hypothyroidism among patients homozygous for T354P are speculative. A combination of high dietary iodide intake and minimal residual NIS activity due to a 10-fold increase in mutated T354P NIS protein expression were reported to compensate for the low RIUT in a patient with euthyroid goiter (12). To estimate the chronic iodide intake of each patient, we added the iodine status of the country of origin to Table 1GoGo (18).

The main problem in ITD is defective iodide accumulation within thyrocytes (5). RIUT is a direct measure of residual NIS activity in vivo. Normal values for newborns were reviewed by Andersen in his landmark study showing that RIUT was higher in newborns than later in life (26). We hypothesized that the genotype-specific age at hypothyroidism onset may depend on differences in residual NIS protein activity across NIS gene defects. First, we showed that residual RIUT in the NOH group was significantly lower than that in the IOH and COH groups. Second, the detection rate by neonatal screening was significantly higher in patients with NOH genotypes than in patients with IOH or COH genotypes. Both results suggest that genotype-specific residual NIS activity in the thyroid may be a major determinant of the onset of hypothyroidism in patients with ITD. However, whether hypothyroidism was detected clinically or by neonatal screening, the concentrations of TSH, T4, and T3 were variable and were not correlated with the genotype. Extrathyroid residual NIS activity, as reflected by the iodide saliva to plasma ratio, showed no genotype-specific differences, probably due to the greater variability of the results compared with RIUT.

The fact that a normal screening result does not exclude ITD with hypothyroidism onset in infancy or childhood has two important diagnostic implications. 1) Although rare, ITD should be considered when hypothyroidism develops after the neonatal period. 2) Genetic studies may be an effective tool for the preclinical diagnosis of ITD in newborns of families with IOH and COH genotypes. Preclinical diagnosis is of the utmost importance, given that 11 of 17 patients had signs of developmental delay at the diagnosis of ITD. In molecularly diagnosed patients, regular clinical follow-up could ensure the early detection and treatment of developing hypothyroidism.

Onset of goiter did not show the same genotype-phenotype correlation as did hypothyroidism onset and was not correlated with residual RIUT (data not shown). G395R patients seem to be protected from goiter (no goiter in 10 of 10 patients), whereas goiter developed in 18 of 21 patients with other NIS defects. Diffuse goiter was diagnosed at a median age of 11 yr. In 15 of 18 cases, goiter developed concomitantly with or years after hypothyroidism despite hormone replacement therapy. These results suggest differences in the cel-lular mechanisms underlying the development of goiter and hypothyroidism.

Our case report extends the clinical heterogeneity of ITD in a patient with a new NIS mutation. Despite the limitations of the study, the genotype-phenotype analysis indicates that onset of hypothyroidism in ITD is genotype specific and may depend on genotype-specific residual NIS activity. In affected families, DNA analysis of the NIS gene will provide an invaluable tool for preclinical diagnosis and genetic counseling.


   Footnotes
 
This work was supported by a research grant from Margarete und Walter Lichtenstein-Stiftung (Basel, Switzerland; to G.S.) and a grant awarded by the Fondation Endocrinologie Genève (Geneva, Switzerland; to G.S.).

The authors of this manuscript have no potential conflicts of interest to declare.

First Published Online January 17, 2006

Abbreviations: CH, Congenital hypothyroidism; COH, childhood onset of hypothyroidism; IOH, infancy onset of hypothyroidism; ITD, iodide transport defect; NOH, neonatal onset of hypothyroidism; NIS, sodium/iodide symporter; RIUT, radioiodide uptake.

Received August 12, 2005.

Accepted January 9, 2006.


   References
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
 References
 

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