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Original Studies |
Department of Laboratory Medicine, Kyoto University School of Medicine (S.K., A.M.), Kyoto 606-8507; the Department of Pathology, Kitasato University School of Medicine (Y.S., T.K.), Sagamihara, Kanagawa 228-0829; Ohyama Clinic (Y.O.), Sagamihara, Kanagawa 228-0802; the Department of Pediatrics, Hokkaido University School of Medicine (K.F.), Sapporo 060-0814; the Department of Pediatrics, Teikyo University Ichihara Hospital (H.I.), Ichihara, Chiba 299-0111; the Department of Medicine, Tokyo Women’s Medical College (O.I.), Tokyo 162-0054, Japan; and the Department of Physiology, Ohio State University (S.M.J.), Columbus, Ohio 43210
Address all correspondence and requests for reprints to: Shinji Kosugi, M.D., Ph.D., Department of Laboratory Medicine, Kyoto University School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: kosugi{at}kuhp.kyoto-u.ac.jp
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Pro (ACACCA)], was found in the homozygous
state in two unrelated Japanese patients with iodide transport defect.
In this study we have identified the homozygous T354P NIS germline
mutation in seven Japanese patients, including one previously reported,
from five unrelated families. No other nucleotide changes were found in
the coding regions and the exon-intron boundaries of the NIS gene in
these seven patients. These results suggest a common prevalence of the
T354P mutation in Japanese patients. Although these seven patients have
the identical NIS mutation, T354P, marked heterogeneity in clinical
pictures, especially concerning goiter and hypothyroidism, were noted
among them. Therefore, another factor(s), but not the nature of the NIS
mutation, may account for the clinical heterogeneity among patients
with the iodide transport defect. We have previously reported that the
NIS messenger ribonucleic acid was markedly increased in the thyroid of
a patient with the homozygous T354P mutation. In this study we
demonstrated that the NIS proteins in the patients’ thyroids were
significantly increased (
10-fold) by Western blot analysis of
integral membrane proteins using an antibody against the C-terminal
peptide of the human NIS. Furthermore, we showed by immunohistochemical
staining that the T354P mutant NIS proteins were overexpressed in the
basal and lateral plasma membranes of patients’ thyrocytes. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recent cloning of the Na+/I- symporter (NIS)
complementary DNA (cDNA) (19, 20) enabled identification of loss of
function mutations in the NIS cDNA from the thyroids of patients with
ITD (15, 16, 17, 18 18A ). We (15) and others (16) independently reported a
homozygous and loss of function mutation of NIS, T354P
[Thr354Pro (ACACCA)], in 2 unrelated Japanese
patients. Pohlenz et al. reported a homozygous nonsense
mutation of C272X (17) and a compound heterozygous mutation of
Q267E/del(57bp) (18). These advances have focused on the NIS
gene as a disease gene for ITD, and further characterization of the NIS
gene in other patients with ITD has become of great interest (21).
Recently, Smanik et al. (22) reported the structure of the
human NIS gene, which contains 15 exons interrupted by 14 introns. This
information has enabled us to characterize the entire NIS gene by PCR
amplification of each exon using genomic DNA extracted from peripheral
blood cells.
In the present report we have identified NIS germline mutations from 7 Japanese patients with ITD, one of whom we have already reported (15). In the course of this study, we identified three patients who have not been reported. Here, we describe detailed clinical histories of these three newly identified patients and discuss the pathophysiology and the genotype-phenotype relationship in ITD.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Case 1. This male patient with ITD was previously described (7) and was reviewed by Wolff (1) as case 11. Very recently, we identified a homozygous NIS gene mutation of T354P in the cDNA of the thyroid and in the genomic DNA from peripheral blood cells; we also described detailed clinical pictures (15).
Case 2. She was a sister of case 1 and had had no health
problems before a large diffuse goiter was noted at the age of 20 yr.
She was essentially euthyroid (Table 1
).
Antimicrosomal and thyroglobulin autoantibodies were negative. After
identifying the NIS gene mutation in case 1, diagnosis of ITD for case
2 was made by thyroidal 123I scintigram and saliva/serum
radioactive iodide ratio (Table 1).
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The two sibling cases were presented in a local report (9).
Neither the parents nor the youngest sibling (Fig. 1) had goiter or thyroid abnormalities.
The thyroid function of the youngest sibling was normal during
iodide-deficient diets.
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). GH levels with and
without insulin stimulation were normal. She was followed up without
medication. At the age of 9 yr, goiter became larger without any
symptoms of hypothyroidism. However, thyroid function tests revealed
severe hypothyroidism (T4, <10 µg/L; T3,
0.64 µg/L; TSH, >320 mU/L). Reevaluation 1 month later showed only
mild hypothyroidism (T4, 35 µg/L; T3, 2.34
µg/L; TSH, 14.7 mU/L). When taking iodide-deficient meals for 2
weeks, marked hypothyroidism became evident again. Her thyroid function
fluctuated even when consuming her usual meals. Low 123I
thyroidal uptake and 123I saliva/serum ratio (Table 1)
established diagnosis of ITD. Administration of 12.6 mg/day iodide made
her euthyroid (T4, 98 µg/L; T3, 1.78 µg/L;
TSH, 1.4 mU/L). Case 4. The younger brother of case 3 was born without abnormality during the fetal period or at birth. At the age of 13 months, he was evaluated because of delayed development (he sat at 10 months old and creeped on hands and knees at 12 months old). His height was -2.37 SD, and bone age was 6 months. Macroglossia, anemia, and decreased muscle tonus were noticed, but goiter was not detected. A thyroid function test confirmed severe hypothyroidism (T4, <10 µg/L; TSH, >320 mU/L), and 123I thyroidal uptake was zero. He had been treated with L-T4 with a diagnosis of cretinism due to thyroid agenesis. At the age of 6 yr, a normal sized thyroid was palpated at the correct position. Therefore, further examinations were performed without administration of L-T4. 123I thyroidal uptakes were 4.7% (3 h) and 1.3% (24 h) without visualization of salivary glands. The saliva/serum radioactive iodide ratio was 1.0. Although iodide-deficient meals made him hypothyroid (T4, <10 µg/L; T3, 0.61 µg/L; TSH, 148 mU/L), administration of 12.6 mg/day iodide made him euthyroid (T4, 90 µg/L; T3, 1.50 µg/L; TSH, 1.8 mU/L).
Family 3
Case 5. A boy was born without problems during the fetal period or at birth. His parents had no thyroid disorders. He was fed with artificial milk after 1 month of age. When he was 8 months old, he was diagnosed with cretinism on the basis of anemia, edematous face, macroglossia, and umbilical herniation. He had been treated with dried thyroid or L-T4 since then and maintained euthyroid. At the age of 2 yr, he was diagnosed with thyroid agenesis because 131I thyroidal uptake was 0%. However, at the age of 21 yr, a large diffuse goiter was noticed. Ultrasonography confirmed a diffuse goiter without nodules. Autoantibodies against thyroglobulin, thyroid peroxidase, and TSH receptor were negative. 123I scinitigram showed low thyroidal uptake (3.0%) without vis-ualization of salivary glands. The saliva/serum radioactive iodide ratio was 1.46 (4 h). He had marked hypothyroidism during an iodide-deficient diets without L-T4 treatment (free T4, 1.9 ng/L; free T3, 1.4 ng/L; TSH, 88.81 mU/L). He became euthyroid (free T4, 11.5 ng/L; free T3, 3.5 ng/L; TSH, 3.83 mU/L) after administration of 1.0 mg/day iodide.
Family 4
Case 6. A boy was born without an abnormality during the
fetal period or at birth. Neonatal screening of cretinism was
performed, and he appeared to be normal. He was fed with breast milk
until 4 months of age. His development gradually slowed down from about
6 months of age; he sat at 12 months and creeped on hands and knees at
16 months. Medical examinations were performed at the age of 18 months
because he was unable to walk by himself then. A large diffuse goiter
was noted. A thyroid function test revealed severe hypothyroidism
(Table 1). Antimicrosomal and thyroglobulin antibodies were negative.
123I thyroidal uptake was negligible (0.99% at 4 h;
1.38% at 24 h). The saliva/serum radioactive iodide ratio was low
(2.0 at 4 h; 2.6 at 24 h). He had been treated with
L-T4. By the age of 7 yr he caught up with
others of the same age in development (intelligence quotient =
97).
Family 5
Case 7. This case was described in a local report (8).
Neither the parents nor the two siblings had goiter or thyroid
abnormalities. The patient had no abnormality during the fetal period
or at birth. At about 2 months of age, she showed poor suckling,
constipation, and vomiting. She then became almost lethargic. At the
age of 4 months, she showed cyanosis after feeding. Administration of
T3 was started because of a diagnosis of hypothyroidism. At
about 6 months of age, attacks of apnea occurred repeatedly, and
further examinations were performed. Her height was -4.0
SD. Dry skin, cretinoid countenance, severe hoarseness, and
stridor were noticed, but goiter was not present. After cessation of
T3 for 1 week, a thyroid function test revealed severe
hypothyroidism (Table 1). Antimicrosomal and thyroglobulin antibodies
were negative. 131I thyroidal uptake was 2.4% at 24 h
and did not increase after administration of 10 U TSH for 3 successive
days (1.6% at 24 h). Thyroid scintigram demonstrated a slightly
enlarged thyroid at the correct position. The saliva/serum radioactive
iodide ratio was 1.77 at 2 h and 1.82 at 4 h. The gastric
juice/serum radioactive iodide ratio was 1.13 at 6 h.
131I in vitro uptake of a thyroid specimen
obtained by open biopsy was 2.10% without TSH and 2.45% with TSH
(controls, 1.61% and 3.42%, respectively), showing a lack of increase
by TSH stimulation. Microscopically, there were a number of small
follicles with poor or no colloid. No goiter development has been noted
during the last 23 yr.
Genomic DNA extraction, PCR of exons of NIS DNA, and direct sequencing
Genomic DNA was extracted as previously described (15) from the patients and their family members with their informed consent. Each exon was PCR amplified with a pair of primers derived from the flanking introns. Exons 3 and 4, 6 and 7, 9 and 10, and 11 and 12 were coamplified with an intervening intron. Direct nucleotide sequencing by GeneScan DNA Sequencer 373A (Perkin Elmer, Norwalk, CT) was performed in both orientations in all seven patients.
Detection of the T354P mutation by HaeIII digestion
Because the T354P mutation itself does not change available
restriction enzyme sites, we performed PCR using a primer with a
mismatch nucleotide (underlined),
5'-CCCCCGTGCCTTCCTCACACGGC-3', together with a reverse
primer, 5'-ATGAGGATGGCACGGTCAAC-3', to amplify a 193-bp fragment
containing exon 9. The mismatched nucleotide creates a new
HaeIII site (GG
CC) at the junction of intron 8 and exon 9
only if the T354P mutation is present, as the nucleotide at +1060 is C
instead of A. There is a natural HaeIII site in the 193-bp
fragment in the wild-type (WT) NIS gene, creating 164- and 29-bp
fragments. After digestion with HaeIII, while the 164-bp
fragment in the WT allele remains undigested, the mutant allele
produces two fragments of 22 and 142 bp.
Western blotting of integral membrane proteins from the patients’ thyroid
A 15-mer peptide corresponding to the C-terminal tail of the human NIS (residues 629–643), NH2-CVGHDGGRDQQETNL-COOH, was synthesized and conjugated with keyhole limpet hemocyanin through the amino terminal Cys residue. Rabbits were immunized every 2 weeks.
Thyroid specimens from patients 1 and 5, obtained by open biopsy, were homogenized with a Teflon-glass homogenizer with buffer A [250 mmol/L sucrose, 10 mmol/L Tris-HCl (pH 7.5), and 1 mmol/L MgCl2] containing protease inhibitors (23). After removing the nuclear fraction, the supernatant was incubated with 0.1 vol 1 mol/L Na2CO3 for 45 min at 4 C to enrich the fraction of integral membrane proteins (23). Pellets by a centrifugation at 100,000 x g for 15 min at 4 C were suspended with buffer A.
Membrane fractions were solubilized for 30 min at 37 C in Laemmli sample buffer. After SDS-PAGE using a 10% acrylamide gel, proteins were transferred to nitrocellulose membranes. The membranes were incubated with Blotto/Tween buffer [PBS, pH 7.4, containing 5% (wt/vol) skim milk, 0.05% (vol/vol) Tween-20, and 0.02% sodium azide] overnight at 4 C and then incubated with the rabbit antiserum diluted to 1:500 for 120 min at room temperature. After being washed, the membrane was incubated with alkaline phosphatase-conjugated goat anti-rabbit IgG (Bio-Rad Laboratories, Inc., Richmond, CA) at a 1:3000 dilution for 60 min at room temperature. After washing, proteins were visualized with alkaline phosphatase substrates.
Immunohistochemistry of patients’ thyroids
The immunodetection of NIS protein using formalin-fixed paraffin-embedded thyroid tissue was performed by the indirect dextran polymer system, Envision (Dako Corp. Japan, Kyoto, Japan) (24). In brief, deparaffinized sections were immersed in 3% hydrogen peroxide for 20 min to eliminate endogenous peroxidase activity. Then, the sections were antigen retrieved in 0.01 mol/L citrate buffer (pH 6.0) by autoclaving for 10 min at 121 C. After cooling to room temperature with a fan and treating with 2% normal swine serum/Tris-HCl-buffered saline (pH 7.6) for 10 min to reduce nonspecific binding of protein, the sections were incubated with the anti-NIS antibody (1:4000) for 16 h at room temperature. Then, the sections were incubated with Envision reagent for 30 min at room temperature. Finally, the sections were visualized with stable diaminobenzidene reagent (Research Genetics, Inc., Huntsville, AL) for 2–3 min. The nuclei were stained with Mayer’s hematoxylin for 20 s.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Mutations in NIS genomic DNA
In all seven cases, a homozygous NIS gene germline mutation of
T354P was identified by direct sequencing of amplified genomic NIS DNA
fragments (data not shown) and HaeIII digestion of the PCR
product containing exon 9, which was obtained with a mismatch primer
(Fig. 1). After digestion with HaeIII while the 164-bp
fragment in the WT allele remains undigested, the mutant allele
produces two fragments of 22 and 142 bp (see Subjects and
Methods). Thr354 is located in the ninth transmembrane
domain and is coded by exon 9. Compared with the reported sequences
(20, 22), no other nucleotide changes were found either in the exonic
regions (nucleotide -37 to +1952) or in the intronic regions at
exon-intron boundaries that contain at least 15 intronic nucleotides
(GenBank accession no. AF049198–AF049220).
HaeIII digestion of the PCR product containing exon 9 with a
mismatch primer was also performed with all available blood samples
obtained from the family members (Fig. 1). The daughter of case 1, the
parents of cases 3–6, the brother of case 6, and the mother of case 7,
none of whom had thyroid abnormalities, were heterozygous for the T354P
mutation, confirming the recessive nature of the disorder by the T354P
NIS mutation. Neither the wife of case 1, the younger sister of cases 3
and 4, nor 81 normal subjects had a T354P mutation. By studying the
corresponding family members, cases 1–6 were confirmed to have a
homozygous T354P mutation. Because a blood sample from the deceased
father of case 7 was not obtained, homozygosity was not confirmed in
case 7.
Western blot analysis of NIS expression
Western blotting was performed to detect NIS proteins in the
enriched fractions of integral membrane proteins from the thyroid
obtained by open biopsy from cases 1 and 5 using an antibody against
the C-terminal portion of human NIS. NIS proteins were specifically
detected by the antibody as 60-kDa and broad 80-kDa bands; the
latter was dominant (Fig. 2). These bands
were not detectable with the antiserum preabsorbed with the peptide
that was used for immunization, confirming the specificity of the
bands. Faint 70- and 45-kDa bands, which were detected with both
antisera with and without antigen absorption, are considered
nonspecific. The 80- and 60-kDa bands were increased
approximately 10-fold in the patients’ thyroids compared with those in
normal thyroids obtained from tissues adjacent to benign thyroid
adenomas. TSH levels at open biopsy and operation were 6.2 mU/L for
patient 1, 3.8 mU/L for patient 5, and 2.0–4.2 mU/L for three patients
with benign thyroid adenoma. The 80- and 60-kDa species might
reflect different posttranslational modifications, such as Asn-linked
glycosylation; further elucidation is necessary.
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The same antibody was used for immunohistochemical staining of the
patients’ thyroid tissue sections. Specific staining was observed on
the basal and lateral plasma membranes of patients’ thyrocytes,
whereas the cytosol and apical membranes of thyrocytes were negative
(see Fig. 3A for case 5). A similar
staining pattern was found in the thyrocytes of case 1 (data not
shown). This staining is specific to NIS, as no staining was detected
when the antibody was preabsorbed with the NIS peptide used for
immunization (Fig. 3B). In comparison, NIS staining was barely detected
(Fig. 3C) in the normal thyroid tissues adjacent to benign thyroid
adenomas from patients (n = 6) whose serum TSH levels were within
normal range. Taken together, we showed that the overexpressed T354P
mutant NIS proteins are properly localized in the basolateral plasma
membranes of the thyroid cells.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In patients with ITD, intake of large amounts of iodide compensates for
poor iodide uptake. The mechanism of this compensation has been
explained by the transport of iodide though nonspecific channels or
carriers or by "simple diffusion" (1, 2). In the previous study
(15) we demonstrated that NIS messenger ribonucleic acid in the thyroid
tissue of case 1 was markedly increased (>100-fold) compared with that
in normal thyroid tissue, and that iodide uptake activity of the T354P
mutant was not completely abolished, suggesting that very low iodide
uptake activity may be compensated for by overexpression of NIS. In the
present study we confirmed the overexpression of NIS at the protein
level by Western blotting and immunohistochemical analyses. The NIS
proteins in the thyroid tissues of cases 1 and 5 were significantly
increased (10-fold) compared with those in normal thyroid tissues.
TSH increases NIS message and protein levels in FRTL-5 rat thyroid
cells. However, maximal increases were only 8-fold for message and
2.5-fold for protein with 1 U/L TSH (25). Therefore, it is unlikely
that the TSH levels at open biopsy account for marked overexpression in
NIS message and proteins in these cases. However, it is not known
whether NIS is also overexpressed in other cases with homozygous T354P
mutation and/or in all patients with ITD. Differences in NIS expression
level in patients’ thyroids may be related to clinical heterogeneity
in ITD, as described below.
It has been noted that clinical features, especially concerning goiter
and hypothyroidism, are heterogeneous among patients with ITD (1, 15).
Indeed, clinical heterogeneity was noted among the seven patients
carrying the T354P homozygous mutation (Table 1). No goiter was
observed in cases 4 and 7, although a diffuse goiter was present in
other cases. It is interesting that the patient with the T354P mutation
reported by others developed thyroid adenoma (16). In our study, cases
1 and 2 were euthyroid, but severe hypothyroidism had been observed
since early childhood in cases 4, 5, and 7.
The amount of iodide intake apparently influences thyroid function in patients with ITD (1, 2). During infancy, this is dependent on the iodide content in milk. Breast milk contains much larger amounts of iodide than artificial milk. This may be more evident for Japanese who take larger amounts of iodide than world standard, especially from seaweeds. Cases 4 and 5, who were fed with artificial milk, developed cretinism before 1 yr of age. Marked differences in clinical features between the siblings in cases 3 and 4 seem to be due at least in part to the difference in nutrition during infancy.
In contrast to hypothyroidism, goiter usually develops in late developmental stages. Except for five reported cases who had goiter at birth or within 3 months after birth (4, 6, 14, 17), goiter seldom or never developed in early childhood (1, 9, 10, 11, 12, 13, 18). Cases 1, 2, and 3 in our study, and cases 12, 17, and 18 reviewed by Wolff (1), all of whom were Japanese, were diagnosed primarily by diffuse goiter developed at the ages of 6–20 yr. These patients are supposed to have taken relatively large amounts of iodide. As an example of our case 3, patients who were maintained euthyroid may have had varied thyroid function when consuming their usual meals. The transient and frequent elevation of TSH may be the major factor to induce goiter development in these cases. However, patients who were diagnosed primarily by hypothyroidism without the presence of goiter and were maintained euthyroid by treatment with L-T4 or dried thyroid, developed diffuse or nodular goiter with age. This is true with our case 5; cases 1, 3, 4, 14, and 15 in Wolff’s review (1); and the two other cases (16, 18). In contrast, our cases 4 and 7, cases 19 and 21 in Wolff’s review (1), and the seven cases reported by Couch et al. (12) had not developed goiter during thyroid hormone treatment over years. Poor drug compliance causing transient elevation of TSH may be related to goiter development. Gilboa et al. (5) speculated that thyroid with ITD might be more sensitive to a normal range of TSH. However, it is curious that goiter develops not before but after starting L-T4 treatment in these cases. We speculate that other important factors in addition to TSH may influence the development of goiter in patients with ITD, such as iodide itself or forms of organic iodine. Furthermore, the mechanism of goiter development may be different in early childhood.
Which is the better treatment for ITD, thyroid hormones or a large amount of iodide? Some considered that iodide treatment was more physiological than L-T4 (11, 14). However, there have been few experiences administering large amounts of iodide for a long period (11, 14), and there is a risk of developing iodide-induced Graves’ disease (5) or hypothyroidism. An advantage of L-T4 therapy is the ease with which it inhibits TSH, which is the only factor known to induce goiter development. However, the answer to the question is largely dependent on the mechanism of goiter development in patients with ITD, as described above. It is noteworthy that no goiter development was observed during the administration of large amounts of iodide over 10 yr in two cases (14).
Together with the findings in Ref. 16, 8 patients from 6 families had the T354P homozygous mutation among 17 known Japanese patients from 12 families. The high prevalence of the T354P NIS mutation in Japanese patients is also suggested by 1) identification of a compound heterozygous mutation of T354P and a novel mutation, G93R, in another case (18A ), 2) identification of T354P in a heterozygous state by the Osaka group in three sibling cases while a mutation on the other allele has not been detected (26), 3) the fact that the T354P homozygous mutation was found in patients whose parents were unrelated (cases 5 and 7), and 4) the fact that the origins of patients’ parents who have the T354P mutation in the heterozygous state are distributed all over Japan. Please note that the NIS mutations found in two non-Japanese patients are not the T354P mutation (17, 18). It is unlikely that T354P is a hot spot for the NIS mutation, because other mutations have been found (17, 18 18A ) to be distributed widely in the entire NIS protein. We speculate that the T354P mutation is from a common ancestor origin specific to Japanese. This may be further investigated if polymorphism of the NIS gene is available.
Neonatal screening for cretinism started country-wide in 1979 in Japan.
The incidence of cretinism is 1 in 5,500–10,000 births (27). Among
them, 84% are due to agenesis or dysgenesis of the thyroid. The
remaining 16% are due to dyshormonogenesis. In a study carried out by
Nakajima et al. (28), in 4.2% (5 of 118) of patients with
dyshormonogenesis it was due to ITD. Based on this estimation, we
expect that there are 80–160 patients with ITD in Japan. However,
including those cases we reported in this paper, only 17 Japanese
patients with ITD have been reported. Although the clinical symptoms of
ITD are expected to be more evident in patients taking smaller amounts
of iodide, 40% (17 cases of 42) of the reported patients with ITD
are Japanese who take relatively large amounts of iodide. The common
prevalence of the T354P mutation in Japanese may account for the high
incidence of patients with ITD in Japan.
The following are possible situations in which ITD was missed or misdiagnosed. 1) Patients were diagnosed as thyroid agenesis because of the lack of thyroidal radioactive iodide uptake and the absence of goiter, as in our cases 4 and 5. 2) The cause of cretinism was not examined in patients identified in early childhood. 3) Patients were diagnosed as euthyroid or transient hypothyroidism by neonatal screening for cretinism, as in our case 6 and another case (10). It is noteworthy that no patient with ITD was given thyroid hormone replacement during the neonatal period under the diagnosis of cretinism in Japan. However, this is the case in Western countries (12). 4) Elder or adult patients with a diffuse or nodular goiter were treated with thyroid hormones or followed up without medication and had never undergone thyroidal scintigram, as in our cases 1, 2, and 3.
We and others have identified loss of function NIS mutations in 13 patients among 42 reported cases with ITD, although factors accounting for clinical heterogeneity among patients with ITD are yet to be identified. Continued investigation of NIS gene mutations (21) and regulation of the NIS gene expression will contribute to the clarification of the pathophysiology, not only of the ITD, but also of the iodide deficiency from which tens of millions of people in the world suffer.
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Acknowledgments |
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Footnotes |
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2 Cases 19 and 21 in Wolff’s review (1 ) are those
in Ref. 11, and the case in Ref. 16 is that in Ref. 10.
Received February 27, 1998.
Revised May 22, 1998.
Revised July 15, 1998.
Accepted July 27, 1998.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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