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High Prevalence of a Novel Mutation (2268 insT) of the Thyroid Peroxidase Gene in Taiwanese Patients with Total Iodide Organification Defect, and Evidence for a Founder Effect

Departments of Pediatrics (D.-M.N., B.H., C.-J.L., P.-L.W.) and Nuclear Medicine (Y.-K.C.), Veterans General Hospital-Taipei; Institutes of Clinical Medicine (D.-M.N.) and Microbiology and Immunology (C.-Y.L.), National Yang-Ming University; and Changhua Christian Hospital (C.-Y.L.), Taipei, Taiwan 11217

Abstract

The mutation of the thyroid peroxidase (TPO) gene that causes the total iodide organification defect (TIOD) is a common and severe condition leading to dyshormonogenesis of the thyroid gland in Caucasians. However, the role of TIOD in Chinese patients with thyroid dyshormonogenesis is unknown. In this study we followed 16 patients from 16 unrelated families in Taiwan and performed perchlorate discharge examination. Seven patients had TIOD and 2 had the partial iodine organification defect (PIOD) among the 16 families. These 9 patients underwent screening in search of TPO gene mutations. Three new mutations (2268 insT, 2243 delT, and G157C) were detected in the 7 patients with TIOD, whereas no mutation in the TPO gene was found in the 2 patients with PIOD. The 2268 insT mutation was noted to be the most common among these TIOD patients (12 of 14 studied alleles, 86%). With 3 intragenic polymorphic markers, we found that the alleles carrying the 2268 insT mutation in Taiwan Chinese TIOD patients were tightly linked to a specific haplotype. The allele frequencies of this haplotype in the 8 patients with homozygous 2268 insT (5 unrelated families, 10 studied alleles) and in 49 normal individuals (98 studied alleles) were 1.00 and 0.02, respectively (P < 0.0001). This indicates that this common novel mutation among Taiwanese patients with TIOD is due to a founder effect.

THE PREVALENCE OF permanent congenital hypothyroidism (CH) is reported to be 1 in 4,000 live births in Europe and North America (1, 2). Thyroid dysgenesis, including thyroid aplasia (agenesis), hypoplasia, ectopy, or hemiagenesis, is responsible for about 80–85% of CH. The remaining 15–20% is caused by dyshormonogenesis of the thyroid gland (3, 4). Different defects in thyroid biosynthesis have been identified. Mutations of various genes, such as the sodium iodide symporter (5, 6), thyroglobulin (7, 8), pendrin (9, 10), and thyroid peroxidase (TPO) genes (11, 12), have been reported in the literature. Among these defects, mutations of the TPO gene, which causes a total iodide organification defect (TIOD), was reported to be the most severe and common condition (13). TIOD is characterized by a rapid and nearly complete release of accumulated intrathyroidal free radioiodine by the administration of perchlorate ions (ClO₄^-) in radionuclide uptake studies. The incidence of the TIOD defect is estimated to be 1 in 66,000 newborns in The Netherlands (13), but few data are available for other populations. The prevalence of permanent CH is reported to be 1 in 5,788 live births in Taiwan. About 20% of CH are caused by dyshormonogenesis (14). However, the role of TIOD in Taiwanese patients with thyroid dyshormonogenesis is unclear. This study was performed to measure the prevalence of TIOD among Taiwanese patients with dyshormonogenesis of the thyroid. We also describe the finding of a common (12 of 14 studied alleles) and novel (2268 insT) mutation among 7 of 16 unrelated families studied.

Subjects and Methods

Babies with abnormal TSH concentrations, found by screening of newborns in this part of northern Taiwan, are referred for confirmatory studies to our hospital, a national referral and consultation center for CH. From 1984 to 1998, a total of 24 patients from 20 nonrelated families were confirmed to have the moderate to severe dyshormonogenetic type CH (TSH, >30 during withdrawal of L-T₄ replacement). Of these, 16 patients from 16 different families agreed to participate in this perchlorate discharge and molecular study. If a family had more than 1 affected member, a single patient was chosen for the perchlorate study. All procedures were approved by the institutional review board of Veterans General Hospital-Taipei. The patients or their parents were informed of the details of this study and granted their written consent to participate.

Perchlorate discharge test

After a 3-wk withdrawal of L-T₄ replacement, patients were given 25 µCi [¹³¹I]NaI orally, and thyroid uptake was measured 2 h later; 0.5 g potassium perchlorate was then administered orally, and sequential uptakes were measured at 1-h intervals for an additional 2 h. The decay of ¹³¹I was corrected by counting a standard placed in a neck phantom at each time point, and counts measured over the thigh were used for the subtraction of body background. The percentage of thyroidal radioiodide uptake (RAIU) was calculated at each time point, and the effect of ClO₄^- was expressed as a percentage of the RAIU at 2 h, the time when KClO₄^- was administered. A blood sample for measurement of thyroid function was collected just before the perchlorate discharge. Serum levels of free T₄, T₄, T₃, and TSH, were determined by RIA, and thyroglobulin (Tg) was determined by ELISA.

Mutation analysis of the TPO gene

Patients from 9 unrelated families, including 10 patients from 7 families with TIOD and 2 patients from 2 families with partial iodine organification defect (POID), were enrolled in this mutation analysis study. Genomic DNA was extracted from peripheral white blood cells using a standard procedure. The TPO gene was amplified by PCR. The oligonucleotide primers used for PCR were modified from those described by Bikker et al. (15) by eliminating the CG clamp. A total of 17 pair primers were used to cover the 17 exons, including the exon/intron junctions and the promoter region of the TPO gene. The PCR conditions for each primer were optimized in our laboratory. Cycle sequencing was performed using the original primers and a commercial kit (Perkin-Elmer, Norwalk, CT) to amplify the PCR products. The reaction products were subjected to electrophoresis in an ABI PRISM 377 automatic DNA sequencer (Perkin-Elmer). All procedures followed the instructions supplied by the manufacturer. If a novel mutation was suspected, 100 Guthrie cards, which originally were used for neonatal screening of CH and had normal neonatal screening results of CH, were screened as a control to evaluate whether the nucleotide change was a mutation or just a polymorphism in our population.

Haplotyping analysis

The 5 families (8 patients) that had members with a homozygote 2268 insT mutation were enrolled in this study. Three intragenic polymorphic markers were used to haplotype the TPO alleles. One marker is a variable number of tandem repeats (VNTRs), which is located 1.5 kb downstream of exon 10, and each repeat was 50 bp long (16). The other 2 markers are single nucleotide polymorphism (SNP). They are located in exons 1 (G-73A) and 17 (G2889C), respectively, and can be identified by specific restriction endonucleases (17). The PCR conditions for each primer were optimized in our laboratory. The products of the amplification were digested with the appropriate endonucleases, and DNA fragments were separated by a 3% agarose gel and visualized under UV light after staining with ethidium bromide. Allele frequencies, marker heterozygosity, and haplotype heterozygosity were determined by analyzing genomic DNA from 50 unrelated and unaffected control subjects.

Statistical analysis

The statistical significance of the comparisons of allele frequencies of these three intragenic markers of the TPO gene between homozygote 2268 insT patients and normal individuals was examined by Fisher’s exact test. P < 0.05 was considered statistically significant.

Results

Perchlorate discharge test

A prompt, more than 80% washout of intrathyroidal free radioiodine after potassium perchlorate administration was found in 7 of the 16 unrelated patients. These 7 patients, who also suffered from a severe form of CH, with very low serum free T₄ and T₃ levels and markedly increased serum TSH and Tg levels during L-T₄ withdrawal, were considered to have TOID. Two patients (no. 8 and 9), who had a 10–30% decrease in RAIU during the perchlorate discharge test and a relatively mild impairment of thyroid function, were considered to have POID. Patients 10–15 were suspected to have a Tg defect because of the finding of increased (no. 10–14) or borderline increased (no. 15) RAIU, and a low Tg level measured during withdrawal of L-T₄. Finally, one patient (no. 16) was suspected to have an iodine transport or a TSH receptor gene defect because of a relatively low RAIU during T₄ withdrawal. As the gene defects of these patients were not identified, the precise etiologies of their disorders remain to be clarified. As the estimated biological half-life of serum T₄ is 3.9–5.9 d in children (18), we considered that the degree of thyroid hormone deficiency after a 3-wk L-T₄ withdrawal would reliably reflect the severity of CH. The detailed results of the thyroid function and discharge tests performed in these patients are shown in Table 1.

Three novel mutants were identified among the 7 unrelated families with TOID, including a common mutant (2268 insT) accounting for 86% (12 of 14 studied alleles) of the mutations, as well as mutants 2243 delT and G157C. The mutation distribution among these patients is also shown in Table 1. Patients 1–5 had a homozygous T insertion in exon 13 at position 2268. This insertion led to a stop codon immediately behind the insertion point, resulting in a truncated polypeptide of 756 amino acids. Patient 6 was found to have compound heterozygous mutations, 2268 insT and 2243 delT. The 2243 delT mutation, also located in exon 13, caused a frameshift and ran into a termination signal after 49 residues at exon 14. Patient 7 also was compound heterozygous for 2268 insT and the other novel mutation, G157C, which led to an amino acid exchange from alanine to proline at codon 53 (exon 3). Mutation studies of the parents of patient 7 were performed and revealed that the father was a carrier of the G157C mutation, and the mother was a carrier of the 2268 insT mutation. No G157C mutation was found among the 100 healthy controls. No mutation was detected in the 2 patients with PIOD (no. 8 and 9).

Haplotyping analysis

The VNTR marker of the TPO gene was highly informative in Taiwan Chinese. In all, 14 different alleles, ranging from 7–20 repeat units, were detected from 50 unrelated and unaffected control subjects. The allele sizes and frequencies are shown in Table 2. For the other two SNP markers, the distinct base of each single base polymorphic site, allele designation, and allele frequency are shown in Table 3. A comparison of the allele frequency of these 3 intragenic markers of the TPO gene between homozygote 2268 insT patients and normal individuals is also shown in Table 3. A specific haplotype (11/2/2) was identified for all alleles carrying this 2268 insT mutation in these 5 families (Fig. 1). In controls, 1 individual was homozygous with 11/2/2, and 1 may be carrying this specific haplotype in 1 allele (data not shown). The allele frequencies of this specific haplotype in the 5 unrelated patients (10 alleles) and 49 normal individuals (98 alleles) were 1.00 and 0.02, respectively, a statistically significant difference (P < 0.0001). This strongly suggests that the 2268 insT mutation in Taiwan is due to a founder effect.

View larger version (25K): [in this window] [in a new window]   Figure 1. Haplotype segregation analysis in five families. The SNP markers are located within the exon 1 or 17 of the TPO gene, and their positions are indicated as the nucleotide number. The number 1 or 2 used in SNP markers indicates the presence or absence, respectively, of digestion with the special restriction enzyme. The VNTR marker is located 1.5 kb downstream of exon 10; each repeat contains 50 bp. The number used in VNTR marker indicates the repeat number of VNTR. The alleles that segregated with the 2268 insT mutation are indicated by a black box. All alleles can be identified to a special haplotype (11/2/2) in all five unrelated families. NA*, Sample not available.

The first finding of this study was the important role played by TIOD in the dyshormonogenesis of the thyroid gland in Taiwan Chinese, as is the case in Caucasians. All patients with TIOD had a TPO defect by TPO gene analysis, consistent with a TPO gene mutation as the predominant cause of TIOD in Taiwan.

The human TPO gene contains 17 exons and covers at least 150 kbp of chromosome 2. In comparison with the human myeloperoxidase gene (19), with the exception of the 7th myeloperoxidase junction, which does not have any counterpart in TPO, the positions of the 3rd through 11th exon-intron junctions in TPO coincide exactly with those of the 2nd through 11th exon-intron junctions. TPO is a membrane-bound hemoprotein. The putative heme-binding histidine residues are contained in the latter half of the 8th, 9th, and 10th exons (20). Hence, exons 8, 9, and 10 are thought to be the catalytic center of the TPO protein, and several mutations of these exons, which may cause major defects of TPO, have been reported (13, 15, 21, 22). In the C-terminal region, 4 exons (13, 14, 15, 16) encompass a different protein module. Three of these modules (exons 13–15) bear significant similarities to C4b-ß₂ glycoprotein, epidermal growth factor-low density lipoprotein receptor, and a typical transmembrane domain, respectively. Less is known about the relationship between the function and the structure of TPO in this region. Foti et al. (23), who created a mutated human TPO cDNA that truncated the carboxyl terminus of hTPO by 85 residues, found a stable enzymatic activity of the truncated protein in conditioned medium from CHO cells after transfection of the mutant human TPO. They suggested that the transmembrane domain does not play a role in TPO functional activity. However, several patients with mutations in this area presented with severe thyroid function, and in 1 patient it was associated with congenital, metastatic carcinoma of the gland (15, 21, 22, 24, 25, 26), suggesting that this region is important for proper folding, and not only as a hinge for the insertion membrane. As most of these mutations contain a mutant stretch of amino acids after the frameshift, whether the proper folding of the TPO enzyme is affected by loss of original domains, the novel stretch of amino acids, or both mechanisms remains to be clarified. In our patients the mutant 2268 insT led to a stop codon immediately behind the insertion point and translated a truncated protein without a mutant stretch of amino acids. Therefore, it seems likely that only a loss of these domains can interfere with the activity of TPO enzyme. Recently, a frameshift mutation (2505+C) in exon 14 was described, responsible for only mild impairment of thyroid function when heterozygous, with a known complete inactive mutant (27). The researchers hypothesized that some TPO activity remained, perhaps in the colloid, due to preservation of the functional portion of the enzyme (exons 8–10). By contrast, the same mutation was thought to cause severe impairment of thyroid function in other reports (15, 24, 26). The divergence in these results remains unexplained and warrants further investigation. The 2243 delT mutation in patient 6, also located in exon 13, caused a frameshift and ran into a termination signal after 49 residues at exon 14. As this frameshift mutation occurs 25 bp before 2268 insT, we believe that, like 2268 insT, it may also cause a severe defect in TPO. Patient 7 was compound heterozygous for 2268 insT and G157C. This novel mutation led to an amino acid exchange from alanine to proline at codon 53 (exon 3). Alanine 53 is located in a conserved part of TPO and is predicted to be in a region of a helix structure (27). Hence, when this small aliphatic chain amino acid (alanine) is substituted by an imino acid, proline, which can consistently bend the -helix of the polypeptides, it appears that this mutation can modify the functional structure of the TPO to cause this enzymatic defect. From the nearly undetectable plasma free T₄ concentrations and the markedly increased plasma TSH and Tg in patient 7 during withdrawal of T₄ therapy, it appears that this mutation also causes a major defect in TPO. No mutation in TPO was identified in patients with POID in this study. Because the sequence analysis detects limited portions of a gene, mutations in 5' regulatory region or intron were not detected by sequence analysis in this study. It remains possible that these patients’ disorder was caused by an unknown TPO gene defect. In addition, other gene defects, such as in the pendrin gene and H₂O₂-generating system, need to be considered and pursued in further studies.

By definition, patients with TIOD are unable to organify iodine ions toward the production of thyroid hormone, and perchlorate ions may displace more than 90% of the intrathyroidal free iodine ions (15). However, the release measured in our patients 1–5 was between 80–90%. Whether the 2268 insT mutation is not within the functional portion of the TPO protein (exons 8–10), closely enough associated with some TPO residual activity to modify the release of iodine, or whether the isotopic properties of ¹³¹I (354 keV radiation and 8-d half-life) used in our study vs. ¹²³I (159 keV radiation and 13-h half-life) used in most earlier studies lowered the measurements of iodine release remains to be determined. A thyroid biopsy, the transfection of the mutant TPO gene in a suitable cell system to assay the possible enzyme activity, or an ¹²³I perchlorate discharge test to compare with previous results obtained with ¹³¹I may clarify this issue. As the patients’ parents did not consent to the thyroid biopsy and exposure to radioisotopes, only the transfection assays of mutant TPO protein are now in progress in our laboratory. We also observed that even in patients 1 and 5, who had the same homozygous mutation, the results of the discharge test varied between 80.3–91.2%, using the same procedure. Therefore, other interindividual or intraindividual factors that may affect the outcome of the test, such as variable gastrointestinal absorption rates of perchlorate ions or different amounts of perchlorate ions needed to completely inhibit thyroid iodide transport, need to be considered when performing and interpreting the results.

In general, the high prevalence of a mutation can be explained by one of two mechanisms: either a mutational hot spot due to some genomic structure or a founder effect. From the linkage study we were able to identify a specific haplotype of the allele carrying the 2268 insT mutant. This implies that the common 2268 insT mutation is caused by a founder effect, rather than by independent mutational events. Interestingly, the ancestors of these unrelated five Taiwanese families originated from the same area of southern Mainland China. We believe that studying the origin and the distribution of the 2268 insT mutation in southern China and Taiwan will be helpful to trace the migrations of Chinese population in these areas.

Acknowledgments

We thank Ms. Yuan-Chih Liu (Biostatistic Task Force, Information Service Center of Veterans General Hospital-Taipei) for performing the statistical analyses.

Footnotes

Address all correspondence and requests for reprints to: Dr. Ching-Yuang Lin, Department of Pediatrics, Veterans General Hospital, Taipei, Taiwan 11217. E-mail: .

This work was supported by Research Grant VGH-900002 from the Department of Medical Research, Veterans General Hospital-Taipei, Taiwan.

Abbreviations: CH, Congenital hypothyroidism; POID, partial iodine organification defect; RAIU, thyroidal radioiodide uptake; SNP, single nucleotide polymorphism; Tg, thyroglobulin; TIOD, total iodide organification defect; TPO, thyroid peroxidase; VNTR, variable number of tandem repeat.

Received February 4, 2002.

Accepted May 24, 2002.

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