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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1002-1005
Copyright © 2003 by The Endocrine Society

The W546X Mutation of the Thyrotropin Receptor Gene: Potential Major Contributor to Thyroid Dysfunction in a Caucasian Population

N. Jordan, N. Williams, J. W. Gregory, C. Evans, M. Owen and M. Ludgate

Departments of Medicine (N.J., M.L.), Medical Biochemistry (N.J., C.E.), Psychological Medicine (N.W., M.O.), and Child Health (J.W.G.), University of Wales College of Medicine, Cardiff CF4 4XN, United Kingdom

Address all correspondence and requests for reprints to: Dr. Marian Ludgate, Department of Medicine, Endocrinology, Metabolism and Diabetes Section, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail: ludgate{at}cf.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Congenital hypothyroidism (CH) occurs in approximately 1 in 3000 births and can be caused by mutations in 9 known genes, including that encoding the TSH receptor (TSHR).

We report on two Welsh siblings, detected by neonatal screening, who had normal sized and placed glands but negative isotope uptake. Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically. Both siblings were homozygous for a previously described G to A transition producing a missense mutation, W546X, in the fourth membrane spanning region of the TSHR, rendering it unresponsive to TSH. Both parents were heterozygous and unrelated; furthermore, the W546X has been described in three further families (one of which is Welsh), suggesting that it may be a relatively common mutation.

We genotyped 368 euthyroid Welsh individuals using single nucleotide primer extension, and found 366 homozygous wild-type (G:G) and 2 heterozygous (G:A) for the mutation.

In conclusion, CH in the siblings is due to the missense mutation, W546X, in their TSHR gene. The W546X allele was detected in approximately 1 in 180 individuals and may be a major contributor to hypothyroidism in the Welsh population.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CONGENITAL HYPOTHYROIDISM (CH) occurs in about 1 in 3000 births (1). The incidence displays wide regional variation indicative of local genetic influences such as the T354P mutation in the sodium/iodide symporter (NIS), which is a common cause of the disorder in Japan (2). In Wales (population about 3 million), the incidence is 1 in 1800 in the north and west but 1 in 3400 in the south and east (3). Furthermore, CH is more prevalent in females than males [e.g. in the Welsh cohort, 1 in 2473 girls were detected compared with 1 in 4770 boys (3)] and has been attributed to an increased incidence of thyroid ectopy and agenesis in females (4). In up to 2% of cases, CH is caused by thyroid-blocking antibodies (TBAB) in the mother crossing the placenta (5). In these cases, disease is transient and does not require lifelong treatment, in contrast to the majority in which CH is due to gene mutations. Neonatal screening and replacement T4 treatment have virtually eradicated the adverse consequences of CH, but patients diagnosed with permanent CH should receive genetic counseling because there is a possibility of further pregnancies being affected.

Recent years have seen the cloning of genes predicted to regulate the development and migration of the thyroid gland itself and also those involved in thyroid hormone production. These include thyroid transcription factors 1 and 2 (TTF 1 and TTF2) (6, 7), Pax 8 (8), TSH receptor (TSHR) (9), NIS (10), thyroglobulin (TG) (11), thyroperoxidase (TPO) (12), Pendrin (13) and the hydrogen peroxidase-generating system (H2O2) (14). There is some correlation between phenotype and genotype and mutations in TTF1/2, PAX8, and the TSHR are found in children with absent, misplaced, unresponsive or hypoplastic glands. In contrast mutations in NIS, TG, TPO, Pendrin, and the H2O2-generating system are found in children displaying dyshormonogenesis.

In the TSHR, identification of the P556L homozygous mutation in the hyt/hyt mouse model of CH (15) was followed by several reports of similar mutations in human disease but with varying phenotype. These ranged from elevated serum TSH concentrations accompanied by normal serum T4 levels in the case of mutations I167N, P162A (9), and R109Q (16) to frank CH with thyroid hypoplasia in children homozygous for A553T (17). Missense mutations in the TSHR result in reduced or even completely abrogated TSH binding and signal transduction. In contrast, nonsense mutations such as W546X (16) produce a truncated receptor. Because the serpentine portion of the receptor is required for G protein coupling, signal transduction is abolished. Furthermore, the lack of a trafficking signal compromises its correct allocation to the basal membrane of the thyrocyte (18). Heterozygous vs. homozygous combinations further refine the phenotype, e.g. a single partially responsive TSHR produces compensated hyperthyrotopinemia (9, 16), but in patients with homozygous nonsense mutations the increased TSH level is accompanied by reduced circulating T4 (17).

We describe our studies on two male siblings, of nonconsanguineous Welsh parents, who had CH identified by newborn screening. The brothers had normally sized and located thyroid glands, no iodide uptake on isotope scanning, and were negative for TBAB. Given the clinical presentation, we investigated the possibility of a TSHR mutation and subsequently evaluated the allele frequency of the mutation detected, which has been previously reported in a Welsh family (16), in the local population.


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

Two male siblings (J.P. and S.P.) were born to unrelated parents and were identified by newborn screening for CH. Their biochemical characteristics are shown in Table 1Go. Apart from CH, S.P. has suffered with recurrent infectious illnesses. J.P. has slight impairment of speech, despite normal hearing, and has developed a benign bone tumor in his left forearm. The brothers are growing normally and otherwise developing satisfactorily. They are euthyroid, on doses of thyroxine between 5–7 µg/kg·d.


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  		Table 1. Clinical and biochemical characteristics of two siblings detected by newborn screening for CH

 
Blood samples were obtained from the boys and their parents, with informed consent and with the approval of the local ethics committee. Both of the parents have normal thyroid function tests with serum TSH concentrations of 3.52 and 3.96 mU/liter.

DNA extraction, TSHR PCR amplification, and sequencing

Genomic DNA was extracted, using the QIAamp Blood Kit (QIAGEN, Crawley, UK) according to the manufacturer’s instructions, from whole EDTA blood samples. The eluted DNA was quantified and the TSHR gene amplified by PCR using nine pairs of intronic primers for exons 1–9 and two pairs of primers for exon 10, each consisting of an intronic primer and overlapping exonic primer, as described (19). The 50-µl PCRs contained 100 ng genomic DNA and 1 U Taq DNA polymerase (Promega Corp., Madison, WI). The PCR program comprised 1 cycle of 3 min at 95 C, followed by 30 cycles of 30 sec at 95 C, 30 sec at the annealing temperatures specific to each primer pair (19), and 1 min at 72 C and an elongation cycle of 10 min at 72 C. PCR amplicons of varying size were generated all as previously described (19). In negative controls, water replaced the genomic DNA.

PCR products were polyethylene glycol precipitated before sequencing, on both strands, using a BigDye Terminator Sequencing Kit [Applied Biosystems, Inc. (ABI), Perkin-Elmer, Norwalk, CT] and the PCR primers as sequencing primers. Sequence analysis was performed on an ABI 377 automatic sequencer.

Bfa1 restriction digest

The restriction digests were performed on approximately 100 ng of polyethylene glycol precipitated PCR product, from fragment 10b of the TSHR, in a total volume of 10 µl containing 5 U Bfa1 (New England Biolabs, Inc., Beverly, MA), incubated at 37 C for 1 h, and analyzed by agarose gel electrophoresis. The predicted sizes of restriction fragments are 1) wild type (WT), a single band of 875 bp (also the size of the uncut fragment of 10b from mutated and WT TSHR); 2) homozygous W546X, two bands of 740 bp and 135 bp; and 3) heterozygous W546X/WT, three bands of 875, 740, and 135 bp.

Individual genotyping using the mini sequencing reaction

Samples of genomic DNA, were obtained from 184 normal healthy Caucasian blood donors (126 males and 58 females with mean age of 42 ± 12 yr), from the South Wales area. Donors were asked to complete a questionnaire, and were considered to be of Welsh descent if their grandparents were born in Wales. Because individuals receiving thyroxine treatment are eligible for blood donation, we cannot exclude the possibility that some of them may have thyroid dysfunction.

Genomic DNA samples were also obtained from 184 patients diagnosed with schizophrenia (134 males and 50 females with mean age of 47 ± 13 yr).

Ethical approval and informed consent for genetic analysis of these samples had also been obtained.

To estimate the allele frequency of the W546X mutation, we individually genotyped each of the 184 blood donors and 184 schizophrenics.

PCRs for primer pair 10b were carried out in a 96-well plate format in a total volume of 10 µl per well containing 30 ng of donor or patient’s DNA and 1 U Taq DNA polymerase (Promega Corp., Madison, WI).

Each PCR was then treated with 1 U shrimp alkaline phosphatase and 0.2 U Exonuclease 1 (Amersham Pharmacia Biotech, Little Chalfont, UK), for 1 h at 37 C followed by 80 C for 15 min, to remove primers and unincorporated deoxy-NTPs (20). PCR products were subjected to allele specific primer extension reactions using the SNaPshot (ABI, Foster City, CA) methodology according to the manufacturers instructions. The extension primer consisted of the 25 bp directly upstream of the W546X mutation 5' GCA TGT GCC ATC ATG GTT GGG GGC T 3'. The samples were incubated at 94 C for 2 min, followed by 25 cycles of 94 C for 5 sec, 43 C for 5 sec, 60 C for 5 sec, and a final hold at 15 C.

The reaction mix was treated again with shrimp alkaline phosphatase and analyzed on an ABI Prism 3100 Genetic Analyzer (20).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mutational analysis of the siblings reveals they are homozygous for W546X

Complete sequencing of exons 1–9 and fragment 10a revealed the absence of any polymorphism and only WT sequence in the two brothers. A previously described G to A transition, producing a missense mutation (16), was found in both TSHR alleles in fragment 10b. The mutation results in a premature stop codon in the fourth membrane-spanning region of the TSHR, rendering it incapable of signal transduction and thus unresponsive to TSH.

Sequencing fragment 10b of the parents (who are not related) revealed that they were both heterozygous for the mutation.

This was confirmed by Bfa1 restriction of fragment 10b from the parents and two brothers, which produced the predicted restriction digest fragments of heterozygotes and homozygotes, respectively.

Determining the allele frequency by mini-sequencing

All 368 samples were individually genotyped by primer extension; 366 of these were homozygous for WT sequence (G:G). However, two were heterozygous for the W546X mutation (G:A), one a 58-yr-old male (sample 6) from the schizophrenia group and the other a 56-yr-old male (sample 216) from the blood donor control group. The results are shown in Fig. 1Go.



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  		Figure 1. Electropherograms from SNaPshot genotyping of W546X mutation (1 ) in homozygous WT G:G, (2 ), and (3 ) heterozygous WT and W546X G:A. In each case, the G allele is shown in the upper panel a and the A allele in the lower panel b. Note the similar peak heights of G and A in the heterozygous samples shown in sections 2 and 3, which contrasts with the strong G and virtually absent A signal in the homozygous sample shown in section 1.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
There are several features about the CH in this family that merit comment. Firstly, apart from CH, one of the children has experienced problems with recurrent infection. Immune deficiency in association with CH has been described previously (21) in a patient with lymphopenia and persistent respiratory infections, and we are aware of a second Welsh child displaying a similar phenotype. Secondly, homozygous mutations have previously been detected, only on a background of consanguinity (8, 22, 23), which is not the case here. Finally, loss-of-function mutations of the TSHR resulting in CH have been identified in at least 15 families. Four of the mutations occur in more than one family, C390W [Germany (24) and France (23)], A553T [Belgium (17) and England (25)], P162A [France (23) and Italy (26)] and W546X [England (25), Wales (16), and France (23)]. Furthermore, of the 15 families with CH, 6 have mutations resulting in a stop codon, W546X accounts for 4 of these, and 2 of the affected families live in Wales and are of Welsh extraction. In 3 of these families, W546X occurs in heterozygous combination with a second (different) TSHR mutation, R109Q, (16), A553T (25), and C390W (23). The phenotype in the affected children ranges from compensated hyperthyropinemia in those with one partially functioning receptor allele such as the R109Q, to frank hypothyroidism in families completely lacking a functional TSHR. The biochemical phenotype also varies with some patients having detectable TG in the circulation (27) and others not (28).

The location of the families harboring W546X prompted us to investigate the frequency of this mutation in the local Caucasian population. The allele was found in about 1 in 180 individuals which is approximately 0.6%. The population tested was predominantly male, because for purely pragmatic reasons we have used well-characterized DNA samples from patients with schizophrenia and age and gender matched controls and found identical frequencies in both. Certain forms of CH, notably thyroid ectopy, are more prevalent in females than males (27). To our knowledge, TSHR mutations have been reported in 16 females and 13 males and have been associated with normal or hypoplastic glands in the correct position, whereas misplaced glands are a feature of mutations in transcription factors (6).

What is the likely impact on the thyroid axis of being heterozygous for a loss of function TSHR mutation? The parents in this family are euthyroid but have TSH values in what has been described as the high-normal range (2.0–5.4 mU/liter) (29), as did the parent heterozygous for R109Q (16). The same feature has been reported in the heterozygous son of a patient who was homozygous for P162A (26).

We hypothesize that individuals in whom one of the TSHR alleles has compromised function may be predisposed to subclinical hypothyroidism (SH) and this has been demonstrated in a recent study in which parents of probands with CH had slightly elevated TSH values (30). SH is a common disorder in which TSH levels are moderately elevated (5.5–20 mU/liter), but circulating T4 and T3 levels are in the normal range (31). SH has a prevalence of about 5% with some patients evolving to frank hypothyroidism, although these tend to be the patients who have circulating antibodies to TPO, up to 80% of cases (Evans, C., unpublished observation). Indeed, the onset of autoimmune-mediated hypothyroidism may be more rapid in individuals with a compromised TSHR allele. Opinion is divided over whether to treat or not because SH can be associated with cardiac disease (32) and high serum cholesterol levels have been reported in persons with high-normal serum TSH concentrations (33). Mild to moderate increases in circulating TSH may be a natural compensation mechanism in heterozygous individuals, and mutational analysis could provide an additional diagnostic measure to assist patient management decisions, avoiding unnecessary treatment and promoting appropriate genetic counseling.

In conclusion, we have defined the molecular cause of CH in two brothers and have identified a defective TSHR allele that is present in approximately 0.6% of euthyroid individuals, making it a possible major contributor not only to CH but also to SH in a Caucasian population.


   Footnotes
 
This work was supported by grants from the Wales Office of Research and Development and the UK Medical Research Council.

Abbreviations: CH, Congenital hypothyroidism; NSIS, sodium/iodide symporter; SH, subclinical hypothyroidism; TBAB, thyroid-blocking antibodies; TG, thyroglobulin; TTF 1 and TTF2, thyroid transcription factors 1 and 2; TPO, thyroperoxidase; TSHR, TSH receptor.

Received August 14, 2002.

Accepted November 25, 2002.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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