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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0727
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 9 3471-3477
Copyright © 2006 by The Endocrine Society

Mosaicism of a Thyroid Hormone Receptor-ß Gene Mutation in Resistance to Thyroid Hormone

Sunee Mamanasiri, Sena Yesil, Alexandra M. Dumitrescu, Xiao-Hui Liao, Tevfik Demir, Roy E. Weiss and Samuel Refetoff

Departments of Medicine (S.M., A.M.D., X.-H.L., R.E.W., S.R.) and Pediatrics (S.R.) and Committees on Genetics (S.R.) and Molecular Medicine (S.R., R.E.W.), The University of Chicago, Chicago, Illinois 60637; and Division of Endocrinology (S.Y., T.D.), Dokuz Eylül University, TR-35240 Izmir, Turkey

Address all correspondence and requests for reprints to: Samuel Refetoff, University of Chicago, MC 3090, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}uchicago.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Heterozygous mutations in thyroid hormone receptor-ß (TRß) gene are the cause of resistance to thyroid hormone (RTH) in more than 85% of families having the syndrome. In 23% of the families, TRß gene mutations occur de novo. Of the 141 families with RTH investigated by us, 21 (15%) had no TRß gene mutations detectable by sequencing from genomic DNA (gDNA) or cDNA (non-TR RTH).

Objective: The objective of the study was to investigate the genotype of a family with RTH and correlate it to the phenotype.

Design: The DNA was isolated from different tissues, and the sequence of the TRß gene was determined. Clinical studies involved the administration of incremental doses of T3.

Setting: The study was conducted at a referral pediatric endocrinology clinic in Turkey and an academic medical center in the United States.

Main Outcome and Measures: Measurement included markers of thyroid hormone action and sequencing of TRß revealing a R338W mutation.

Patients and Family: We studied two siblings with short stature, panic disorder, psychosis, and high free iodothyronine concentrations with nonsuppressed TSH and their father with similar thyroid function tests without growth or psychiatric abnormalities.

Results: Direct sequencing of gDNA obtained from the father’s leukocytes, buccal mucosa cells, and prostate tissue showed less amplification of the mutant allele (R338W) than the normal allele as confirmed by PCR/restriction fragment length polymorphism analysis. No sequence abnormalities were detected in gDNA from fibroblasts. Similar results were found in mRNA from the leukocytes and fibroblasts. The sensitivity of various tissues to thyroid hormone was not uniform. The progeny had equal amounts of mutant and wild-type gDNA in leukocytes and skin.

Conclusions: The father has a mosaicism for the R338W mutation as it was present in some cell lineages, including his germline, because it was transferred to his children but not in fibroblasts. This indicates that the mutation occurred de novo in early embryonic life. Here is the first report of mosaicism in RTH. The possibility of mosaicism should be considered in subjects with RTH without apparent mutations in the TRß gene.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RESISTANCE TO thyroid hormone (RTH), first described by Refetoff et al. in 1967 (1), is a syndrome of reduced responsiveness of target tissues to thyroid hormone (2). Clinically these patients are identified by their persistent elevation of circulating free T4 (FT4) and free T3 levels with persistent normal or slightly elevated serum TSH. The phenotype is heterogeneous. The most common clinical findings are goiter, learning disabilities with or without hyperactive behavior, developmental delay, and sinus tachycardia (2, 3, 4, 5). The variability in clinical manifestations may be due to the severity of the hormonal resistance, effectiveness of compensatory mechanisms, modulating genetic factors, and effects of prior therapy (2, 5, 6).

Linkage between RTH and the thyroid hormone receptor (TR)-ß gene was shown in 1988 (7). Since then, more than 300 families with the RTH phenotype have been found to harbor mutations in that gene (2). RTH is usually transmitted in an autosomal dominant fashion, but de novo cases are common, and recessive inheritance is rare (8). In our laboratory de novo mutations occurred in 22.5% of the 120 families in which TRß gene mutations were excluded in the parents of an affected individual (2); 44.4% of the de novo mutations occurred in mutagenic CpG dinucleotide hot spots. The mutant TRß molecules have either a reduced affinity for T3 (6, 9) or impaired interaction with one of the cofactors involved in the mediation of thyroid hormone action (10, 11).

However, RTH can occur in the absence of mutations in the TR{alpha} or TRß gene and is referred to as non-TR RTH. Since the first demonstration of non-TR RTH (12), 29 subjects belonging to 23 different families have been identified (2, 13, 14, 15). The phenotype is indistinguishable from that in subjects harboring TRß gene mutations. Distinct features are an increased female to male ratio of 2.5:1 and the high prevalence of sporadic cases (2, 13). In only three families had linkage analysis excluded the involvement of the TRß gene (12, 16).

Although not previously reported, the variable presence of a TRß mutation in certain tissues may present as non-TR RTH, depending on the tissue analyzed for the TRß mutation in a subject with RTH. We report for the first time the occurrence of mosaicism in RTH that might be misdiagnosed as non-TR RTH. The affected individual had variable tissue expression of the de novo TRß gene mutation, R338W, which was transmitted to his children.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The proposita (II.1), a 36-yr-old Turkish woman, presented with a multinodular goiter, short stature (144 cm), and a depressive disorder. She had serum free T3 of 5.83 pg/ml (1.57–4.71), FT4 of 4.23 ng/dl (0.8–1.9), and TSH of 1.21 µIU/ml (0.4–5), increased thyroidal radioiodide uptake of 52.5% at 24 h, but positive thyroid peroxidase (TPO) and thyroglobulin (TG) antibodies, and normal pituitary magnetic resonance imaging. Her 32-yr-old brother (II.2) was agitated and had evidence of psychosis. He had similar abnormal thyroid function tests (TFTs) and antibodies. Blood samples were obtained from all family members. We found that the father (I.1) also had abnormal TFTs (Fig. 1Go), whereas the mother (I.2) had only positive TPO and TG antibodies. The father had normal growth and no psychological problems. Informed consents were obtained for this study approved by the Institutional Review Board of the University of Chicago.


Figure 1
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  		FIG. 1. Pedigree of the family and results of thyroid function tests. AITD, Autoimmune thyroid disease. Proposita, arrow. Conversion to SI: TT4 (nanomoles per liter) and FT4I, multiply by 12.84; total T3 (TT3) and TrT3 (nanomoles per liter), multiply by 0.0154.

 
Measurement of hormones in serum

Total thyroxine (TT4), total T3, and TSH were measured by chemiluminescence using Elecsys 2010 technology (Roche Molecular Biochemicals GmbH and Hitachi, Ltd., both located in Indianapolis, IN). Total reverse T3 (TrT3) and TG were measured by RIAs. FT4 index (FT4I) was estimated from the resin T4 uptake ratio and the TT4 concentrations. TPO and TG antibodies were measured by an agglutination method.

Clinical studies

To assess the sensitivity of various tissues to thyroid hormone, the father was given incremental doses of L-T3 (50, 100, and 200 µg/d, each for 3 consecutive days). L-T3 was administered orally as a split dose, every 12 h, for a total of six doses per incremental dose (3). Just before beginning the study and 12 h after the last of each incremental dose, blood was drawn for the determination of the hormonal measurements described above as well as for the measurement of serum cholesterol, creatine kinase (CK), ferritin, and SHBG. In addition, body weight and resting pulse rate were recorded. Fifteen healthy volunteers served as controls.

Sequencing of the TRß gene

Genomic DNA (gDNA) was extracted from peripheral blood lymphocytes (PBLs) of the proposita and members of her family. A second blood sample was drawn from the father. In addition, primary cultures of fibroblasts were generated from skin punch biopsies obtained from the proposita and her father. Additional tissues examined were buccal mucosa cells and prostate tissue obtained for diagnostic purposes unrelated to this study. Total RNA was extracted from skin of proposita, her father’s PBLs, and cultured skin fibroblasts (17).

All coding exons of the TRß gene were sequenced from gDNA extracted from PBLs and using primers and conditions described previously (9, 16). The oligonucleotide primers used for amplification and sequencing of the two exons containing nucleotide substitutions were as follows. For exon 4 of the TRß1 gene, primers were 5'-GCCTTCGAAAACTCTGCATCTCA-3' (sense) and 5'-CTTGTTGAAACACAT GATAATGGGCTA-3' (antisense) at 55 C annealing temperature, and those for exon 9 were 5'-CTGTATGTTGTTCCTGACTGGCAT-3' (sense) and 5'-GTGATTGGAATTAGCGCTAG ACAAGCA-3' (antisense) at 59 C annealing temperature. PCR products were confirmed by direct sequencing using ABI PRISM BigDye terminator cycle sequencing reading reaction kits (Applied Biosystem, Foster City, CA).

cDNA was prepared by reverse transcription of mRNA with the Superscript III first-strand synthesis system for RT-PCR (Life Technologies/Invitrogen, Carlsbad, CA) and random hexamers to sequence exons 9–10 of the TRß gene. The primers for amplification and sequencing were 5'-ACCAGATCATCCTCCTCAAAGG-3' (sense) and 5'-TGAATCCAGTCAGTCTAATCCTCG-3' (antisense). Annealing was at 58 C for 1 min and extension at 72 C for 1 min for each of the 35 cycles.

Genotyping

The mutation was confirmed in gDNA and cDNA by restriction fragment length polymorphism (RFLP) using the restriction endonuclease NlaIII (New England Biolabs, Beverly, MA), which cleaves only the mutant sequences at the site of the nucleotide substitution. The primers, 5'-GTGCGCTATGACCCAGAAAG-3' (sense) and 5'-AGGAGGGCTA CTTCAGTGTC-3' (antisense), amplify a 164-bp segment of exon 9 at 56 C annealing temperature. cDNA was amplified by a two-step PCR. The product of a first PCR amplification using primers located in exons 9 and 10 was used as template for a second PCR to amplify the 164-bp fragment of exon 9 as described above.

The sizes of fragments after restriction with NlaIII were 61, 55, and 48 bp for the mutant allele and 116 and 48 bp for the wild-type (WT) allele. Fragments were well separated on a 16% nondenaturing polyacrylamide gel at 100 V for 1 h.

To determine the relative amounts of mutant and WT alleles, ethidium bromide-strained gels were scanned, and the density of the respective bands was measured using Image J, version 1.34 S (Rasband, W. S., Image J, U.S. National Institutes of Health, Bethesda, MD, http://rsb.info.nih.gov/ij/ (18). Because the mutant allele generated two closely migrating bands, the combined densities were divided by two and corrected for molecular size (x 0.83). The total amount of combined mutant and WT alleles is represented by the density of the 48-kb band (see Fig. 5Go). Results are expressed as percentage of the mutant allele relative to the WT allele in heterozygous subjects.


Figure 5
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  		FIG. 5. Genotyping by PCR-based RFLP analysis. All PCR products were 164 bp in size. After digestion with NlaIII, the WT allele produces two fragments of 116 and 48 bp and the mutant allele, three fragments of 61, 55, and 48 bp. cDNA isolated from PBLs of the affected father (I.1) and gDNA isolated from PBLs, and prostate tissue of the affected father have faint mutant 61- and 55-bp bands.

 
Haplotyping

All family members were assigned the TRß1 allele haplotypes using a PCR-based silent substitution of nucleotide 461 (TCG->TCA, S54S), which was found in the affected father. The products of PCR amplification using primers for exon 4, as described above, were determined by sequencing.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical studies

We measured serum TSH at baseline and after administration of incremental doses of L-T3 to the father and 15 normal individuals. Serum TSH level of the father at baseline was 1.3 µU/ml. L-T3 doses of 50, 100, and 200 µg/d suppressed TSH to 46.2, 15.4, and 7.7%, respectively, whereas in control subjects TSH was suppressed to means ± SD of 9.6 ± 4.4, 3.6 ± 1.9, and 2.5 ± 1.7% of baseline (Fig. 2Go). Thus, response of the pituitary thyrotrophs to L-T3 in the father was reduced, compared with the normal subjects.


Figure 2
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  		FIG. 2. Response of the pituitary thyrotrophs to L-T3. The father was given three incremental doses of L-T3, each for 3 consecutive days, as described in Subjects and Methods. The serum levels of T3 achieved were as expected, as was the reduction of FT4I. However, the suppression of TSH was much less pronounced than normal. Dot symbols indicate mean responses of control subjects and bars ± SD. The asterisk is the value observed in the father. Encircled asterisk indicates abnormal response.

 
The sensitivity of peripheral tissues to thyroid hormone was also assessed using the serum cholesterol, CK, ferritin, and SHBG as markers. The responses of the father’s peripheral tissues were not uniform. The stimulation of SHBG and suppression of cholesterol and CK were not different from those of control subjects, whereas ferritin failed to normally respond to L-T3 (Fig. 3Go). His resting pulse increased from 68 to 84 beats/min, whereas his weight declined by 1.5 kg (from 60.0 to 58.5 kg), both normal responses to the hormone (3).


Figure 3
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  		FIG. 3. Response of peripheral tissues of the father to the administration of L-T3, as described in the legend to Fig. 2Go. Responses of SHBG, cholesterol, and CK were in the normal range, whereas ferritin increase was attenuated. Different dot symbols indicate mean responses of control subjects and bars ± SD. The asterisk is the value observed in the father. Encircled asterisk indicates abnormal response.

 
Genetic studies

We identified in the proposita (II.1) and her brother (II.2) a heterozygous mutation at codon 338 (nucleotide 1297 CGG->TGG), located in exon 9 of the TRß gene, which results in the replacement of the normal arginine with tryptophan (R338W). Sequencing of gDNA extracted from PBL of her affected father (I.1) showed a reduced amplification of the mutant allele, compared with the normal allele (Fig. 4Go). We obtained a second blood sample and additional tissues from the affected father. These included buccal mucosa cells, prostate tissue, and skin fibroblasts. gDNA extracted from the second blood sample, buccal mucosa, and prostate tissue showed the same results, namely low amounts of the mutant allele relative to the WT allele. However, no sequence abnormalities in exon 9 of TRß gene were detected in gDNA isolated from skin fibroblasts. Findings were similar in cDNA derived from the respective tissues. As shown in Fig. 4Go, both TRß gene alleles of the proposita’s mother (I.2) were WT.


Figure 4
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  		FIG. 4. Sense and antisense sequences of the WT R388 (CGG) and mutant 338W (TGG) alleles. The tissue of origin for the shown sequences is underlined. Similar patterns were observed in gDNA and cDNA sequence of the listed tissues but not underlined. The proposita (II.1) and her affected bother (II.2) are heterozygous, whereas their mother (I.2) is normal; gDNA and cDNA isolated from the affected father (I.1) cultured skin fibroblasts are also normal. gDNA and cDNA isolated from PBLs and gDNA from prostate tissue and buccal mucosa of the father have a T in position 1297, but the peak height is substantially lower than that in his children.

 
The PCR/RFLP method was also used to identify the mutant allele in members of the family (Fig. 5Go). The mutation CGG->TGG in codon 338 creates an additional restriction site (61 and 55 bp) for NlaIII. gDNA extracted from PBLs and cDNA isolated from skin biopsy of the proposita showed the expected additional fragment, whereas these were absent in her mother’s gDNA. Similarly gDNA and cDNA isolated from cultured skin fibroblasts of the affected father had only the WT allele. In contrast, gDNA extracted from blood sampled on different occasions, from prostate tissue as well as cDNA isolated from second blood sample of the father showed a weak, though detectable, fragment generated by NlaIII. The average amount of the mutant allele in gDNA of the father extracted from PBL was 8.6%, and that from prostate was 3.9%, compared with 50% of WT in PBLs of the proposita.

To determine the transmission of the mutation to the proposita and her affected brother, family members were haplotyped for a silent substitution of nucleotide 461 (TCG->TCA, S54S) present in the father. As shown in Fig. 6Go, both the proposita and her brother inherited the mutant TRß1 allele from their father. Although samples from the parents of the affected father were not available because they were deceased, we could deduce that the mutation occurred de novo in the father during early embryonic life because it was present in some but not all lineages of somatic cells and in the germline (Table 1Go).


Figure 6
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  		FIG. 6. Haplotyping of family members. Haplotypes are shown below each symbol of the pedigree, and identical alleles have the same shading. The affected father (I.1) and his children (II.1 and II.2) share the same mutant allele. The de novo mutation occurred on the paternal allele harboring the nucleotide 461A silent mutation.

 

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  		TABLE 1. Relative abundance of the mutant allele in gDNA and cDNA of different tissues in members of the family

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We studied a Turkish family with RTH. The proposita and her brother had TFTs characteristic of RTH, short stature, and psychiatric symptoms. The father had similar TFTs but no growth or psychiatric disturbances. The mother had a normal phenotype and TFTs. In the two siblings, we identified mutant TRß gene, R338W, previously reported (5, 9, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28). However, gDNA extracted from the father’s two different PBL preparations, buccal mucosa, and prostate tissue showed a lesser amount of the mutant, compared with the normal allele. More importantly, no sequence abnormalities were detected in gDNA isolated from skin fibroblasts. This was evident in cDNA obtained from the respective tissues and was also demonstrated by PCR/RFLP in both gDNA and cDNA.

These results demonstrate that the father has a mosaicism for the mutant TRß R338W because it was present in some lineages of somatic cells but not in skin fibroblasts. The transmission of the mutation to his children proves that it is also present in his germline, indicating that the mutation occurred de novo in his early embryonic life. The mutation R338W (CGG->TGG) has been identified in 25 different families (5, 9, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and unpublished data from our laboratory). This DNA site is likely to be prone to de novo mutation (eight of 25 families) because of its location in a mutagenic CpG dinucleotide hot spot (29). The presence of a single nucleotide difference (G/A 461) in the father, which was also found in his children, demonstrates that it was the paternal allele that underwent the R338W mutation.

The clinical presentation of RTH and the severity of hormone resistance are highly variable. The possibility of variable levels of expression of the mutant allele relative to the normal counterpart has been explored, but results have been inconsistent (30, 31). Somatic mutations in the TRß gene have been reported only in TSH-secreting pituitary tumors presenting as TSH-induced thyrotoxicosis (32, 33). As expected, our clinical studies showed that mosaicism resulted in a variable degree of RTH in different tissues. The thyrotrophs were resistant to thyroid hormone as evidenced by the reduced suppressibility of TSH by L-T3. Failure of ferritin to respond to L-T3 suggests hormonal resistance in red blood cells, spleen, and other tissues that regulate serum ferritin levels. In contrast, the normal responses of SHBG, cholesterol, and CK to L-T3 suggest that the hepatocytes express predominantly the WT-TRß. These results also provide an explanation for the difference in the father’s clinical manifestation, compared to his two children.

Potential mechanisms of non-TR-mediated RTH involve abnormalities at all steps in the mediation of thyroid hormone action (34). Defects in the thyroid hormone transporter MCT8 have been recently identified, but they do not produce a phenotype of RTH (35, 36). Another thyroid hormone transporter, LST-1, was not linked to the RTH phenotype in three families with non-TR RTH studied (Macchia, P. E., R. E. Weiss, and S. Refetoff, unpublished data). Aberrant alternative splicing was the defect causing pituitary RTH in one somatic TRß gene mutation (33). Mutations in the promoter of the TRß gene could reduce the level of gene expression; however, such a defect will produce RTH only in the homozygous state because subjects heterozygous for TRß gene deletion do not manifest RTH (8). Finally, based on mouse models of RTH (37, 38), search for mutations of coregulators in subjects with non-TR RTH have yielded negative results (39). Mosaicism has been reported in a small number of autosomal dominant disorders including pseudoachondroplasia (40), tuberous sclerosis (41), retinoblastoma (42), neurofibromatosis type 2 (43), familial isolated hyperparathyroidism (44), familial hypocalcemia (45), Albright hereditary osteodystrophy (46), and monogenic diabetes mellitus (47). The mosaicism rate for autosomal disorders is 6–19% (48). Thus, it is reasonable to speculate that TRß gene mutations could have been missed in some patients reported as having non-TR RTH. Often the degree of mosaicism is different among tissues, and the mutation might not be present in the tissue examined. Linkage analysis is also prone to miss the possibility of mosaicism because this method is based on allele inheritance and germline transmission (43, 44). Thus, this is of particular concern in disorders that are frequently sporadic and have increased rates of de novo mutations (49).

Our findings in this family are pertinent to RTH studies because they point to an issue not previously considered in patients with RTH in whom a mutation in TRß is not detected. Therefore, the examination of several different tissues should be considered in cases of putative non-TR RTH.


   Footnotes
 
This work was supported by Grants RR00055, RR18372, DK58281, DK17050, and DK20595 from the National Institutes of Health; a Ratchaburi Hospital Scholarship, Ratchaburi, Thailand (to S.M.); and a Howard Hughes Medical Institute Predoctoral Fellowship (to A.M.D.).

S.R. is Academic Associate for Quest Diagnostics (San Juan Capistrano, CA).

First Published Online June 27, 2006

Abbreviations: CK, Creatine kinase; FT4, free T4; FT4I, FT4 index; gDNA, genomic DNA; PBL, peripheral blood lymphocyte; RFLP, restriction fragment length polymorphism; RTH, resistance to thyroid hormone; TFT, thyroid function test; TG, thyroglobulin; TPO, thyroid peroxidase; TR, thyroid hormone receptor; TrT3, total reverse T3; TT4, total thyroxine; WT, wild type.

Received April 4, 2006.

Accepted June 16, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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N K Agrawal, R Goyal, A Rastogi, D Naik, and S K Singh
Thyroid hormone resistance
Postgrad. Med. J., September 1, 2008; 84(995): 473 - 477.
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