Printer Friendly

Resistance to thyroid hormone: probable de novo mutation (P453S) in the receptor beta gene/Tiroid hormon rezistansi: reseptor beta geninde muhtemel yeni mutasyon (P453S).


Resistance to thyroid hormone (RTH) is a syndrome characterized by decreased responsiveness of target tissues to the action of thyroid hormone (TH) (1). The common features of RTH include elevated serum TH and normal or slightly increased thyrotropin (TSH) concentrations. The clinical presentation of RTH is variable. The majority of individuals are completely asymptomatic. Some may manifest symptoms suggestive of TH deprivation such as growth retardation, impaired cognitive ability, and learning disabilities, while others show signs of TH excess such as advanced bone age or hyperactivity and tachycardia (1,2). The first case of RTH was reported by Refetoff in 1967 (3). Mosaicism of the TR[beta] gene was described for the first time in a Turkish patient by Mamanasiri as a cause of variable sensitivity to TH in different tissues (4).

RTH is generally transmitted in an autosomal dominant manner, but sporadic, de novo cases are also common (5). RTH is mostly caused by mutations in the thyroid hormone receptor (TR) [beta] gene (6). The mutant TR molecules have either reduced affinity for truodothyronine (T3) or impaired interaction with one of the cofactors involved in the mediation of TH action (1,7). The linkage between RTH and the TR[beta] gene was elucidated in 1988 (8) and the first demonstration of a TR[beta] mutation was in 1989 (9). Thereafter, by using sequencing techniques, approximately 122 different mutations in TR[beta] gene have been identified in subjects with RTH belonging to 300 families (10).

In this study, we described a Turkish family with RTH caused by a single nucleotide change in exon 10 of the TR[beta] gene resulting in the substitution of serine for proline at codon 453 (P453S). This mutation has been identified in 11 other families, 9 of which have been published (11-16).

Materials and Methods


The proband was a 19-year-old male who presented with diffuse goiter, nervousness, and palpitations that have persisted for approximately 5 years. Treatment with propylthiouracil (PTU) was initiated 3 years earlier, assuming that he had a toxic diffuse goiter. He was admitted to the Endocrinology Unit of Suleyman Demirel University with the above mentioned complaints after having ceased the PTU treatment. He weighed 50 kg, his height was 172 cm, blood pressure was 120/80 mmHg, and pulse rate was 96 beats/min. He had a moderate, diffuse goiter and anxious mood. Physical examination was otherwise normal. Laboratory evaluation revealed normal blood count, renal and hepatic function tests and urinalysis.

Thyroid function tests showed a TSH of 1.79 mU/L (normal range 0.4-4.0), a free thyroxine (T4) of 4.4 ng/dl (normal range 0.8-1.8), and a free T3 of 5.6 pg/ml (normal range 1.6-4.6). Magnetic resonance imaging revealed a normal pituitary gland. Administration of L-T3 did not result in the usual TSH suppression. Thyroid function tests of first-degree relatives demonstrated that his father, sister and two brothers had elevated serum TH levels with normal TSH concentrations. The patient and 21 family members underwent laboratory and genetic analysis.


Laboratory analyses

Total T4, 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 and thyroglobulin (TG) were measured by RIAs. FT4 index was estimated by calculating the ratio of T3 resin uptake and the total T4 concentration. Thyroid peroxidase and TG antibodies were measured by an agglutination method.

Genomic DNA was extracted from peripheral blood leukocytes of the proband and 21 family members. Genomic DNA was amplified by the polymerase chain reaction and all coding exons and intron junctions of the TR[beta]1 gene were sequenced using oligonucleotide primers, described previously (12).

A written informed consent was obtained from all subjects for genetic analysis and the study was approved by the local ethics committee. The study was also approved by the Institutional Review Board of the University of Chicago.


We identified the same mutation in one allele of the TR[beta] gene in the proband (subject III-3 in Figure 1), his two brothers (III-5 and III-6) and father (II-8). It involves the substitution of the normal cytosine 1642 with a thymidine. This results in the replacement of the normal proline 453 with a serine (P453S) in the T3-binding domain of the TR[beta]. All four subjects harbouring the mutation exhibited the typical phenotype of RTH including increase in the concentration of all iodothyronines (T4, T3 and rT3), normal or slightly elevated TSH and, with the exception of subject III-5, high serum TG concentration. The mild increase in FT41 and rT3 concentrations of subject II-5 is compatible with the use of L-T4. We have no explanation for the slight increase of rT3 in subjects II-7 and III-1, and for the slight reduction of TSH in subject II-13. Four individuals had autoimmune thyroid disease based on the detection of thyroperoxidase antibodies (see Fig. 1). None of the 6 sibling of the affected father (II-1-7), nor the paternal grandfather (I-1), or 8 nephews and nieces of the deceased paternal grandmother of the proband (II-10-17) expressed the RTH phenotype. Thus, it is likely that the father has a de novo TR[beta] gene mutation.


RTH is characterized by elevated serum levels of TH and normal or slightly increased serum TSH concentration that responds to TRH (17). Although the precise incidence of RTH is unknown, a limited neonatal survey estimated an incidence of 1 case per 40.000-50.000 live births (18). While most thyroid diseases show a female preponderance, RTH occurs in males and females with equal frequency (17). Familial occurrence of RTH has been documented in approximately 75% of cases. Inheritance is autosomal dominant, with the exception of the RTH caused by complete deletion of the protein-coding of the TR[beta] gene, which had autosomal recessive inheritance (19).

Before TR gene defects were recognized, patients with RTH were clinically classified as having generalized resistance to TH (GRTH) and selective pituitary resistance to TH (PRTH), based principally on symptoms and signs. Those with GRTH appeared to be eumetabolic and those with PRTH, hypermetabolic, based on restlessness and tachycardia. However, it has been suggested that PRTH may not constitute an entity distinct from GRTH (20). In fact, the clinical manifestations are variable among the families with RTH and also among the affected family members. Furthermore, one and the same subject with RTH may exhibit symptoms and signs of hypothyroidism in one tissue, while in another tissue, findings may be suggestive of thyrotoxicosis. This situation results from the dissimilar distribution of TR isoforms among tissues. For example, TRx is expressed predominantly in the heart, bone and brain, whereas TR[beta] is more abundant in the liver and kidney (22).

At least three different molecular alterations may cause reduced sensitivity to TH in humans: (a) mutations in the gene encoding TR[beta] isoform causing RTH, (b) mutations of the specific TH transporter, monocarboxylate transporter 8 (MCT8), and (c) mutations in selenocysteine insertion sequence binding protein 2 (SECISBP2) which reduces the synthesis of selenoproteins, including the TH deiodinases (22).

Approximately 85% of subjects with RTH, studied at the gene level, have mutations in the TR[beta] gene, located on chromosome 3. The TR[beta] molecule contains a DNA-binding domain, a hinge region, and a ligand (T3)-binding domain. Mutations are located in the T3-binding domain and its adjacent hinge region. Most are single amino acid substitutions with fewer single amino acid insertions or deletions and even less large deletions. Almost all mutations cluster around the ligand-binding pocket observed in the ligand-binding domain of the TR[beta] crystal structure (1,23). 122 different mutations have been so far identified in approximately 300 families (10). We identified a mutation in one allele of the TR[beta] gene of the proband, his two brothers and father. The single nucleotide substitution resulted in the replacement of the normal proline 453 with a serine (P453S) in the T3-binding domain of the TR[beta]. This identical mutation was reported in 9 other families (11-16 and personal observations) and shown to have a reduced affinity to T3, being 25 to 36% of the normal one (12,14). In three families the mutations had occurred de novo. It should be noted that the mutation occurs in a cytosine-rich region (5 consecutive cytosines) which has been shown to be prone to mutations (24). Although the paternal grandmother could not be tested, because she was deceased, based on the fact that 6 of 7 siblings of the father and 8 nephews of the paternal grandmother had no TR[beta] gene mutation, it is likely that the mutation also occurred de novo in the father of the proband. Familial occurrence of RTH has been documented in approximately 75% of cases. Taking into account only those families in whom both parents of the affected subjects have been studied, the true incidence of sporadic cases is 21.3%. This is in agreement with current estimate of the frequency of de novo mutations of 22.5% (10).

In addition, the same codon has been found to harbour five different mutations other than P453S: in 7 families-P453A (12,16,25-28 and personal observations), 16 families-P453T (12,16, 29-36 and personal observations), 1 family-P453N (personal observation), 1 family-P453Y (16), and 3 families-P453N (11,31,37). RTH is rarely diagnosed at birth as neonatal screening programs are most often based on the determination of TSH concentration in dried blood. Screening programs that measure both TSH and T4, and using an assay reliable in the high T4 range, would rarely identify a case at birth. However, children of women with known TR[beta] gene mutations should be tested either prenatally or at birth.


This work was supported in part by grants DK15070 and RR04999 from the National Institutes of Health USA.

Recevied: 04.10.2009 Accepted: 04.10.2009


(1.) Refetoff S, Weiss RE, Usala SJ. The Syndromes of Resistance to Thyroid Hormone. Endocrine Reviews 1993;14: 348-399.

(2.) Chatterjee VK. Resistance to thyroid hormone. Norm Res 1997; 48: 43-46.

(3.) Refetoff S, DeWind LT, DeGroot U. Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 1967; 27: 279-294.

(4.) Mamanasiri S, Yesil S, Dumitrescu AM, Liao XH, Demir T, Weiss RE, Refetoff S. Mosaicism of a Thyroid Hormone Receptor (TR) Beta Gene Mutation in Resistance to Thyroid Hormone (RTH). J Clin Endocrinol Metab 2006; 91: 3471-3477.

(5.) Brucker-Davis F, Skarulis MC, Grace MB, Benichou J, Hauser P, Wiggs E, Weintraub BD. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study. Ann Intern Med 1995;123: 572-583.

(6.) Weiss RE, Hayashi Y, Nagaya T, Petty KJ, Murata Y, Tunca H, Seo H, Refetoff S. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor. J Clin Endocrinol Metab 1996; 81: 4196-4203.

(7.) Liu Y, Takeshita A, Misiti S, Chin WW, Yen PM. Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors. Endocrinology 1998;139: 4197-4204.

(8.) Usala SJ, Bale AE, Gesundheit N, Weinberger C, Lash RW, Wondisford FE, McBride OW, Weintraub BD. Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene. Mol Endocrinol 1988; 2:1217-1220.

(9.) Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, Bell GI, Refetoff S, DeGroot LJ. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor b. Proc Natl Acad Sci (USA)1989; 86: 8977-8981.

(10.) Refetoff S. Resistance to thyroid hormone. In Werner and Ingbar's The Thyroid: a fundamental and clinical text 9th edition (Ed: Braverman LE, Utiger REI. Philadelphia, Lippincott, Williams and Wilkins, 2005; 1109-1129.

(11.) Takeda K, Weiss RE, Refetoff S. Rapid localization of mutations in the thyroid hormone receptor-[beta] gene by denaturing gradient gel electrophoresis in 18 families with thyroid hormone resistance. J Clin Endocrinol Metab 1992; 74: 712-719.

(12.) Adams M, Matthews C, Collingwood TN, Tone Y, Beck-Peccoz P, Chatterjee KK. Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone: identification of thirteen novel mutations in the thyroid hormone receptor [beta] gene. J Clin Invest 1994; 94: 506-515.

(13.) Refetoff S, Weiss RE, Wing JR, Sarne D, Chyna B, Hayashi Y. Resistance to thyroid hormone in subjects from two unrelated families is associated with a point mutation in the thyroid hormone receptor [beta] gene resulting in the replacement of the normal proline 453 with serine. Thyroid 1994; 4: 249-254.

(14.) Ozata M, Suzuki S, Takeda T, Malkin DG, Miyamoto T, Liu R-T, Suzuki N, Silverberg JDH, Daneman D, DeGroot U. Functional analysis of a proline to serine mutation in codon 453 of the thyroid hormone receptor [beta]1 gene. J. Clin Endocrinol Metab 1995; 80: 3239-3245.

(15.) Yun YS, Hong SK, Ahn CW, Nam JH, Park SW, Cha BS, Song YD, Lee EJ, Lim SK, Kim KR, Lee HC, Huh KB. Mutations in thyroid hormone receptor-[beta] associated with patients with generalized resistance and pituitary resistance to thyroid hormone. Journal of Korean Society of Endocrinology 2000;15:113-120.

(16.) Margotat A, Sarkissian G, Malezet-Desmoulins C, Peyrol N, Vlaeminck Guillem V, Wemeau JL, Torresani J. Identification de huit mutations dans le gene c-erbA[beta] chez des patients atteints de resistance aux hormones thyroidiennes. [Identification of eight new mutations in the c-erbAB gene of patients with resistance to thyroid hormone]. Ann Endocrinol 2001; 62: 220-225.

(17.) Weiss RE, Refetoff S. Resistance to thyroid hormone. Rev Endocr Metab Disord 2000;1: 97-108.

(18.) Lafranchi SH, Snyder DB, Sesser DE, Skeels MR, Singh N et al. Follow-up of newborns with elevated screening T4 concentrations. J Pediatr 2003; 143: 296-301.

(19.) Takeda K, Sakurai A, DeGroot U, Refetoff S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-beta gene. J Clin Endocrinol Metab 1992; 74:49-55.

(20.) Beck-Peccoz P, Chatterjee VK. The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 1994; 4: 225-232.

(21.) Cheng SY. Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance. Trends in Endocrinology and Metabolism 2005;16:176-182.

(22.) Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007; 21: 277-305.

(23.) Yen PM. Physiological and Molecular Basis of Thyroid Hormone Action. Physiological Reviews 2001; 81:1097-1142.

(24.) Weiss RE, Weinberg M, Refetoff S. Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene: Analysis of 15 families. J Clin Invest 1993; 91: 2408-2415.

(25.) Aksoy DY, Gurlek A, Ringkananont U, Weiss RE, Refetoff S. Resistance to thyroid hormone associated with autoimmune thyroid disease in a Turkish family. J Endocrinol Invest 2005; 28: 379-383.

(26.) Liu Y, Takeshita A, Misiti S, Chin WW, Yen PM. Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors. Endocrinology 1998;139: 4197-4204.

(27.) Florkowski CM, Brownlie BE, Croxson MS, Manning P, Farrand S, Smith G, Potter HC, George PM. Thyroid hormone resistance: the role of mutational analysis. Intern Med 2006; 36: 738-741.

(28.) Bayraktaroglu T, Noel J, Alagol F, Colak N, Mukaddes NM, Refetoff S. Thyroid hormone receptor beta gene mutation (P453A) in a family producing resistance to thyroid hormone. Exp Clin Endocrinol Diabetes 2009;117:34-37.

(29.) Parrilla R, Mixson AJ, McPherson JA, McClaskey JH, Weintraub BD. Characterization of seven novel mutations of the c-erbA[beta] gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain. J. Clin. Invest 1991; 88: 2123-2130.

(30.) Shuto Y, Wakabayashi I, Amuro N, Minami S, Okazaki T. A point mutation in the 3,5,3'-truodothyronine-binding domain of thyroid hormone receptor [beta] associated with a family with generalized resistance to thyroid hormone. J Clin Endocrinol Metab 1992; 75: 213-217.

(31.) Reinhardt W, Jockenhovel F, Deuble J, Chatterjee VKK, Reinwein D, Mann K. Thyroid hormone resistance: variable clinical manifestations in five patients. Nuklearmedizin 1997; 36: 250-255.

(32.) Ishay A, Dumitrescu A, Luboshitzky R, Rakover Y, Refetoff S. A New Case of Resistance to Thyroid Hormone Caused by a De Novo P453T Mutation in the Thyroid Hormone Receptor Gene in an Israeli Child. Thyroid 2003; 13: 409-412.

(33.) Rivolta CM, Feijoo MC, Targovnik HM, Funes A. Identification de una transversion heterocigota 1337C>A (P453T) en el exon 10 del gen del receptor de hormonas tiroideas [beta] en una familia con resistencia a hormonas tiroideas. Rev Arg Endocinol Metab 2003; 40:13-22.

(34.) Wu SY, Sadow PM, Refetoff S, Weiss RE. Tissue responses to thyroid hormone in a kindred with resistance to thyroid hormone harboring a commonly occurring mutation in the thyroid hormone receptor beta gene (P453T). J Lab Clin Med 2005;146: 85-94.

(35.) Sato H, Sakai H. A Family Showing Resistance to Thyroid Hormone Associated with Chronic Thyroiditis and its Clinical Features: A Case Report. Endocr J 2006; 53: 421-425.

(36.) Magalhaes PK, Rodrigues Dare GL, Rodrigues Dos Santos S, Nogueira CR, de Castro M, Zanini Maciel LM. Clinical features and genetic analysis of four Brazilian kindreds with resistance to thyroid hormone. Clin Endocrinol 2007; 67: 748-753.

(37.) Collingwood TN, Adams M, Tone Y, Chatterjee VKK. Spectrum of transcriptional, dimerization, and dominant negative properties of twenty different mutant thyroid hormone [beta]-receptors in thyroid hormone resistance syndrome. Mol. Endocrinol 1994; 8:1262-1277.

Banu Kale Koroglu, Sunee Mamanasiry *, Adem Kucuk **, Mehmet Numan Tamer, Ramazan Yilmaz ***, Samuel Refetoff

Suleyman Demirel University, Department of Endocrinology and Metabolism, Isparta, Turkey

* University of Chicago, Department of Medicine, Chicago, USA

** Suleyman Demirel University, Department of Internal Medicine, Isparta, Turkey

*** Suleyman Demirel University, Department of Medical Biology, Isparta, Turkey B.K.K. and S.M. should be considered co-first authors.

Address for Correspondence: Banu Kale Koroglu, MD, Suleyman Demirel University, Department of Endocrinology and Metabolism, Isparta, Turkey Phone: +90 246 211 26 00 Fax: +90 246 237 02 40 E-mail:
COPYRIGHT 2009 Galenos Yayincilik
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2009 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Original Article/Orijinal Makale
Author:Koroglu, Banu Kale; Mamanasiry, Sunee; Kucuk, Adem; Tamer, Mehmet Numan; Yilmaz, Ramazan; Refetoff,
Publication:Turkish Journal of Endocrinology and Metabolism
Article Type:Report
Geographic Code:7TURK
Date:Sep 1, 2009
Previous Article:Melkersson-Rosenthal syndrome and Hashimoto's thyroiditis: a case report/Melkersson-Rosenthal sendromu ve Hashimoto tiroidit'li bir olgu.
Next Article:Comparison of papillary thyroid microcarcinoma and carcinoma/Papiller tiroid mikrokarsinom ve karsinomun karsilastirilmasi.

Terms of use | Copyright © 2018 Farlex, Inc. | Feedback | For webmasters