OMIM Entry - *190160 - THYROID HORMONE RECEPTOR, BETA; THRB

*190160

THYROID HORMONE RECEPTOR, BETA; THRB

Alternative titles; symbols

V-ERB-A AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG 2; ERBA2
ONCOGENE ERBA2
ERBA-BETA

HGNC Approved Gene Symbol: THRB

Cytogenetic location: 3p24.2 Genomic coordinates (GRCh37): 3:24,158,643 - 24,536,312 (from NCBI)

Gene Phenotype Relationships

Location	Phenotype	Phenotype MIM number
3p24.2	Thyroid hormone resistance	188570
	Thyroid hormone resistance, autosomal recessive	274300
	Thyroid hormone resistance, selective pituitary	145650

TEXT

Cloning

Jansson et al. (1983) cloned the human ERBA2 gene.

Weinberger et al. (1986) reported that the deduced THRB protein contains 450 amino acids. However, subsequent sequencing of the THRB cDNA and genomic clones predicted a 461-amino acid protein (Sakurai et al., 1990)

Evans (1988) reviewed the molecular biology and physiology of the thyroid hormone receptor superfamily.

Nomenclature

Lazar and Chin (1990) reviewed nuclear thyroid hormone receptors and noted the possible confusion of nomenclature. They stated that the so-called placental thyroid hormone receptor encoded by human chromosome 3 is the prototype beta form; its gene is referred to as ERBA2 or THRB. Isoform beta-1 is found in liver, heart, and brain; isoform beta-2 is specific for pituitary in the mouse and rat. The thyroid hormone alpha-1 receptor (ERBA1 or THRA, 190120) is encoded by a gene on human chromosome 17. Alternative splicing of the gene transcript yields a species called alpha-2 or variant I, which is identical to alpha-1 for 370 amino acids, including the DNA-binding domain, but then diverges completely. The mRNA for this form is particularly abundant in the brain.

Mapping

Thompson et al. (1987) presented evidence for the existence of at least 2 human thyroid hormone receptors. They noted that the receptor that is expressed in the mammalian central nervous system and in most other tissues except liver is encoded by a gene on chromosome 17 (THRA; 190120). The receptor that is present in liver and some other tissues is encoded by a gene on chromosome 3 (THRB).

By Southern blot analysis of DNA from somatic cell hybrids and in situ hybridization using the same human genomic probe, Rider et al. (1987) concluded that ERBA2 is located in the region 3pter-p21, rather than on chromosome 17 as previously held. Malignant lymphomas and salivary gland tumors consistent with chromosomal changes in that region have been observed.

Dobrovic et al. (1987) mapped ERBA2, the thyroid hormone receptor gene, to 3p25-p21 and showed that it was deleted in small cell lung carcinoma (SCLC; 182280) in all 6 cases studied. The assignment was done by study of somatic cell hybrids containing various translocations involving human chromosome 3.

Drabkin et al. (1987) mapped an ERBA gene to 3p22-p21.33 by study of somatic cell hybrids and in situ hybridization with a DNA probe.

By both somatic cell hybridization and in situ hybridization, Drabkin et al. (1988) showed that the ERBA2 gene is located on 3p24.1-p22. Drabkin et al. (1988) found, furthermore, that the ERBA2 locus was deleted in some but not in all cases of SCLC. Thus, the putative suppressor gene involved in that neoplasm is probably located centromeric to ERBA2.

By nonisotopic in situ hybridization to metaphase chromosomes, Albertson et al. (1989) mapped the THRB gene to 3p24.3. THRB and 95 other loci on 3p were used by Tory et al. (1992) in the construction of a genetic linkage map through studies of 59 CEPH families.

Gene Function

Maternal thyroid hormone is transferred to the fetus early in pregnancy and is postulated to regulate brain development. Iskaros et al. (2000) investigated the ontogeny of TR isoforms and related splice variants in 9 first-trimester fetal brains by semiquantitative RT-PCR analysis. Expression of the TR-beta-1, TR-alpha-1, and TR-alpha-2 isoforms was detected from 8.1 weeks' gestation. An additional truncated species was detected with the TR-alpha-2 primer set, consistent with the TR-alpha-3 splice variant described in the rat. All TR-alpha-derived transcripts were coordinately expressed and increased approximately 8-fold between 8.1 and 13.9 weeks' gestation. A more complex ontogenic pattern was observed for TR-beta-1, suggestive of a nadir between 8.4 and 12.0 weeks' gestation. The authors concluded that these findings point to an important role for the TR-alpha-1 isoform in mediating maternal thyroid hormone action during first-trimester fetal brain development.

Most thyroid hormone receptor isoforms associate with coactivator proteins and mediate transcriptional activation only in the presence of thyroid hormone. The pituitary-specific THR-beta-2 isoform departs from this general rule and is able to interact with p160 coactivators, and to mediate transcriptional activation in both the absence and presence of hormone. Yang and Privalsky (2001) reported that this hormone-independent activation is mediated by contacts between the unique N terminus of THR-beta-2 and an internal interaction domain in the steroid receptor coactivator-1 (SRC1; 602691) and glucocorticoid receptor-interacting protein-1 (GRIP1; 601993) coactivators. These hormone-independent contacts between THR-beta-2 and the p160 coactivators are distinct in sequence and function from the LXXLL motifs that mediate hormone-dependent transcriptional activation and resemble instead a mode of coactivator recruitment previously observed only for the steroid hormone receptors and only in the presence of steroid hormone. The authors concluded that the transcriptional properties of the different thyroid hormone receptor isoforms represent a combinatorial mixture of repression, antirepression, and hormone-independent and hormone-dependent activation functions that operate in conjunction to determine the ultimate transcriptional outcome.

Molecular Genetics

In a kindred with autosomal dominant generalized thyroid hormone resistance (GRTH; 188570), Bale et al. (1988) found that 1 allele of the ERBA-beta gene cosegregated with the resistance trait; maximum lod score = 3.91 at theta = 0.0. In this kindred a decrease in T3-binding affinity of salt-extracted fibroblast nuclear receptors had been demonstrated.

In a father and son with generalized resistance to thyroid hormone, Sakurai et al. (1989) identified heterozygosity for a missense mutation in the THRB gene (190160.0001).

In affected members of the original family reported by Refetoff et al. (1967), in which GRTH segregated as an autosomal recessive trait (274300), Takeda et al. (1991) identified deletion of the THRB gene (190160.0003).

Takeda et al. (1992) evaluated denaturing gradient gel electrophoresis (DGGE) in the rapid diagnosis of thyroid hormone resistance. In studies of affected members from 21 families, putative mutations were identified in 18 unrelated individuals. Sequencing confirmed the nature of the mutations in 9 of these individuals. All of the mutations were in the hormone-binding domain of the receptor; 13 of the 18 were in its center, exon 7. In 3 families, no mutations in the THRB gene were identified, suggesting the existence of mutations at other loci, possibly the THRA gene or other proteins involved in a thyroid hormone-dependent transactivation system. Of 22 families, the inheritance was recessive in 1, dominant in 15, and unknown in 6. Takeda et al. (1992) stated that they had studied 1 of the 7 families reported by Parrilla et al. (1991), bringing the total of known families close to 30. Nagaya et al. (1992) presented experiments indicating that thyroid hormone receptor mutations that result in generalized growth hormone resistance compete with normal receptors at DNA binding sites in target genes to block normal receptor function; thus, the dominant-negative activity of such mutants may be explained by competition for receptor binding to DNA. However, Yen et al. (1992) presented observations of the gly340-to-arg mutation (190160.0001) in the MF family suggesting that the decreased sensitivity to T3 in the cells of the affected persons with this mutation is not due to abnormal interactions with the thyroid hormone receptor. Instead, the dominant-negative activity likely occurs by one or both of the following mechanisms: repression by mutant homodimers that bind to thyroid hormone response elements (TREs) in the presence of T3, and/or diminished ligand-regulated transcription by heterodimers of the mutant receptor or TRAP (thyroid hormone receptor auxiliary protein) heterodimers.

In an analysis of 7 previously unreported families with GRTH, Parrilla et al. (1991) identified 6 single base substitutions and 1 single base insertion in the THRB gene. The 7 mutations were clustered in 2 regions of exons 9 and 10 in the ligand-binding domain of the receptor. Three of the families had a familial disorder; at least 3 of the others had a sporadic mutation as indicated by the fact that both parents were found to have 2 normal alleles. Thus, a 'dominant-negative' phenomenon is demonstrated.

Weiss et al. (1993) indicated that 28 different point mutations in the THRB gene had been associated with GRTH. These mutations are clustered in 2 regions of the T3-binding domain of the gene at codons 310 to 347 and 417 to 453. Weiss et al. (1993) reported 6 examples of mutations occurring in apparently unrelated families; 3 of the mutations occurred in 3 different families each and the other 3 in 2 families each. In 11 of 15 families, the mutation was shown to be distinct either by the fact that de novo mutation was involved or that different polymorphisms were found in the gene. In other instances, ethnic difference, e.g., Japanese and Caucasian, supported distinctness. Weiss et al. (1993) pointed out that 28 of the 38 point mutations so far identified, including all those occurring in more than 1 family, are located in CG-rich areas of the THRB gene. Differences in clinical and laboratory findings in unrelated families harboring the same THRB mutations suggested that genetic variability of other factors modulate the expression of thyroid hormone action.

Beck-Peccoz et al. (1994) presented a revised nomenclature for the THRB mutations causing resistance to thyroid hormone. They presented a tabulation of 27 mutations that had been published using the old notation; more recent publications already using the revised nomenclature were not included. The revision was necessitated by the advances in knowledge of the structure of the THRB gene. Cloning of the cDNA encoding THRB (Weinberger et al., 1986) initially had suggested an open reading frame of 450 amino acids. However, subsequent sequencing of this cDNA, as well as genomic clones, showed a guanine rather than adenine at nucleotide 288, generating a new initiation codon (Sakurai et al., 1990) and leading to a predicted protein sequence that contains 461 amino acids. In addition to differences in the numbering of the amino acids used in reported mutations, the exons had been numbered either from 00 to 8 or from 1 to 10, depending on the designation of noncoding exons. To avoid the confusion arising from a double nomenclature, Beck-Peccoz et al. (1994) recommended that the exons be numbered 1 through 10 with 1 and 2 corresponding to the previously designated 00 and 0, respectively, at the 5-prime end. A deduced sequence for THRB consisting of 461 amino acids and incorporating 5 additional residues (MTPNS) at the amino terminus was to be used. (Codons in the THRB gene are numbered according to the corrected coding sequence, which adds 5 amino acids to the amino terminus (Sakurai et al., 1990).) In the allelic variants listed below, 2 statements of the nature of the mutation are given when both have appeared in the literature.

Hayashi et al. (1994) noted that the growing list of THRB mutations found in subjects with resistance to thyroid hormone led to the identification of 2 mutational 'hot' areas in the T3-binding domain of the protein. One of these 2 areas spans from codon 310 to 347 and the other from codon 438 to 459, the latter located 2 amino acids upstream of the carboxy terminus. The mutations occur with high frequency in CG-rich sequences. Not a single mutation had been identified in the region between the 2 'hot' areas. Forman and Samuels (1990) described this 'cold region,' which encodes 90 amino acids, contains 8 of the 9 heptad repeats, and appears to play an important role in receptor dimerization. Hayashi et al. (1994) produced 10 artificial mutant THRB genes in this 'cold' region according to the hotspot rule, i.e., C-to-T or G-to-A substitutions in CpGs. The properties of artificial mutants were compared with those of 6 naturally occurring mutants. Among all natural mutants, arg320 to his (190160.0015), manifesting a mild form of thyroid hormone resistance, showed the least impairment of T3-binding affinity. In contrast, T3-binding affinity was normal in 6 artificial mutants and reduced to a lesser extent than that of R320H in 3. One truncated mutant, R410X, did not bind T3. All natural mutants had impaired ability to transactivate T3-responsive elements and exhibited a strong dominant-negative effect on cotransfected wildtype receptor.

Since the serum thyroid hormone levels required to compensate for the reduced binding affinity would be inferior to those found in subjects with R320H, natural mutations occurring in the cold region of the THRB gene should fail to manifest as thyroid hormone resistance or should escape detection. The artificial mutant R410X, resulting in a truncated protein, manifested thyroid hormone resistance only in the homozygous state. The cold region of the putative T3-binding domain is relatively insensitive to amino acid changes and, thus, may not be involved in a direct interaction with T3.

Pohlenz et al. (1996) stated that 38 different point mutations had been documented in the THRB receptor as the cause of thyroid hormone resistance. Except for 2, all previously reported mutations were located in exons 9 or 10 in the hormone binding domain. In 45% of the mutations, a CpG dinucleotide was involved, indicating 2 hotspots at codons 310 to 347 and 438 to 459. Pohlenz et al. (1996) reported the second mutation in exon 7, R243W (190160.0038). Seto and Weintraub (1996) used PCR-coupled automated direct sequencing of genomic DNA for rapid molecular detection of mutations associated with GRTH to detect 2 novel mutations.

In a 29-year-old woman with selective pituitary thyroid hormone resistance (145650), Asteria et al. (1999) identified a mutation in exon 9 of the THRB gene (T337A; 190160.0040). She presented with symptoms and signs of hyperthyroidism and was successfully treated with 3,5,3-prime-triiodothyroacetic acid (TRIAC) until the onset of pregnancy, when the therapy was discontinued to avoid possible adverse effects on fetal development. TRIAC therapy was reinstituted following recurrence of thyrotoxic features, and the fetus was shown also to be heterozygous for the T337A mutation. The authors advocated prenatal diagnosis of thyroid hormone resistance and adequate treatment of the disease in the case of maternal hyperthyroidism, to avoid fetal thyrotrope hyperplasia, reduce fetal goiter, and maintain maternal euthyroidism during pregnancy.

Ando et al. (2001) performed RT-PCR to detect mutations in THRB from a surgically-resected TSH-secreting pituitary tumor (TSHoma). Analyses of the RT-PCR products revealed a 135-bp deletion within the sixth exon that encodes the ligand-binding domain of THRB2. This deletion was caused by alternative splicing of THRB2 mRNA, as near-consensus splice sequences were found at the junction site and no deletion or mutations were detected in the tumoral genomic DNA. This THRB variant lacked thyroid hormone binding and had impaired T3-dependent negative regulation of both TSH-beta (188540) and glycoprotein hormone beta-subunit genes in cotransfection studies. Furthermore, the THRB variant showed dominant-negative activity against the wildtype THRB2. The authors concluded that aberrant alternative splicing of THRB2 mRNA generated an abnormal TR protein that accounted for the defective negative regulation of TSH in the TSHoma.

Animal Model

Thyroid hormone (triiodothyronine, T3) and its receptors are essential to the development of hearing. Congenital thyroid disorders impair hearing, and profound deafness is common in geographic areas where there is a prevalence of iodine deficiency. Also, hypothyroidism in mice and rats causes deformities in the organ of Corti and studies in these species indicate a critical window of development preceding the onset of hearing during which the hormone is required. To elucidate the role of thyroid hormone receptors alpha-1 (THRA; 190120) and beta in the development of hearing, Rusch et al. (1998) investigated cochlear functions in mice lacking THRA1 or THRB. Both THRA1 and THRB are expressed during embryonic and postnatal development of the cochlea. Deletion of THRB by gene targeting in mice severely impairs the auditory-evoked brainstem response (Forrest et al., 1996). Also, human resistance to thyroid hormone is associated with THRB mutations, and some cases of resistance to thyroid hormone resulting from THRB mutations exhibit deafness or mild hearing impairment.

Because THRB knockout mice do not display histologic defects in the cochlea (Forrest et al., 1996), Rusch et al. (1998) tested the hypothesis that THRB regulates functional rather than morphologic development of the cochlea. Their studies showed a defect in a potassium current in inner hair cells (IHCs). At the onset of hearing, IHCs in wildtype mice express a fast-activating potassium conductance, I(K,f), which transforms the immature IHC from a regenerative, spiking pacemaker to a high-frequency signal transmitter (Kros et al., 1998). Rusch et al. (1998) found that expression of I(K,f) was significantly retarded in THRB -/- mice, whereas the development of the endocochlear potential and other cochlear functions, including mechanoelectrical transduction in hair cells, progressed normally. THRA1 -/- mice expressed I(K,f) normally, in accord with their normal auditory-evoked brainstem response. Adult THRB -/- mice remained deaf with a permanently impaired auditory-evoked brainstem response, even when I(K,f) eventually approached normal magnitudes (Forrest et al., 1996). Rusch et al. (1998) suggested that this could be explained if early I(K,f) expression is required to facilitate the development of normal hearing in accord with the presence of a critical period for sensory inflow necessary for development of auditory function. This may be analogous to the visual system, in which studies of sensory deprivation have indicated a critical window for activity-dependent development of the ocular-dominance columns in the visual cortex (Katz and Shatz, 1996). These results implicated retarded expression of I(K,f) as a possible cause of hearing deficiency in the syndrome of resistance to thyroid hormone. Failure to activate this THRB-dependent function may also contribute to deafness in cases of congenital hypothyroidism. The studies of Rusch et al. (1998) suggested that it is unlikely that THRA1 mutations will be found to underlie deafness in human disorders.

Whereas THRA1 and THRB1 are widely expressed, expression of the THRB2 splicing isoform is mainly limited to the pituitary, triiodothyronine-responsive thyrotropin-releasing hormone neurons, the developing inner ear, and the retina. Mice with targeted disruption of the entire Thrb locus exhibit elevated thyroid hormone levels as a result of abnormal central regulation of thyrotropin, and also develop profound hearing loss. To clarify the contribution of the THRB2 splicing isoform to the function of the endocrine and auditory systems in vivo, Abel et al. (1999) generated mice with targeted disruption of the Thrb2 isoform. Thrb2-null mice had preserved expression of the Thra and Thrb1 isoforms. They developed a degree of central resistance to thyroid hormone similar to that in Thrb-null mice, indicating the important role of THRB2 in the regulation of the hypothalamic-pituitary-thyroid axis. Growth hormone (139250) gene expression was marginally reduced. In contrast to Thrb-null mice, Thrb2-null mice exhibited no evidence of hearing impairment, indicating that THRB1 and THRB2 subserve divergent roles in the regulation of auditory function.

To understand the molecular basis underlying the action of mutant THRB in vivo, Kaneshige et al. (2000) generated mice with a targeted mutation in the Thrb gene by using homologous recombination and the Cre/loxP system. The mutation in the THRB gene, referred to as PV, was the pro448-to-thr mutation (190160.0012). Mice expressing a single PV allele showed the typical abnormalities of thyroid function found in heterozygous humans with generalized resistance to thyroid hormone. Homozygous PV mice exhibited severe dysfunction of the pituitary-thyroid axis, impaired weight gains, and abnormal bone development. This phenotype was distinct from that seen in mice with a null mutation of the Thrb gene.

Araki et al. (2005) found that Thrb with the dominant-negative PV mutation bound as a homodimer or as a heterodimer with Pparg (601487) or retinoid X receptor (see RXRA; 180245) to peroxisome proliferator response elements (PPREs), thereby inhibiting interaction of Pparg with Rxr on PPREs. Thrb with the PV mutation repressed ligand-dependent Pparg activation following expression in monkey kidney cells, and chromatin immunoprecipitation studies indicated that repression was due to recruitment of corepressors to the promoters of Pparg target genes in vivo.

Ying et al. (2006) found elevated Pttg1 (604147) levels in the thyroid tumors of PV mutant mice. Pttg1 was physically associated with Thrb as well as mutant PV receptor; however, T3-induced Thrb-mediated proteasomal degradation of Pttg1 did not occur when Pttg1 was associated with mutant Thrb, and accumulated Pttg1 impeded mitotic progression in Thrb mutant-expressing cells. Proteasomal degradation was activated by direct interaction of liganded Thrb with Src3 (NCOA3; 601937). Ying et al. (2006) concluded that PTTG1 is regulated by liganded THRB and that loss of this regulatory function in THRB mutants leads to an accumulation of PTTG1 that disrupts mitotic progression and thus may contribute to thyroid carcinogenesis.

To evaluate the respective contributions of THRA and THRB in the regulation of CYP7A (118455), the rate-limiting enzyme in the synthesis of bile acids, Gullberg et al. (2000) studied the responses to 2% dietary cholesterol and T3 in THRA and THRB knockout mice under hypo- and hyperthyroid conditions. Their experiments showed that the normal stimulation in CYP7A activity and mRNA level by T3 is lost in THRB -/-, but not in THRA-/-, mice, identifying THRB as the mediator of T3 action on CYP7A and, consequently, as a major regulator of cholesterol metabolism in vivo. Somewhat unexpectedly, T3-deficient THRB -/- mice showed an augmented CYP7A response after challenge with dietary cholesterol, and these animals did not develop hypercholesterolemia to the extent that wildtype controls did. The authors concluded that the latter results lend strong support to the concept that THRs may exert regulatory effects in vivo independent of T3.

THRB2 is a ligand-activated transcription factor that is expressed in the outer nuclear layer of the embryonic retina. Ng et al. (2001) deleted the Thrb gene in mice, causing the selective loss of middle (M, 'green') cones and a concomitant increase in short (S, 'blue') opsin immunoreactive cones. Moreover, the gradient of cone distribution was disturbed, with S-cones becoming widespread across the retina. The results indicated that cone photoreceptors throughout the retina have the potential to follow a default S-cone pathway and revealed an essential role for THRB2 in the commitment to an M-cone identity. The findings raised the possibility that mutations of the THRB gene may be associated with human cone disorders.

Although thyroid hormones are thought to act principally by binding to their nuclear receptors, thyroid receptor knockout animals have normal CNS structure and function. To investigate this discrepancy further, Hashimoto et al. (2001) introduced a T3-binding mutation into the mouse Thrb gene by homologous recombination. Because of this T3-binding defect, the mutant thyroid hormone receptor constitutively interacted with corepressor proteins and mimicked the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrated the specific and deleterious action of unliganded thyroid hormone receptor in the brain and suggested the importance of corepressors bound to thyroid receptor in the pathogenesis of hypothyroidism.

Ng et al. (2001) determined that a targeted mutation in the THRA gene suppresses deafness and thyroid hyperactivity in transgenic Thrb-null mice. The THRA splice variant TR-alpha-1 receptor is nonessential for hearing, and the shorter TR-alpha-2 splice variant has unknown function but neither binds thyroid hormone nor transactivates. The targeted mutation deletes TR-alpha-2 and concomitantly causes overexpression of TR-alpha-1 as a consequence of the exon structure of the gene. The Thra-null mice had normal auditory thresholds, suggesting that TR-alpha-2 is dispensable for hearing, and have only marginally reduced thyroid activity. However, a potent function for the mutated allele was revealed upon its introduction into Thrb-null mice, where it suppressed the auditory and thyroid phenotypes caused by loss of THRB. The authors proposed a modifying function for a THRA allele and suggested that increased expression of TR-alpha-1 may substitute for the absence of THRB.

Puzianowska-Kuznicka et al. (2002) tested the hypothesis that the functions of TRs could be impaired in cancer tissues by aberrant expression and/or somatic mutations. As a model system, they selected human thyroid papillary cancer. They found that the mean expression levels of THRB mRNA and THRA mRNA were significantly lower, whereas the protein levels of THRB1 and THRA1 were higher in cancer tissues than in healthy thyroid. Sequencing of THRB1 and THRA1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such THRB1 or THRA1 mutations, respectively. The majority of the mutated TRs lost their trans-activation function and exhibited dominant-negative activity. The authors concluded that these findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma.

History

Middleton et al. (1986) identified a RFLP for the ERBA2 gene.

By in situ hybridization, Gosden et al. (1986) mapped the ERBA2 gene as well as a related gene to chromosome 17q21.3.

Douglas et al. (1991) discussed the confusion that surrounded the ERBA genes. By screening a genomic library with v-erbA, Jansson et al. (1983) isolated 2 types of clones. One clone, called erbA1, is now known to define the THRA locus on chromosome 17 (190120). The second clone, erbA2, seemed to map both to chromosome 17 and chromosome 3. In response to this inconsistent assignment, the genes for erbA2 and erbA-beta were given different designations (ERBA2 and ERBA1, respectively) by Human Gene Mapping 9. Using pulsed field gel electrophoresis, Douglas et al. (1991) reported that the ERBA2 and ERBA1 loci are both on chromosome 3 separated by 50 to 120 kb. They stated that the erbA-beta probe may recognize a separate but closely linked gene on chromosome 3.

ALLELIC VARIANTS (Selected Examples):

Table View

.0001 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, GLY345ARG

In a father and son with inherited generalized resistance to thyroid hormone (188570), Sakurai et al. (1989) found a single guanine-to-cytosine replacement in the codon for amino acid 340 resulting in a glycine-to-arginine substitution (GLY340ARG) in the hormone-binding domain of the THRB gene. In vitro translation products of this mutant gene did not bind triiodothyronine. The mutation was not found in the unaffected mother. Takeda et al. (1991) referred to this mutation as gly345 to arg. The new numbering system takes into account the presence of 5 additional amino acids at the amino terminus as deduced from the corrected nucleotide sequence (Sakurai et al., 1990). The mutation was in exon 7 and occurred in family Mf studied in Chicago.

In accordance with a new nomenclature recommended by Beck-Peccoz et al. (1994), this mutation is designated G345R (gly345 to arg) in exon 9.

.0002 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, PRO453HIS [dbSNP:rs121918687]

In a family ('kindred A' originally reported by Magner et al., 1986) with generalized thyroid hormone resistance (188570), Usala et al. (1990) sequenced a major portion of the T3-binding domain of the ERBA2 gene because in vivo studies had shown an abnormality in T3-binding affinity of nuclear receptors. They showed a base substitution, cytosine to adenine, at cDNA position 1643, altering the proline codon at position 448 to histidine (PRO448HIS). By allele-specific hybridization, this base substitution was demonstrated in only 1 allele of 7 affected members and in none of 10 unaffected members of the kindred. It was not found in 2 other kindreds (kindreds B and D) in which linkage to ERBA2 had been demonstrated and was not found in 92 randomly tested ERBA2 alleles. All 3 kindreds showed inappropriately normal or elevated TSH with high levels of thyroid hormones. In addition to pituitary resistance to thyroid hormones, the kindreds also showed varying patterns of target organ resistance to the action of thyroid hormones. Only kindred A had short stature. Affected members of one of the other kindreds showed marked cognitive deficits. A 'hyperactivity' syndrome was present in some affected members. Takeda et al. (1991) referred to this mutation as pro453 to his (P453H), based on the revised count of amino acid residues. The mutation occurred in exon 8 and was identified in family Mh studied at the National Institutes of Health. Takeda et al. (1991) failed to find either the pro453-to-his mutation or the gly345-to-arg mutation (190160.0001) in any of 19 unrelated families with GRTH. The mode of inheritance was dominant in 13 families, unknown in 5 families, and clearly recessive in 1 family in which only the offspring of consanguineous subjects were affected.

This mutation occurred in exon 10, according to the new numbering system of Beck-Peccoz et al. (1994).

.0003 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL RECESSIVE

THRB, EX4-10DEL

In affected members of the original family reported by Refetoff et al. (1967), in which GRTH segregated as an autosomal recessive (274300), Takeda et al. (1991) identified deletion of the THRB gene. Heterozygous members of the family were clinically normal. Takeda et al. (1991) concluded that the presence of a single normal allele was sufficient for normal receptor function, and suggested that in the dominant mode of GRTH inheritance the presence of an abnormal thyroid hormone receptor interferes with the function of the normal receptor in a dominant-negative fashion.

This mutation is designated EX4-10DEL in the nomenclature of Beck-Peccoz et al. (1994).

.0004 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, GLN340HIS [dbSNP:rs121918688]

In 10 affected members of a family known as 'kindred D,' in which generalized thyroid hormone resistance segregated as an autosomal dominant trait (188570), Usala et al. (1991) identified heterozygosity for a 1305G-C transversion in the THRB gene, resulting in gln335-to-his (GLN335HIS) substitution. The mutation was not found in 6 unaffected family members.

This mutation is designated gln340-to-his (Q340H) according to the revised numbering system of Beck-Peccoz et al. (1994).

.0005 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL RECESSIVE

THRB, THR337DEL [dbSNP:rs121918689]

Usala et al. (1991) reported a 3-bp deletion in the T(3)-binding domain of the beta-receptor in kindred S with GRTH. The proband was the product of a consanguineous union of 2 heterozygotes and was homozygous for the defect (274300). The deletion of nucleotides 1295-1297 (CAC) resulted in the deduced loss of amino acid residue threonine at codon 332 (THR332DEL). The heterozygotes displayed elevated free T(4) levels and inappropriately normal thyroid-stimulating hormone levels characteristic of other kindreds with GRTH. However, the homozygote had markedly elevated TSH and free T(4) levels, and displayed profound abnormalities in brain development and linear growth. The findings in this family demonstrated the effects in man of both the heterozygous and the homozygous expression of a dominant-negative mutation. The clinical features of the homozygote were described by Ono et al. (1991). He was born of first-cousin parents, both of whom were heterozygotes for GRTH. His clinical status suggested tissue-specific hyperthyroidism and hypothyroidism. He had delayed growth and skeletal maturation and developmental delay but showed tachycardia. There were laboratory signs of profound pituitary resistance to thyroid hormone.

In the nomenclature of Beck-Peccoz et al. (1994), this mutation involved deletion of amino acid 337 (thr337) encoded by exon 9.

.0006 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, ALA317THR [dbSNP:rs121918690]

In a patient with a sporadic form of GRTH (188570), Parrilla et al. (1991) identified an ala312-to-thr mutation (ALA312THR) due to a GCT-to-ACT change at nucleotide 1234 in exon 9. Parrilla et al. (1991) used the nucleotide and codon numbering as originally described by Weinberger et al. (1986).

This mutation is designated ala317-to thr(A317T) according the revised numbering system of Beck-Peccoz et al. (1994).

In 2 unrelated families and an unrelated individual with GRTH (188570), Weiss et al. (1993) identified heterozygosity for the A317T mutation in the THRB gene.

In a father and 2 of his children with goiter and raised thyroid hormone levels, Pohlenz et al. (1995) identified heterozygosity for the same mutation. They commented on the fact that 'significant articulation problems' were present in the patient studied by Parrilla et al. (1991). Mixson et al. (1992) found that more language abnormalities were thought to occur in kindreds with mutations in exon 9 than in those with mutations in exon 10. However, no abnormalities in language development, articulation problems, or signs consistent with dyslexia were found in the 3 affected members of the kindred they studied. Pohlenz et al. (1995) noted that a total of 38 different mutations in the THRB gene causing generalized resistance to thyroid hormone had been identified.

.0007 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, GLY332ARG [dbSNP:rs28999969]

Parrilla et al. (1991) found a gly327-to-arg mutation (GLY327ARG) due to a GGG-to-AGG change at nucleotide 1279 in exon 9.

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated G332R (gly332 to arg).

.0008 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, GLY345VAL [dbSNP:rs28999970]

Parrilla et al. (1991) found a gly340-to-val (GLY340VAL) mutation due to a GGT-to-GTT change at nucleotide 1319 in exon 9. The same codon is involved in the gly340-to-arg mutation (190160.0001).

In the new nomenclature of Beck-Peccoz et al. (1994), this mutation was designated G345V (gly345 to val).

.0009 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, GLY347GLU [dbSNP:rs28999971]

Parrilla et al. (1991) found a GGG-to-GAG change at nucleotide 1325 of exon 9 resulting in substitution of glutamic acid for glycine-342 (GLY342GLU). This mutation was found in 4 individuals in 2 generations of a family, including a father-son combination.

In accordance with the new nomenclature of Beck-Peccoz et al. (1994), this mutation was designated G347E (gly347 to glu).

.0010 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, MET442VAL [dbSNP:rs121918691]

Parrilla et al. (1991) found an AGT-to-GTG change at nucleotide 1609 of exon 10 resulting in substitution of valine for methionine-437 (MET437VAL).

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated M442V (met442 to val).

.0011 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, 1-BP INS, 1627C

In 1 of 7 unrelated families with generalized thyroid hormone resistance, Parrilla et al. (1991) found a frameshift mutation caused by insertion of a C in codon 443 in exon 10, resulting in a stop codon at 458. The patient was a sporadic case, i.e., neither parent showed the allele. Kaneshige et al. (2001) referred to this mutation as the PV mutation, presumably derived from the name of the patient.

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was referred to as (C1627i)fr.sh.448(stop463) in exon 10.

.0012 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, PRO453THR [dbSNP:rs28933408]

In 6 members of 3 generations of a family, Parrilla et al. (1991) found heterozygosity for a pro448-to-thr mutation (PRO448THR) due to a CCT-to-ACT change involving nucleotide 1642 in exon 10. In a family in which the father and a son and daughter had generalized resistance to thyroid hormone, Shuto et al. (1992) found a cytosine-to-adenine transversion at nucleotide 1642 resulting in substitution of threonine (ACT) for proline (CCT) at codon 448. Usala et al. (1990) described a cytosine-to-adenine transversion at nucleotide position 1643 in a family with generalized thyroid hormone resistance (190160.0002). The phenotype was autosomal dominant in both families with mutations in codon 448; however, it differed in that hyperactivity syndrome, learning disability, and short stature were stressed as features of the phenotype in the family of Usala et al. (1990). Studies of the 10 affected members demonstrated that they all had at least 3 of the following tissues resistant to thyroid hormone: pituitary, bone, liver, brain, and heart. In contrast, none of the affected members in the kindred of Shuto et al. (1992) showed short stature, bradycardia, elevated serum cholesterol, hyperactivity syndrome, or learning disability. The family was called to attention by a soft, symmetrically enlarged thyroid gland in the 11-year-old son. All 3 members had high levels of thyroid hormones with inappropriate secretion of TSH, and the father and sister also had small diffuse goiters with no stigmata of thyrotoxicosis.

According to the new nomenclature by Beck-Peccoz et al. (1994), Weiss et al. (1993) designated this mutation as P453T (pro453 to thr) in exon 10. The mutation was found in 2 separate families and consisted of a C-to-A transversion at nucleotide 1642.

.0013 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, LYS443GLU [dbSNP:rs121918692]

In a Korean-Japanese kindred, Sasaki et al. (1992) found an A-to-G mutation at nucleotide 1612 resulting in substitution of glutamic acid for lysine-438 (LYS438GLU). The mutation was present in heterozygous state in each of the affected members of the family.

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated K443E (lys443 to glu) in exon 8.

.0014 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, GLY345SER [dbSNP:rs121918686]

In a family with thyroid hormone resistance reported by Cooper et al. (1982), Adams et al. (1992) identified heterozygosity for a glycine-to-serine mutation at codon 340 (GLY340SER) in the hormone-binding domain of the receptor gene.

In the new nomenclature of Beck-Peccoz et al. (1994), this mutation was designated G345S in exon 7.

.0015 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, ARG320HIS [dbSNP:rs121918693]

Cugini et al. (1992) described autosomal dominant GRTH due to a guanine-to-adenine transition at nucleotide 1244, resulting in a change of arginine-315 to histidine (ARG315HIS). Affected members of this kindred appeared to have a relatively mild degree of resistance, with mean total thyroxine of only 192 +/- 24 nmol/L and inappropriately normal TSH levels. The oldest affected member studied was 62. The mutation was located further upstream than most previously described mutations; only ala312 to thr was further upstream.

Weiss et al. (1993) found this mutation (designated arg320 to his in the new nomenclature) in 2 separate families with generalized thyroid hormone resistance. The distinctness of the mutant allele in the 2 families was supported by the fact that each was associated with a different CA repeat polymorphism. The change was a G-to-A transition at nucleotide 1244 in exon 9.

.0016 MOVED TO 190160.0002

.0017 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, ALA234THR [dbSNP:rs121918694]

Behr and Loos (1992) demonstrated an ala229-to-thr (ALA229THR) mutation in heterozygous state in a mother, son, and daughter with generalized thyroid resistance. The 3 had some features of mild hyperthyroidism: slightly elevated resting pulse, experienced periodic tachycardia, weight loss, nervousness, and sweating were also observed, cold intolerance, and moderate goiter. All previously described mutations in THRB leading to GRTH had involved the T3-binding domain of the gene; this mutation was identified in the carboxy-terminal part of the hinge domain. It represented a GCC-to-ACC transition.

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated A234T (ala234 to thr) in exon 5.

.0018 THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY

THRB, ARG316HIS [dbSNP:rs121918695]

Geffner et al. (1993) described a patient with a severe form of selective pituitary resistance to thyroid hormones (PRTH; 145650). The patient manifested inappropriately normal thyrotropin-stimulating hormone, markedly elevated serum free thyroxine (T4) and total triiodothyronine (T3), and clinical hyperthyroidism at the age of 12 years (Dulgeroff et al., 1992). Bone age was advanced. Serum cholesterol was below the normal range and serum sex hormone binding globulin was 146% above the mean of the other female members of the kindred, consistent with hepatic hyperthyroidism. The father was unaffected. However, in both the proposita and her father, a G-to-A transition at nucleotide 1232 was found in 1 allele of the THRB gene, altering codon 311 from arginine to histidine (ARG311HIS). A half sister of the proposita also harbored the mutant allele and, like the father, was clinically normal. The receptor protein in the patient, synthesized with reticulocyte lysate, had significantly defective T3-binding activity. RNA phenotyping using leukocytes and fibroblasts demonstrated an equal level of expression of wildtype and mutant alleles in both the patient and her unaffected father. Finally, the mutant receptor had no detectable dominant-negative activity in a transfection assay. Thus, in contrast to the many other THRB mutants responsible for the generalized form of thyroid hormone resistance, the receptor in this case appeared unable to antagonize normal receptor function. The arg311-to-his mutation may contribute to PRTH in this patient by inactivating 1 of the 2 THRB alleles but it cannot be the sole cause of the disease. Geffner et al. (1993) speculated about the possible reason for the disorder in the patient, e.g., the presence of a second mutation.

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated R316H (arg316 to his) in exon 9.

.0019 THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY

THRB, LEU325PHE

Geffner et al. (1993) stated that they had found a leu325-to-phe mutation of the THRB gene in a previously published (Dulgeroff et al., 1992) patient with PRTH (145650).

.0020 MOVED TO 190160.0006

.0021 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, ARG320CYS [dbSNP:rs121918696]

Weiss et al. (1993) found heterozygosity for a 1243C-T transition in exon 9 of the THRB gene, resulting in an arg320-to-cys substitution in 2 separate families with generalized resistance to thyroid hormone (188570). Both families were of European ancestry, living in the United States, but were not known to be related.

.0022 MOVED TO 190160.0015

.0023 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY, INCLUDED

THRB, ARG338TRP [dbSNP:rs121918697]

Weiss et al. (1993) identified a 1297C-T transition in exon 9 of the THRB gene in 3 separate families with generalized thyroid hormone resistance (188570). The separateness of the mutations was indicated by the fact that in 1 family it was de novo and in the other 2 families it was associated with different CA repeat polymorphisms. This recurrent mutation occurred, like other recurrent ones, in a region of high CG content.

The arg338-to-trp (R338W) mutation was associated with selective pituitary resistance to thyroid hormone (145650) in 4 of 5 kindreds studied by Adams et al. (1994), as well as in 2 other reported cases (Mixson et al., 1993; Sasaki et al., 1993). The patient studied by Mixson et al. (1993) was the original patient (L-F3) reported as having PRTH by Gershengorn and Weintraub (1975).

Mamanasiri et al. (2006) studied a Turkish family in which 2 sibs had thyroid function tests (TFTs) characteristic of RTH, short stature, and psychiatric symptoms; their father had similar TFTs but no growth or psychiatric disturbances, and the mother had a normal phenotype and TFTs. Both sibs were found to be heterozygous for the R338W mutation, which was inherited from the father. The father was mosaic for the mutation, which was present in some lineages of somatic cells but not in skin fibroblasts.

.0024 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, ARG438HIS [dbSNP:rs121918698]

Boothroyd et al. (1991) identified heterozygosity for an arg438-to-his (R438H) mutation in a family with generalized thyroid hormone resistance (188570).

The same mutation was found by Weiss et al. (1993) in 3 separate families. The separate origin of the mutation in these families was indicated by the fact that in one it was a de novo mutation and in the other 2 it was associated with different polymorphisms elsewhere in the gene. The mutation consisted of a G-to-A transition at nucleotide 1598.

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated R438H in exon 10.

.0026 THYROID HORMONE RESISTANCE, GENERALIZED

THRB, MET310THR [dbSNP:rs121918699]

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated M310T in exon 7.

.0027 THYROID HORMONE RESISTANCE, GENERALIZED

THRB, ASP322HIS [dbSNP:rs121918700]

This mutation was described as ASP317HIS by Mixson et al. (1992).

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated D322H in exon 9.

.0028 MOVED TO 190160.0004

.0029 THYROID HORMONE RESISTANCE, GENERALIZED

THRB, GLY345ASP

This mutation was described as GLY340ASP by Takeda et al. (1992).

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated G345D in exon 7.

.0030 THYROID HORMONE RESISTANCE, GENERALIZED

THRB, LEU450HIS [dbSNP:rs121918701]

This mutation was described as LEU445HIS by Mixson et al. (1992).

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated L450H in exon 10.

.0031 THYROID HORMONE RESISTANCE, GENERALIZED

THRB, 1-BP INS, 1644C

This mutation was described by Takeda et al. (1992).

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was referred to as (C1644i)fr.sh.454(stop463) in exon 10.

.0032 THYROID HORMONE RESISTANCE, GENERALIZED

THRB, PHE459CYS [dbSNP:rs121918702]

This mutation was described as PHE454CYS by Mixson et al. (1992).

In the nomenclature of Beck-Peccoz et al. (1994), this mutation was designated F459C in exon 10.

.0033 THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY

THRB, ARG320LEU

In a patient with a marked preponderance of thyrotoxic signs and symptoms associated with evidence of selective resistance to thyroid hormone (PRTH; 145650), Adams et al. (1994) found a G-to-T transversion at nucleotide 1244 converting CGC (arg) to CTC (leu). The change occurred in exon 9. In the same study, the arg320-to-leu mutation was also found in a family with generalized resistance to thyroid hormone, which they concluded is fundamentally the same disorder. In the family in which the proband had PRTH, other relatives harboring the same receptor defect remained asymptomatic and clinically euthyroid despite comparably elevated thyroid hormone levels. Of 9 cases of PRTH studied by Adams et al. (1994), 6 were associated with exon 9 mutations and 3 with exon 10 mutations.

.0034 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, CYS446ARG [dbSNP:rs121918703]

Weiss et al. (1994) studied 21 members of a family, of whom 12 exhibited the resistance to thyroid hormone phenotype (188570). They demonstrated heterozygosity for a T-to-C transition in the THRB gene that resulted in the replacement of cysteine-446 with an arginine. This mutation was present in the T3-binding domain and abolished T3 binding and hormone-mediated transactivation. The clinical characteristics in this family included goiter, tachycardia, and learning disabilities.

.0035 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL RECESSIVE

THRB, VAL458ALA [dbSNP:rs121918704]

In a patient with generalized thyroid hormone resistance (274300), Weiss et al. (1996) identified homozygosity for a 1658T-C transition in the TRHB gene, resulting in the replacement of the normal val (GTG) with an ala (GCG) at codon 458. The proposita was 52 years old when she came to medical attention because of atrial fibrillation. There were no other stigmata of thyrotoxicosis or goiter despite serum T4 and free T4 levels that were elevated. The daughter had undergone subtotal thyroidectomy at 8 years of age, and at ages 16 and 19 years had been treated with radioiodine. They were of Irish and Scottish origin. The mutation was found in heterozygous state in both the mother and the father.

.0036 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, CYS434TER [dbSNP:rs121918705]

Behr et al. (1997) described the analysis of a THRB gene in a patient with resistance to thyroid hormone (188570). The patient had both hypothyroid (severe mental retardation, hypoactivity, obesity) and hyperthyroid (tachycardia, low serum cholesterol) symptoms, as well as relatively early puberty, advanced bone age, and short stature. The patient was heterozygous, with a point mutation producing a premature stop-codon in exon 10, resulting in a 28-amino acid carboxy-terminal deletion of the THRB protein.

.0037 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, ARG243GLN [dbSNP:rs121918706]

In a Japanese mother and son with resistance to thyroid hormone (188570), Onigata et al. (1995) identified heterozygosity for a G-to-A transition at codon 243 in exon 7 of the THRB gene. Yagi et al. (1997) studied the arg243-to-gln and arg243-to-trp (190160.0038) mutations, located in the hinge domain of THRB, and found that they do not significantly alter the binding affinity for T3, measured in vitro. These results suggested to Yagi et al. (1997) that the substitution of arg243 in thyroid hormone resistance acts by increasing the propensity for the formation of tightly bound homodimers or by reduction of the receptor affinity for T3 only after it binds to DNA.

.0038 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, ARG243TRP [dbSNP:rs121918707]

In 6-year-old female twins with generalized thyroid hormone resistance (188570), Pohlenz et al. (1996) identified heterozygosity for a 1012C-T transition in exon 7 of the THRB gene, resulting in an arg243-to-trp (R243W) substitution. The affected mother and maternal grandfather were also heterozygous for the mutation. See also 190160.0037.

.0039 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, ARG383HIS [dbSNP:rs121918708]

Clifton-Bligh et al. (1998) reported an 11-year-old female with generalized thyroid hormone resistance (188570) who presented with goiter and elevated serum free thyroxine (T4) and total triiodothyroxine (T3), with detectable thyroid-stimulating hormone (TSH; see 188540) that responded normally to the administration of thyrotropin-releasing hormone (TRH). Abnormal thyroid function tests were also noted in her father and grandfather. PCR and direct sequencing of exon 10 of the THRB gene showed that all 3 individuals were heterozygous for a G-to-A transition (CGC to CAC) at nucleotide 1433, resulting in an arg383-to-his (R383H) substitution. While this mutation is located in a region not known to harbor naturally occurring mutations, it should be noted that it occurs at a CpG dinucleotide. Although the R383H mutant receptor activated positively regulated genes to an extent comparable to wildtype, negative transcriptional regulation of human TSH and TRH promoters was impaired in either THRB1 or THRB2 contexts, and wildtype receptor function was dominantly inhibited.

Safer et al. (1999) reported an individual with striking peripheral sensitivity to graded T3 administration. The subject was enrolled in a protocol in which she received 3 escalating T3 doses over a 13-day period. Indexes of central and peripheral thyroid hormone action were measured at baseline and at each T3 dose. Although the patient's resting pulse rose only 11% in response to T3, her serum ferritin, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 117%, 121%, and 30%, respectively. In addition, her serum cholesterol, creatinine phosphokinase, and deep tendon reflex relaxation time fell 25%, 36%, and 36%, respectively. Centrally, the patient was sufficiently resistant to T3 that her serum TSH was not suppressed with 200 microg T3, orally, daily for 4 days. The patient's C-terminal THR exons were sequenced, revealing the mutation R383H in a region not otherwise known to harbor THRB mutations. The authors stated that their clinical evaluation represented the most thorough documentation of the central thyroid hormone resistance phenotype in an individual with an identified THRB mutation.

.0040 THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY

THRB, THR337ALA [dbSNP:rs121918709]

In a 29-year-old woman with pituitary thyroid hormone resistance (145650), Asteria et al. (1999) identified a 1296G-A transition in exon 9 of the THRB gene that resulted in a thr337-to-ala substitution. Her daughter was found to be heterozygous for the same mutation through chorionic villus sampling.

.0041 THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT

THRB, 1-BP DEL, CODON 438, C

Phillips et al. (2001) reported a child with extreme thyroid hormone resistance (188570) and a severe phenotype. The 22-month-old female presented with goiter, growth retardation, short stature, and deafness. Additionally, the patient had hypotonia, mental retardation, visual impairment, and a history of seizures. Brain MRI showed evidence of demyelination and bilateral ventricular enlargement. The patient had markedly elevated free T3 and free T4 levels of more than 2000 pg/dl (normal, 230-420 pg/dl) and more than 64 pmol/liter (normal, 10.3-20.6 pmol/liter), respectively, and TSH of 6.88 mU/liter (normal, 0.6-6.3 mU/liter). Molecular analyses of the patient's DNA identified a single-base deletion in her TR-beta gene, a C in codon 438 in exon 10, that resulted in a frameshift and premature termination at codon 442. Thus, the truncated receptor lacked the last 20 amino acids, including part of the hormone-binding domain. Cotransfection studies showed that the mutant thyroid receptor was transcriptionally inactive even in the presence of 10(-6)M T3 and had strong dominant-negative activity over the wildtype receptor.

.0042 THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY

THRB, 1-BP INS, 1590T

Wu et al. (2006) reported a newborn Turkish male, the child of nonconsanguineous parents, with severe but predominantly pituitary thyroid hormone resistance (145650) who presented at 6 days of age with respiratory distress, tachycardia, diaphoresis, and a thyroid gland 4 times normal size. The authors hypothesized that the RTH was due to reduced ligand binding and/or abnormal interaction with nuclear cofactors. Sequencing of the THRB gene demonstrated a de novo heterozygous mutation, 1590_1591insT, resulting in a frameshift producing a mutant THR-beta with a 28-amino acid nonsense sequence and 2-amino acid carboxyl-terminal extension. The mutant TR-beta had impaired ability to recruit nuclear receptor corepressor (NCOR1; 600849) but intact association with silencing mediator of retinoid and thyroid receptor (SMRT; 600848). Wu et al. (2006) concluded that alterations in codons 436-453 in helix 11 of THR-beta result in significantly diminished association with NCOR but not with SMRT.

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Contributors:	John A. Phillips, III - updated : 7/18/2007
	John A. Phillips, III - updated : 7/6/2007 Marla J. F. O'Neill - updated : 11/30/2006 Patricia A. Hartz - updated : 3/24/2006 Marla J. F. O'Neill - updated : 2/3/2006 John A. Phillips, III - updated : 8/2/2002 John A. Phillips, III - updated : 7/29/2002 John A. Phillips, III - updated : 7/26/2002 John A. Phillips, III - updated : 7/11/2002 John A. Phillips, III - updated : 7/1/2002 George E. Tiller - updated : 5/30/2002 Victor A. McKusick - updated : 1/9/2002 John A. Phillips, III - updated : 9/27/2001 Victor A. McKusick - updated : 4/17/2001 John A. Phillips, III - updated : 3/2/2001 Victor A. McKusick - updated : 1/3/2001 Victor A. McKusick - updated : 1/2/2001 John A. Phillips, III - updated : 9/29/2000 John A. Phillips, III - updated : 10/6/1999 Victor A. McKusick - updated : 8/24/1999 John A. Phillips, III - updated : 4/15/1999 Victor A. McKusick - updated : 3/1/1999 John A. Phillips, III - updated : 5/29/1997 John A. Phillips, III - updated : 4/17/1997 Stylianos E. Antonarakis - updated : 7/16/1996
Creation Date:	Victor A. McKusick : 6/25/1986
Edit History:	carol : 04/20/2009
	carol : 11/28/2007 wwang : 7/30/2007 alopez : 7/18/2007 carol : 7/6/2007 carol : 7/6/2007 wwang : 11/30/2006 mgross : 3/28/2006 terry : 3/24/2006 carol : 2/21/2006 carol : 2/6/2006 carol : 2/6/2006 carol : 2/3/2006 joanna : 5/27/2005 terry : 3/23/2005 terry : 2/22/2005 terry : 6/2/2004 alopez : 3/17/2004 cwells : 8/2/2002 tkritzer : 7/29/2002 tkritzer : 7/26/2002 alopez : 7/11/2002 alopez : 7/1/2002 cwells : 5/30/2002 joanna : 5/16/2002 joanna : 5/16/2002 carol : 1/19/2002 terry : 1/9/2002 alopez : 10/30/2001 alopez : 9/27/2001 mcapotos : 5/8/2001 mcapotos : 4/25/2001 terry : 4/17/2001 mgross : 3/2/2001 mcapotos : 1/10/2001 terry : 1/3/2001 mgross : 1/2/2001 mgross : 10/3/2000 terry : 9/29/2000 carol : 4/18/2000 alopez : 10/6/1999 alopez : 10/6/1999 mgross : 9/2/1999 terry : 8/24/1999 mgross : 6/22/1999 carol : 6/12/1999 carol : 6/11/1999 terry : 6/9/1999 mgross : 4/15/1999 carol : 3/22/1999 terry : 3/1/1999 alopez : 11/13/1998 dkim : 9/11/1998 alopez : 5/15/1998 dholmes : 11/11/1997 dholmes : 11/11/1997 dholmes : 10/24/1997 terry : 7/8/1997 alopez : 6/26/1997 mark : 6/16/1997 jenny : 6/5/1997 jenny : 5/29/1997 jenny : 5/27/1997 jenny : 5/21/1997 jenny : 5/20/1997 jamie : 1/15/1997 jamie : 1/8/1997 terry : 1/6/1997 mark : 11/7/1996 terry : 10/31/1996 mark : 7/17/1996 mark : 7/16/1996 mark : 1/31/1996 terry : 1/25/1996 mark : 6/21/1995 mimadm : 6/7/1995 carol : 11/29/1994 terry : 11/23/1994 carol : 10/20/1993 carol : 7/13/1993

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