Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta (original) (raw)
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The Journal of Clinical Endocrinology & Metabolism, 2006
Context: Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone (TH).Objective: We report a newborn who presented with severe RTH (Mkar) with serum TSH 1500 mU/liter and free T3 greater than 50 pm (normal 3.1–9.4) and free T4 25.3 pm (normal 12–22). We hypothesized that the RTH was due to reduced ligand binding and/or abnormal interaction with nuclear cofactors.Design: These were prospective in vivo and in vitro studies.Setting: The study was conducted at a tertiary care university hospital.Patients: Patients included a newborn child and two other subjects with RTH.Intervention: The effect of various TH-lowering agents in the subject with RTH was studied. In vitro studies including EMSA and mammalian two-hybrid assay as well as in vitro transfection studies were conducted.Main Outcome Measures: Sequencing of the TH receptor (TR)β and in vitro measurements of receptor-cofactor interaction were measured.Results: ...
Journal of Clinical Investigation, 1992
Generalized resistance to thyroid hormone (GRTH) is a syndrome of hyposensitivity to triiodothyronine (T3) that displays autosomal dominant inheritance. The genetic defect commonly lies in the ligand-binding domain of one of the TRY8 alleles. Since there are two major thyroid hormone receptor (TR) isoforms, TRa and TRI, it is not known how the mutant receptor mediates a dominant negative effect. Previously, we showed that T3 caused dissociation of TR homodimers and TRa/TR,8 dimers from several thyroid hormone response elements (TREs). Hence, we used the electrophoretic mobility shift assay to compare the effect of T3 on the DNA binding of mutant TRfi-1 (Mf-1) from a kindred with GRTH with normal TRfl. Mf-I bound better as a homodimer than TR.6, but dissociated from DNA only at high T3 concentrations. Both receptors heterodimerized with nuclear auxiliary proteins. They also dimerized with TRa and with each other. Surprisingly, T3 disrupted the DNA binding of the Mf-l /TR isoform dimers. Thus, mechanisms for the dominant negative effect by mutant TRs likely involve either increased binding to TREs by mutant homodimers that cannot bind T3 (hence cannot dissociate from DNA) and/or the formation of inactive mutant TR/nuclear protein heterodimers.
The Journal of Clinical Endocrinology & Metabolism, 2005
Resistance to thyroid hormone (RTH) is a syndrome of reduced sensitivity to thyroid hormone, most commonly caused by mutations in the thyroid hormone receptor (TR)  gene. Mutations are mostly located in the ligand-binding domain of the TR, decreasing T 3 binding to the mutant TR molecule, which in turn interferes with the function of the wild-type (WT) TR. A total of 122 different TR gene mutations have been identified so far, with 46 occurring in more than one family. We now report a family with two novel TR mutations occurring in the same nucleotide. The proposita had two children from each of her two marriages. One daughter and one son from each marriage had severe RTH with free T 4 and T 3 levels 3-to 4-fold the mean normal values and unsuppressed TSH, mental retardation, and deafness. The proposita had a missense mutation (GTG to GGG) in codon 458 of the TR gene, resulting in the replacement of the normal valine with glycine (V458G). Although this mutation was transmitted to her affected son, the mutated codon in her affected daughter was GAG, encoding glutamic acid (V458E). Haplotype analysis showed that this de novo mutation occurred on the already mutant allele of the proposita. Cotransfection of each of these mutant TRs with the wild-type TR showed a potent dominant negative effect. Large amounts of T 3 were required to dissociate homodimers of the mutant TR bound to DNA. In addition, and in contrast to other mutant TRs with severe T 3-binding defects, homodimer release failed to recruit the steroid receptor coactivator. No defects in heterodimerization with retinoid X receptor-␣ or association with a nuclear receptor corepressor, were identified. These in vitro data are in agreement with the in vivo phenotype of severe RTH. Unique and previously unreported in human inherited diseases is the occurrence of a de novo mutation at an already mutant nucleotide. Because the occurrence by chance is extremely unlikely, it is postulated that the presence of three guanines in the sequence created by the mutant nucleotide of the proposita results in a mutagenic site prone to de novo mutation.
Journal of Clinical Investigation, 1994
Resistance to thyroid hormone (RTH), with elevated serum free thyroid hormones and nonsuppressed thyrotropin levels, is either relatively asymptomatic, suggesting a generalized disorder (GRTH) or associated with thyrotoxic features, indicating possible selective pituitary resistance (PRTH). 20 GRTH and 9 PRTH cases, sporadic or dominantly inherited, were analyzed. Affected individuals were heterozygous for single nucleotide substitutions in the thyroid hormone receptor fi gene, except for a single case of a seven nucleotide insertion. With one exception, the corresponding 13 novel and 7 known codon changes localized to and extended the boundaries of two mutation clusters in the hormone-binding domain of the receptor. 15 kindreds shared 6 different mutations, and haplotype analyses of the mutant allele showed that they occurred independently. The majority (14 out of 19) of the recurrent but a minority (1 out of 10) of unique mutations were transitions of CpG dinucleotides. Mutant receptor binding to ligand was moderately or severely impaired and did not correlate with the magnitude of thyroid dysfunction. There was no association between clinical features and the nature or location of a receptor mutation. These observations suggest that GRTH and PRTH are phenotypic variants of the same genetic disorder, whose clinical expression may be modulated by other non-imutation-related factors. (J. Clin. Invest. 1994. 94:506-515.)
Biochemical and Biophysical Research Communications, 1991
Thyroid hormone resistance is a syndrome of considerable clinical heterogeneity. Three mutations in the c-e& A p gene encoding the human B thyroid hormone receptor have been described in different kindreds. We report here, in a family affected with peripheral thyroid hormone resistance, a unique point mutation in the ligand binding domain of the c-em A B gene resulting in histidine replacement of an arginine residue at position 438. The region in which the mutation occurred was identified by single stranded conformation polymorphism analysis and confirmed by subcloning and sequencing of the mutant alleles from each of the affected members. Binding of tri-iodothyronine to isolated nuclei from family members was normal suggesting the mechanism of thyroid hormone resistance in this family is not mediated by abnormal binding of ligand and receptor.
Resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha
Biochimica et Biophysica Acta (BBA) - General Subjects, 2013
Background: Thyroid hormone acts via receptor subtypes (TRα1, TRβ1, TRβ2) with differing tissue distributions, encoded by distinct genes (THRA, THRB). THRB mutations cause a disorder with central (hypothalamic-pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels. Scope of review: This review describes the clinical features, genetic and molecular pathogenesis of a homologous human disorder mediated by defective THRA. Clinical features include growth retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels and a low T4/T3 ratio, together with subnormal reverse T3 levels. Heterozygous TRa1 mutations in affected individuals generate defective mutant receptors which inhibit wild-type receptor action in a dominant negative manner. Major conclusions: Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis. General significance: Human THRA mutations could be more common but may have eluded discovery due to the absence of overt thyroid dysfunction. Nevertheless, in the appropriate clinical context, a thyroid biochemical signature (low T4/T3 ratio, subnormal reverse T3 levels), may enable future identification of cases. This article is part of a Special Issue entitled Thyroid hormone signalling.
The Journal of Clinical Endocrinology & Metabolism, 2000
The syndrome of resistance to thyroid hormone (RTH) is characterized by decreased tissue responsiveness to thyroid hormones. Inheritance is usually autosomal dominant due to mutations in the ligand-binding domain or adjacent hinge region of the thyroid hormone receptor  (TR) gene. Six of 65 families with the RTH phenotype studied in our laboratory had normal TR1 and TR2 gene sequences. Their clinical characteristics were not different from those of subjects with TR gene mutations. Four of the 6 families were amenable to linkage analysis, and TR␣ involvement was excluded. Candidate genes were then evaluated for their possible involvement in the RTH phenotype in these 4 families: 2 coactivators [NCoA-1 (SRC-1) and NCoA-3 (AIB-1)], 2 corepressors (NCoR and SMRT), and a coregulator (RXR␥). DNA was obtained from 8 affected subjects and 41 of 45 living first degree relatives. In 2 of the 4 families, the mode of inheritance could be determined by pedigree analysis and was found to be autosomal dominant. Linkage analyses were performed using polymorphic markers near or within the 5 candidate genes. When analyses were not informative or linkage could not be excluded, direct sequencing of the genes in question was performed. Involvement of NCoA-1 was excluded in all four families assuming autosomal dominant inheritance. Roles for NCoR, SMRT, and NCoA-3 were excluded in three and a role for RXR␥ was excluded in two of the four families. However, if the two families without proven dominant mode of inheritance were compound heterozygous, only the involvement of NCoA-1 could be excluded in both. Roles for NCoR, SMRT, and RXR␥ were excluded in one of these two families. Thus, NCoA-1 and RXR␥ genes were not found to be the cause of RTH in subjects without TR gene mutations even though the absence of NCoA-1 and RXR␥ is the cause of RTH in mice. Involvement of other candidate genes in the mediation of thyroid hormone action as well as intracellular hormone transport needs to be explored in these families with non-TR, TR␣ RTH.
The Journal of Clinical Endocrinology and Metabolism, 2000
The syndrome of resistance to thyroid hormone (RTH) is characterized by decreased tissue responsiveness to thyroid hormones. Inheritance is usually autosomal dominant due to mutations in the ligand-binding domain or adjacent hinge region of the thyroid hormone receptor  (TR) gene. Six of 65 families with the RTH phenotype studied in our laboratory had normal TR1 and TR2 gene sequences. Their clinical characteristics were not different from those of subjects with TR gene mutations. Four of the 6 families were amenable to linkage analysis, and TR␣ involvement was excluded. Candidate genes were then evaluated for their possible involvement in the RTH phenotype in these 4 families: 2 coactivators [NCoA-1 (SRC-1) and NCoA-3 (AIB-1)], 2 corepressors (NCoR and SMRT), and a coregulator (RXR␥). DNA was obtained from 8 affected subjects and 41 of 45 living first degree relatives. In 2 of the 4 families, the mode of inheritance could be determined by pedigree analysis and was found to be autosomal dominant. Linkage analyses were performed using polymorphic markers near or within the 5 candidate genes. When analyses were not informative or linkage could not be excluded, direct sequencing of the genes in question was performed. Involvement of NCoA-1 was excluded in all four families assuming autosomal dominant inheritance. Roles for NCoR, SMRT, and NCoA-3 were excluded in three and a role for RXR␥ was excluded in two of the four families. However, if the two families without proven dominant mode of inheritance were compound heterozygous, only the involvement of NCoA-1 could be excluded in both. Roles for NCoR, SMRT, and RXR␥ were excluded in one of these two families. Thus, NCoA-1 and RXR␥ genes were not found to be the cause of RTH in subjects without TR gene mutations even though the absence of NCoA-1 and RXR␥ is the cause of RTH in mice. Involvement of other candidate genes in the mediation of thyroid hormone action as well as intracellular hormone transport needs to be explored in these families with non-TR, TR␣ RTH.