A De Novo Mutation in an Already Mutant Nucleotide of the Thyroid Hormone Receptor β Gene Perpetuates Resistance to Thyroid Hormone (original) (raw)
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Proceedings of the National Academy of Sciences, 1989
The syndrome of generalized resistance to thyroid hormone is characterized by elevated circulating levels of thyroid hormone in the presence of an overall eumetabolic state and failure to respond normally to triiodothyronine. We have evaluated a family with inherited generalized resistance to thyroid hormone for abnormalities in the thyroid hormone nuclear receptors. A single guanine----cytosine replacement in the codon for amino acid 340 resulted in a glycine----arginine substitution in the hormone-binding domain of one of two alleles of the patient's thyroid hormone nuclear receptor beta gene. In vitro translation products of this mutant human thyroid hormone nuclear receptor beta gene did not bind triiodothyronine. Thus, generalized resistance to thyroid hormone can result from expression of an abnormal thyroid hormone nuclear receptor molecule.
Molecular and Cellular Endocrinology, 1995
We identified unusual mutations in the T3 receptor (TR) p gene in a 6-year-old Japanese girl with generalized resistance to thyroid hormone. Two consecutive base substitutions, T to A and C to A at nucleotide positions 1637 and 1638, respectively, changed the 451st codon coding for Phe(TTC) to stop codon (TAA), resulting in an 11-amino acid carboxyl(C)-terminus truncation. The patient was a heterozygote. Western blotting using an anti-TR antibody demonstrated the truncated receptor protein. The patient showed severe mental retardation (IQ41), disturbance in speech development, and attention deficit hyperactivity disorder. Thyroid functional status by clinical evaluation was considered within the normal range in spite of high serum thyroid hormone levels (T4 725.9 nmol/l, T3 12.7 nmol/l, FT4 166.0 pmol/l). TSH increased from 0.6 to 24 mU/L after TRH (150 pg) injection. TSH secretion as well as lz31-uptake was suppressed only partially by T3 (75 pg/day for a week). Close examination of thyroid functions and TRP gene analysis were not possible in the family, except for paternal grandmother and one of her two sisters who showed no abnormality. The patient's truncated TRP showed very low T3 binding activity (K, = 0.1 x lo-" M) transcriptional activity, and a very strong dominant negative effect. When co-expressed with wild-type TR/3 at the molar ratio 1:l in CV-1 cells, the mutant receptor inhibited the wild-type TR/3 transcriptional activity by 74% at 10 nM T3. Even 1 PM T3 could not normalize these impaired functions.
2016
Mutations in the human beta thyroid hormone receptor (h-TRB) gene are associated with the syndrome of generalized resistance to thyroid hormone. We investigated the interaction of three h-TR,61 mutants representing different types of func-tional impairment (kindreds ED, OK, and PV) with different response elements for 3,3',5-triiodothyronine(T3) and with reti-noid X receptor 13 (RXR,6). The mutant receptors showed an increased tendency to form homodimers on a palindromic T3-response element (TREpal), a direct repeat (DR + 4), and an inverted palindrome (TRElap). On TRElap, wild typeTR bind-ing was decreased by T3, while the mutant receptors showed a variably decreased degree of dissociation from TRElap in re-sponse to T3. The extent of dissociation was proportional to their T3 binding affinities. RXRf induced the formation of h-TRfi1:RXRf heterodimers equally well for mutants and the wild type h-TR$1 on these T3 response elements. However, the T3-dependent increase in heterodim...
European Journal of Endocrinology, 2004
Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but can occasionally present with signs and symptoms of thyrotoxicosis or rarely with hypothyroidism. Affected individuals are usually heterozygous for mutations in the thyroid hormone receptor beta gene (TR-beta).We present a patient with RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single nucleotide substitution I280S…
A Mutation in the Thyroid Hormone Receptor Alpha Gene
New England Journal of Medicine, 2012
Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using wholeexome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues. T hyroid hormones have diverse actions, which include regulation of skeletal growth, maturation of the central nervous system, cardiac and gastrointestinal function, and energy homeostasis. In addition, thyroid hormones control their own production by feedback inhibition of hypothalamic thyrotropinreleasing hormone and pituitary thyroid-stimulating hormone, which direct their synthesis or release. These physiological effects are principally mediated by hormone action through nuclear receptor proteins that act as ligand-inducible transcription factors and either positively or negatively regulate the expression of target genes in different tissues in a hormone-dependent manner.
Thyroid, 1994
Resi stance to thyroid hormone (RTH), is usually dominantly inherited and characterised by elevated thyroid hormone levels together with reduced central and peripheral tissue responsiveness to hormone action. Following linkage of this disorder to the thyroid hormone receptor ß (TRß) gene locus (1), a number of studies have identified TRß mutations in RTH. Cloning of the cDNA encoding human TRßl (2) initially suggested an open reading frame of 456 amino acids. However, subsequent sequencing of this cDNA as well as genomic clones showed a guanine rather than adenine at nucleotide position 288, generating a new initiation codon (3), and leading to a predicted protein sequence which contains 461 amino acids. In addition, the exons of the TRß gene have been numbered either from 00 to 8 or from 1 to 10, depending on the designation of non-coding exons. Publications to date have used both notations to describe TRß mutations leading to confusion. To avoid this, we suggest that the following nomenclature be adopted henceforth: a. The nucleotide position used to describe mutations remains unchanged as published previously (2).
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.
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.
Thyroid, 2008
Background: Up to date, three thyroid-stimulating hormone receptor (TSHR) germline variants have been reported for which no functional consequences have been detected by in vitro characterizations. However, familial nonautoimmune hyperthyroidism and hot nodules are clearly associated with constitutively activating TSHR germline mutations. We describe a family with a new TSHR germline mutation that is associated with euthyroidism in 13 family members and hyperthyroidism in 1 family member. Methods: Mutation analysis of the TSHR gene was performed by denaturing gradient gel electrophoresis. TSHR constructs were characterized by determination of cell surface expression, 3 0-5 0-cyclic adenosine monophosphate (cAMP) accumulation, and constitutive cAMP activity. Results: A novel TSHR germline mutation (N372T) was found in a man who presented with thyrotoxicosis. The mutation was also detected in 13 family members, all of whom were euthyroid. Interestingly, an additional constitutively active somatic mutation (S281N) was identified on the second parental TSHR allele of the hyperthyroid index patient. Linear regression analysis showed a lack of constitutive activity for N372T. Moreover, coexpression studies of N372T with S281N did not reveal any evidence for a functional influence of N372T on the constitutively active mutation (CAM). Conclusions: N372T is unlikely to cause altered thyroid function. This is consistent with the finding that only the index patient with the additional somatic mutation S281N was hyperthyroid.