A novel mutation of the THRB gene in a Japanese family with resistance to thyroid hormone.
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ABSTRACT:
SUBMITTER: Ito J
PROVIDER: S-EPMC4738189 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
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A novel mutation of the THRB gene in a Japanese family with resistance to thyroid hormone.
Ito Jumpei J Narumi Satoshi S Nishizawa Kazumichi K Kamimaki Tsutomu T Hori Naoaki N Hasegawa Tomonobu T
Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 20160130 1
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Project description:IntroductionThyroid hormone resistance (RTH) (mim # 188570) is a rare autosomal dominant genetic disorder characterized by reduced thyroid hormone response in target tissues. The clinical manifestations of RTH vary from no symptoms to symptoms of thyroid hormone deficiency to symptoms of thyroid hormone excess.Patient concern and clinical findingsA 24-month-old girl presented with growth retardation, tachycardia, and persistently elevated thyroid hormones despite antithyroid treatment.Diagnosis/intervention/outcomesThe patient was diagnosed with RTH, after whole exon gene sequencing, found a de novo missense mutation (c.1375T > G,p.Phe459Val) in a novel locus of the thyroid hormone receptor beta gene. She had only mild growth retardation, so the decision was made to monitor her development without intervention. At her last follow-up at 5 years and 8 months of age, she continued to show growth retardation (-2 standard deviation below age-appropriate levels), in addition to delayed language development. Her comprehension ability and heart rate have remained normal.ConclusionsWe report a mild case of RTH caused by a novel thyroid hormone receptor beta gene mutation. RTH should be considered in the differential diagnosis of abnormal serum thyroxine levels during neonatal screening.
| S-EPMC10145980 | biostudies-literature
Project description:A 13-year-old female with a novel THRB gene mutation (c.1033G>T, p.G345C) presented with 3- to 6-fold higher serum iodothyronine levels and more severe clinical manifestation than 2 other family members carrying the same mutation. The leukocytes of the proband expressed both wild-type and mutant THRB mRNAs, excluding the possibility of a partial deletion of the allele not carrying the mutation. The proband's fibroblasts showed reduced responsiveness to triiodothyronine compared with those of another affected family member. The more severe clinical and biochemical phenotype suggest a modifier-mediated worsening of the resistance to thyroid hormone.
| S-EPMC6797074 | biostudies-literature
Project description:Inactivating mutations of THRB, which encodes the thyroid hormone receptor β (TRβ), cause resistance to thyroid hormone (RTH; OMIM 190160). To date, more than 100 THRB mutations have been reported among RTH patients. Most mutations substitute a single amino-acid residue in the ligand-binding domain. In this report, we describe clinical and molecular findings of three families with RTH. Three families harbored one novel (p.I431M) and two recurrent (p.R320H and p.R383C) THRB mutations. To examine the pathogenicity of identified mutations, we introduced a novel computational mutation prediction method based on three-dimensional structure data of TRβ-T3 complex. First, to define the accuracy of our prediction system, we evaluated ten previously reported 'positive control' mutations, as well as 30 seemingly benign sequence variations observed among vertebral species as 'negative controls'. We found that our system had a sensitivity of 80% and a specificity of 93%. We then analyzed three mutations detected in the present study and found that all three mutations are predicted to be deleterious. Our data suggest that our structure-based prediction system would be a prompt, inexpensive and feasible method for evaluating the pathogenicity of missense THRB mutations.
| S-EPMC3687625 | biostudies-literature
Project description:BackgroundResistance to thyroid hormone beta (RTHβ) is a rare and usually dominantly inherited syndrome caused by mutations of the thyroid hormone receptor β gene (THRB). In severe cases, it is rarely challenging to control manifestations using daily therapeutic replacement of thyroid hormone.Case presentationThe present case study concerns an 8-year-old Japanese girl with a severe phenotype of RTH (TSH, fT3, and fT4 were 34.0 mU/L, >25.0 pg/mL and, >8.0 ng/dL, respectively), caused by a novel heterozygous frameshift mutation in exon 10 of the thyroid hormone receptor beta gene (THRB), c.1347-1357 del actcttccccc : p.E449DfsX11. RTH was detected at the neonatal screening program. At 4 years of age, the patient continued to suffer from mental retardation, hyperactivity, insomnia, and reduced resting energy expenditure (REE), despite daily thyroxine (L-T4) therapy. Every-other-day high-dose liothyronine (L-T3) therapy improved her symptoms and increased her REE, without thyrotoxicosis.ConclusionIn a case of severe RTH, every-other-day L-T3 administration enhanced REE and psychomotor development, without promoting symptoms of thyrotoxicosis. Every-other-day L-T3 administration may be an effective strategy for the treatment of severe RTH.
| S-EPMC4709977 | biostudies-literature
Project description:BackgroundTo summarize the clinical characteristics, genetics and follow-up data of four children with thyroid hormone resistance (RTH) syndrome and review the related literatures.MethodsThe clinical data of the four children diagnosed with RTH syndrome in our hospital from 2018 to 2020 were retrospectively analyzed. Next-generation sequencing of the candidate genes related to thyroid diseases was performed using the blood collected from all the children and their parents who signed an informed consent. Then, relevant cases were retrieved on medical literature databases for analysis and summary.ResultsAmong the four cases, three cases of goiter; two cases of tachycardia, palpitations, personality change, hyperactivity, weight loss; one case of academic performance decline, and no hearing and vision loss were observed. Laboratory thyroid function tests indicated a mild increase in free triiodothyronine and with or without increased free thyroxine levels. Thyroid-stimulating hormone (TSH) levels were normal or slightly elevated, but thyrotropin receptor autoantibodies were negative. Octreotide inhibition test showed that the TSH levels of all the children decreased by more than 50% compared with the basal value (the genes of four cases were positive). However, magnetic resonance imaging of the pituitary gland showed no abnormalities. Related gene detection in the children and their families showed that four cases had THRB mutations: two proband mutations were from their fathers, and two cases had de novo mutations.ConclusionsThe clinical manifestations of pediatric RTH syndrome vary, and the diagnosis mainly depends on thyroid function tests. Heterozygous mutations in THRB are overall rare, even if with the advanced development of next-generation sequencing, not all the children with RTH syndrome have mutations. Furthermore, octreotide inhibition tests cannot be used as a diagnostic criterion to distinguish RTH syndrome from pituitary tumors in children.
| S-EPMC9732597 | biostudies-literature
Project description: Not available
| S-EPMC4361411 | biostudies-literature
Project description:Resistance to thyroid hormone (RTH) is a rare condition usually diagnosed in patients with classic thyroid function tests (TFTs) of elevated thyroid hormone levels with nonsuppressed TSH. The presence of autoimmune thyroid disease (AITD) can confound the clinical diagnosis of RTH. A family was evaluated because several members had elevated TSH and normal or low serum T4 concentrations with AITD. While these individuals were initially reported to have RTH, they were found to have a normal thyroid hormone receptor beta (THRB) gene sequence, and three other asymptomatic family members were found to harbor the variant TR? G339S.The THRB gene was sequenced in 19 members of a large Mexican/Aztec family. In vitro expression of the mutant TR? protein was performed, as well as computer modeling of the variant compared to known mutations in the flanking codons.Investigation of an individual with AITD who was incorrectly diagnosed with RTH led to the fortuitous discovery of a THRB gene variant (G339S) in the proposita's father, paternal aunt, and cousin. This variant was not detected in analysis of 124 unrelated alleles. All individuals harboring G339S had normal TFTs. Normal in vitro expression and function of G339S and molecular modeling predicted that this variant would not have an effect on the hypothalamic-pituitary-thyroid axis as determined by thyroid hormone binding in vitro and thyroid function tests in vivo, despite profound effects seen in mutations in the adjacent codons 338 and 340.We report an individual with normal TFTs and AITD harboring a novel THRB gene variant. In addition to illustrating the importance of accurate diagnosis of thyroid disease so that proper treatment and counseling can be given, TR? codon 339 is not essential for normal TR? function.
| S-EPMC3868256 | biostudies-literature
Project description:Thyroid hormone resistance syndrome (RTH) is a rare disorder and is characterized by elevated levels of circulating free thyroid hormones, inappropriate secretion of thyroid stimulating hormone (TSH), and reduced peripheral tissue response to thyroid hormone. 90% of RTH subjects, when studied at the level of the gene, have been found to harbor mutations in the thyroid hormone receptor-beta(THRB) gene. These affected individuals have been shown to possess a variety of missense mutations, resulting from changes in a single nucleotide in the THRB gene that corresponds to amino acid alternation. However, insertion or deletion mutations in the THRB gene sequence are quite rare, and have been observed in only a very few cases. In this study, we describe two such cases, in which two members of the same family were determined to harbor an insertion mutation in exon 10, and had also been diagnosed with generalized RTH. This insertion mutation, specifically the insertion of a cytosine at nucleotide 1358 of the THRB gene, is, to the best of our knowledge, the first such mutation reported among RTH patients in Korea.
| S-EPMC2693656 | biostudies-literature
Project description:IntroductionResistance to thyroid hormone β (RTHβ) is an inherited syndrome caused by dominant negative variants in the THRB gene (NM_000461.5). The clinical picture of RTHβ is variable, and patients harboring the same variant may display different degrees of disease severity.Case presentationA 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of THRB gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives' thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHβ in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly' the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHβ.ConclusionVariable results of TFTs on some immunoassays can be a cause of RTHβ diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel THRB variant expanding the spectrum of gene variants causing RTHβ. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of THRB variants.
| S-EPMC8647126 | biostudies-literature
Project description:RationaleThyroid hormone resistance syndrome (THRS) is an inherited condition characterized by reduced responsiveness of target tissues to thyroid hormone. Due to their nonspecific symptomatic manifestations, these patients can be misdiagnosed. This study reports a pedigree with THRS caused by a mutation in the thyroid hormone receptor β (THRβ) gene.Patient concernThe proband, a 36-year-old woman at 19+4 weeks of gestation, was referred to our hospital because of abnormal thyroid function results. She was diagnosed with hyperthyroidism in October 2015, and had been treated with methimazole until her pregnancy.DiagnosisThe proband and 2 of her children were diagnosed with THRS based on genetic analysis. Sequence analysis of the THRβ gene showed a heterozygous mutation C>A located at exon 10. The mutation results in a change in proline for threonine at amino acid position 453, P453T.InterventionsNo treatment will fully and specifically correct the defect. All 3 patients were in normal metabolic status, and thus treatment was not required.OutcomesDuring a 2-year follow-up period, none of them had any complaints. The 20-year-old son (167 cm in height) and the 18-year-old daughter (150 cm in height) both had low academic performance.LessonsElevated serum thyroid hormone (TH) levels associated with nonsuppressed thyroid-stimulating hormone (TSH) levels usually leads to the diagnosis of THRS. Genetic analysis provides a short cut to diagnosis and the treatment should be based on the patient's clinical manifestations.
| S-EPMC7598850 | biostudies-literature