Computer modeling of a newly identified THRB gene mutation (S350L) associated with resistance to thyroid hormone in three unrelated patients.
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ABSTRACT:
SUBMITTER: Nagavalli S
PROVIDER: S-EPMC4361411 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
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Computer modeling of a newly identified THRB gene mutation (S350L) associated with resistance to thyroid hormone in three unrelated patients.
Nagavalli Sravanthi S Fletterick Robert J RJ Ford George G Boston Bruce A BA Gianoukakis Andrew G AG
Thyroid : official journal of the American Thyroid Association 20140701 9
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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
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| S-EPMC4738189 | 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: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: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: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:ContextLoss of the thyroid hormone receptor is common in tumors. In mouse models, a truncated THRB gene leads to thyroid cancer. Previously, we observed up-regulation of the expression of eight microRNAs (miRs) in papillary thyroid carcinoma (PTC) tumors.ObjectiveOur objective was to determine whether THRB might be inhibited by miRs up-regulated in PTC.DesignThe potential binding of miR to the 3'-untranslated region of THRB was analyzed in silico. Direct inhibition by miRs binding to the cloned 3'-untranslated region of THRB was evaluated using luciferase assays. Inhibition of endogenous THRB and its target genes (DIO1 and APP) was examined in cell lines transfected by pre-miRs. The impact on thyroid hormone response element (TRE) was evaluated in promoter assays. Correlations between the expression of THRB and miRs was evaluated in 13 PTC tumor/normal tissue pairs.ResultsTHRB contains binding sites for the top seven miRs up-regulated in PTC (P = 0.0000002). Direct interaction with THRB was shown for miR-21 and miR-146a. We observed lower levels of THRB transcripts in cell lines transfected with miR-21, -146a, and -221 (down-regulation of 37-48%; P < 0.0001), but not with miR-181a. THRB protein was suppressed down to 10-28% by each of four miRs. Concomitant expression of DIO1 and APP was affected (down-regulation of 32-66%, P < 0.0034 and up-regulation of 48-57%, P < 0.0002, respectively). All four miRs affected TRE activity in promoter assays. Down-regulation of luciferase occurred after transfection with pTRE-TK-Luc construct and each of four miRs. The analysis of tumor/normal tissue pairs revealed down-regulation of THRB in 11 of 13 pairs (1.3- to 9.1-fold), and up-regulation of miR-21, -146a, -181a, and -221 in almost all pairs.ConclusionsMiRs up-regulated in PTC tumors directly inhibit the expression of THRB, an important tumor suppressor gene.
| S-EPMC3047217 | 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.
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Project description:Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 × 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.
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