RARE DISEASE
Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha
Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha
Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha
Synonyms: RTHa, Resistance to thyroid hormone alpha, Resistance to thyroid hormone due to a mutation in TRa
Synonyms: RTHa, Resistance to thyroid hormone alpha, Resistance to thyroid hormone due to a mutation in TRa
Synonyms: RTHa, Resistance to thyroid hormone alpha, Resistance to thyroid hormone due to a mutation in TRa
Drug discovery
0
drugs
With orphan designations
Overview
Resistance to thyroid hormone alpha (RTHα) is a rare genetic disorder caused by heterozygous mutations in the THRA gene, impairing thyroid hormone receptor α1 (TRα1) function. It manifests as tissue-specific hypothyroidism with near-normal thyroid function tests, presenting with growth retardation, skeletal dysplasia, constipation, neurodevelopmental delays, and dysmorphic features. Biochemical findings include low/normal free thyroxine (FT4), high/normal free triiodothyronine (FT3), reduced FT4/FT3 ratio, and low reverse T3 levels. Diagnosis requires genetic confirmation of THRA mutations.
Therapies
Levothyroxine supplementation improves growth, constipation, metabolic rate, and neurocognitive symptoms in some patients [4][5][8].
Symptomatic management includes addressing anemia, dyslipidemia, and bone health (e.g., vitamin D/calcium) [4][17].
Beta-blockers for tachycardia; avoid overtreatment due to variable tissue responsiveness [11][17].
Categories: rare endocrine diseases, rare genetic diseases
Research Papers
66 drug discovery papers about Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
66 drug discovery papers about Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-11 | Thyroxine Treatment of Adult RTHα Patients: Safety, Efficacy, and Metabolomic Changes.
Resistance to thyroid hormone alpha (RTHα) is a rare genetic disorder with symptoms of hypothyroidism, but normal or close-to-normal thyroid function tests. Treatment with levothyroxine (L-T4) may be beneficial. This study investigated the efficacy, safety and biochemical changes of high-dose L-T4 and liothyronine (L-T3) treatment. Four RTHα (Ala263Val) patients were treated with L-T4 (1.75 µg/kg) in a pilot open-label study and monitored for three years. Quality of life (QoL) was assessed using ThyPro. Analysis of auxiological- and biochemical-parameters, bone mineral density (BMD) and exploratory metabolomics was performed. A partial replacement of L-T4 with L-T3 was attempted. Treatment with L-T4 increased FT4, FT3, and rT3 to supraphysiological concentrations (relative to reference intervals) and suppressed thyroid-stimulating hormone with no adverse effects. Heart rate, bone markers, and sex hormone-binding globulin transiently increased. Several classes of lipids were reduced. BMD appeared unaltered. Patients reported improved QoL. One patient presented a short non-sustained ventricular tachycardia on L-T3 + L-T4. L-T4 treatment of adult RTHα patients was safe and improved QoL in adherent patients.
2026-06-01 | Resistance to thyroid hormone alpha (RTHα) due to a de novo THRA p.Asp268Asn variant: Early levothyroxine treatment and outcome
Resistance to thyroid hormone alpha (RTHα) is a rare disorder that may present with clear hypothyroid features despite normal thyroid-stimulating hormone (TSH) and marginally low free thyroxine (FT4), leading to underrecognition. We report a 12-year-old with a de novo thyroid hormone receptor alpha ( THRA ) variant (c.802G>A, p.Asp268Asn), treated with levothyroxine from the age of 14 months, who showed improved energy, motor milestones, and school performance. This case highlights that children with disproportionate hypothyroid signs and subtle thyroid function test abnormalities warrant early assessment of free triiodothyronine (FT3), timely THRA genetic testing, and a monitored levothyroxine trial, which may benefit milder RTHα phenotypes.
2026-05-12 | Saroglitazar, a novel PPAR-α/γ agonist, modulates thyroid hormone homeostasis through hepatic UGT expression in wistar rats.
PPAR agonists are promising therapeutic agents approved for managing dyslipidemia and insulin resistance, and emerging evidence suggests they may also affect thyroid hormone metabolism by modulating hepatic enzymes and transporters. We aimed to determine whether dual PPAR activation via saroglitazar modulates hepatic enzymes involved in thyroid hormone clearance, thereby bridging metabolic regulation with thyroid function. To investigate this possibility, female rats were dosed orally with saroglitazar (3, 10, or 30 mg/kg/day) for 28 days. Serum T4, T3, and TSH levels were measured using high-sensitivity immunoassays, and hepatic UGT isoforms and thyroid gene expression were assessed by qPCR. Saroglitazar modestly increased T4 and slightly reduced T3, while serum TSH remained stable, suggestive of a well-compensated HPT axis under the study conditions. Mechanistically, saroglitazar markedly induced hepatic UGT1A1 and UGT1A6, key enzymes in T4 glucuronidation and triggered compensatory upregulation of thyroid-specific genes (TSH, TPO, thyroglobulin, and the TSH receptor). Histological analysis revealed no adverse changes in the liver, thyroid, or pituitary glands. Overall, our findings indicate that saroglitazar modulates thyroid hormone homeostasis in rodents primarily via PPAR-mediated peripheral metabolism and intrinsic thyroidal compensation without central HPT disruption; these adaptive changes are rodent-specific due to the lack of thyroxine-binding globulin and unlikely to translate to humans.
2026-01-01 | The Role of Transdermal 3,5-Diiodo-L-Thyronine (T2) in Hypothyroid Metabolic Recovery: A Formulation Rationale and Consumer Case Series
Weight loss resistance remains one of the most prevalent and clinically frustrating complaints among hypothyroid patients, persisting in a substantial proportion of individuals despite normalization of serum thyroid-stimulating hormone (TSH) on levothyroxine (T4) monotherapy. Conventional thyroid hormone replacement corrects circulating thyroxine deficits but fails to address the downstream mitochondrial metabolic impairment that underlies depressed basal metabolic rate (BMR) in these patients. 3,5-Diiodo-L-thyronine (T2), once considered a biologically inert byproduct of thyroid hormone deiodination, has emerged in the past two decades as a potent, rapid-acting stimulator of mitochondrial respiration with a distinct mechanism of action from its parent hormones T4 and triiodothyronine (T3). T2 exerts its metabolic effects primarily through direct, non-genomic activation of cytochrome c oxidase (Complex IV) and upregulation of mitochondrial uncoupling proteins (UCPs), resulting in increased lipid oxidation and thermogenesis without proportional activation of nuclear thyroid hormone receptors (TR-alpha and TR-beta). This receptor selectivity profile confers a meaningful clinical advantage: T2 stimulates basal metabolic rate while exhibiting substantially lower potential for cardiac overstimulation and TSH suppression compared with T3. Transdermal delivery of T2 bypasses hepatic first-pass metabolism and gastrointestinal degradation, offering pharmacokinetic advantages including sustained systemic release and more consistent steady-state serum concentrations. This white paper presents the formulation rationale for a transdermal 3,5-Diiodo-L-thyronine product, including the biophysical mechanism of action, pharmacokinetic basis for transdermal delivery, clinical application framework, and an observational consumer case series detailing outcomes in weight-loss-resistant hypothyroid individuals utilizing the formulation in real-world settings.
2025-08-05 | Multigenerational thyroid hormone resistance due to THRβ mutation.
Resistance to thyroid hormone (RTH) is a rare genetic disorder caused by mutations in the thyroid hormone receptors α or β (THRα, THRβ) genes, leading to impaired tissue responsiveness to thyroid hormones. While its systemic effects are well-documented, the cardiac manifestations of RTH, including hypertrophic and dilated cardiomyopathy (DCM), arrhythmias, and heart failure, are often underrecognized, particularly in cases of treatment refractory heart failure. This case report aims to highlight the importance of cardiological awareness in diagnosing and managing RTH-related cardiomyopathy. We report the case of a 50-year-old Caucasian female with a confirmed variant c.1357C > A, p.P453T mutation in the THRβ gene, presenting with recurrent goitre, hypothyroidism, and progressive cardiovascular complications. Her clinical course was marked by episodes of angina-like symptoms, atrial fibrillation, left heart failure, and severe pulmonary oedema, eventually progressing to DCM with an ejection fraction below 30%. Despite optimal guideline-directed medical therapy, her cardiac condition deteriorated, necessitating orthotopic heart transplantation. Genetic testing confirmed the same mutation in her mother, brother, and two sons, highlighting the autosomal dominant inheritance of the disease. Thyroidectomy and lifelong levothyroxine therapy, combined with post-transplant immunosuppression, further complicated her management, underscoring the systemic interplay of RTH with cardiac function. This case emphasizes the rarity and clinical significance of RTH as a potential aetiology in refractory cardiac failure. Cardiologists should maintain a high index of suspicion for thyroid dysfunction in unexplained or treatment-resistant cardiomyopathy, particularly when associated with familial thyroid disorders or arrhythmias. Early diagnosis and a multidisciplinary approach involving endocrinology and cardiology are essential for improving outcomes and tailored therapeutic strategies for patients with RTH-related cardiomyopathy.
proteins
2024-05-15 | Clinical Characteristics of Children with THRA Mutations: Variable Phenotype and Good Response to Recombinant Human Growth Hormone Therapy.
Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases. Three patients (P1, P2, and P3) from unrelated families presented to their endocrinologists with short stature and abnormalities in thyroid function results. P1 showed hypoactivity and mild thyroid-stimulating hormone (TSH) elevation. P2 presented with a mild developmental delay and a hormonal profile initially interpreted as central hypothyroidism. Patient P3 had severe symptoms, including hypotonia, developmental delay, normal TSH, hypercholesterolemia, severe hypertriglyceridemia, high amylase levels, and mild pericardial effusion. All the patients had low free thyroxine (FT4) levels, mild constipation, and short stature. The patients underwent exome sequencing analysis that identified three different heterozygous variants in the THRA gene (P1 and P2 had missense variants, and P3 had a stop codon variant). All patients were treated with levothyroxine replacement, improving their clinical symptoms, such as constipation, and neurological symptoms. P1 and P2 were also treated with the recombinant human growth hormone (rhGH). The improvements in growth velocity and height standard deviation scores (SDS) were remarkable. Notably, P1 had a total height gain of 2.5 SDS, reaching an adult height within the normal range. THRA gene defects can lead to growth disorders with different phenotypes. Children with THRA mutations can benefit from adequate treatment with levothyroxine and may respond well to rhGH treatment.
2021-12-13 | Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha.
Thyroid hormone signaling plays an essential role in muscle development and function, in the maintenance of muscle mass, and in regeneration after injury, via activation of thyroid nuclear receptor alpha (THRA). A mouse model of resistance to thyroid hormone carrying a frame-shift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury. The expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA-PV mice and it is known to negatively regulate myogenesis. Here, we report that in murine myoblasts COUP-TFII interacts with THRA and modulates THRA binding to thyroid response elements (TREs). Silencing of COUP-TFII expression restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts. Moreover, COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice.
2020-05-19 | CREG1 stimulates brown adipocyte formation and ameliorates diet-induced obesity in mice.
Increased formation of brown and beige adipocytes is critical for adaptive thermogenesis to maintain homeothermy in cold or to circumvent diet-induced obesity (DIO). Cellular repressor of adenovirus early region 1A-stimulated genes 1 (CREG1) exhibits the ability to stimulate brown adipogenesis, including the induction of uncoupling protein 1 (UCP1), in vitro. Thus, we aimed to clarify whether CREG1 promotes brown adipocyte formation and inhibits DIO at the whole-animal level. In mouse brown adipose tissue (BAT), CREG1 expression was markedly increased in cold but was decreased under thermoneutrality, suggesting CREG1 involvement in BAT thermogenesis. Moreover, in BAT and white adipose tissue, expression of UCP1 and fibroblast growth factor-21 and browning were both significantly higher in adipocyte P2-Creg1-transgenic (Tg) mice than in wild-type (WT) littermates. Following stimulation with a β3-adrenergic agonist, energy consumption was elevated in the Tg mice, which showed increased resistance to DIO and improvement of obesity-associated complications including fatty liver relative to WT mice. The CREG1 stimulatory effect on brown adipogenesis was confirmed in Tg-BAT primary cultures. It was also found that CREG1 binds to retinoid X receptor α, which interacts with thyroid hormone receptor for brown adipogenesis. Our findings demonstrate that CREG1 stimulates brown adipocyte formation and browning, ameliorating obesity and its related pathology in vivo.-Hashimoto, M., Kusudo, T., Takeuchi, T., Kataoka, N., Mukai, T., Yamashita, H. CREG1 stimulates brown adipocyte formation and ameliorates diet-induced obesity in mice.
2018-06-06 | Thyroid Hormone Receptor Alpha is Essential to Maintain the Satellite Cell Niche During Skeletal Muscle Injury and Sarcopenia of Aging.
Myopathic changes are commonly described in hypothyroid and hyperthyroid patients, including muscular atrophy and weakness. Satellite cells (SCs) play a major role in skeletal muscle maintenance and regeneration after injury. A mouse model of resistance to thyroid hormone-TRα1PV demonstrated impaired skeletal muscle regeneration after injury with significant reduction of SCs, suggesting that exhaustion of the SC pool contributes to the impaired regeneration. To test this hypothesis, SC activation and proliferation were analyzed in vivo in response to skeletal muscle injury and during aging. SCs of TRα1PV male mice were analyzed four days after cardiotoxin-induced muscle injury, and they were compared to wild-type (WT) male animals. TRα-knockdown C2C12 myoblasts were injected into injured skeletal muscle, and four days after transplantation, the in vivo behavior was compared to control C2C12 myoblasts. Skeletal muscle regeneration was compared in younger and older TRα1PV and WT animals. The total number of SCs in skeletal muscle of TRα1PV mice was significantly lower than control, both before and shortly after muscle injury, with significant impairment of SC activation, consistent with SC pool exhaustion. TRα-knockdown myoblasts showed impaired in vivo proliferation and migration. TRα1PV mice had skeletal muscle loss and significant impairment in skeletal muscle regeneration with aging. This translated to a significant reduction of the SC pool with aging compared to WT mice. TRα plays an important role in the maintenance of the SC pool. Impaired skeletal muscle regeneration in TRα1PV mice is associated with insufficient SC activation and proliferation, as well as the progressive loss of the SC pool with aging. Regulation of the SC pool and SC proliferation provides a therapeutic target to enhance skeletal muscle regeneration and possibly slow age-associated sarcopenia.
1997-02-13 | A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators.
The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone beta receptor (TR beta) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic alpha-helix at the carboxyl terminus of TR beta and the position of the homologous residue in the crystal structure of TR alpha indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone alpha promoter by this mutant, suggests that the amphipathic alpha-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.
small molecules
2026-06-11 | Thyroxine Treatment of Adult RTHα Patients: Safety, Efficacy, and Metabolomic Changes.
Resistance to thyroid hormone alpha (RTHα) is a rare genetic disorder with symptoms of hypothyroidism, but normal or close-to-normal thyroid function tests. Treatment with levothyroxine (L-T4) may be beneficial. This study investigated the efficacy, safety and biochemical changes of high-dose L-T4 and liothyronine (L-T3) treatment. Four RTHα (Ala263Val) patients were treated with L-T4 (1.75 µg/kg) in a pilot open-label study and monitored for three years. Quality of life (QoL) was assessed using ThyPro. Analysis of auxiological- and biochemical-parameters, bone mineral density (BMD) and exploratory metabolomics was performed. A partial replacement of L-T4 with L-T3 was attempted. Treatment with L-T4 increased FT4, FT3, and rT3 to supraphysiological concentrations (relative to reference intervals) and suppressed thyroid-stimulating hormone with no adverse effects. Heart rate, bone markers, and sex hormone-binding globulin transiently increased. Several classes of lipids were reduced. BMD appeared unaltered. Patients reported improved QoL. One patient presented a short non-sustained ventricular tachycardia on L-T3 + L-T4. L-T4 treatment of adult RTHα patients was safe and improved QoL in adherent patients.
2026-06-01 | Resistance to thyroid hormone alpha (RTHα) due to a de novo THRA p.Asp268Asn variant: Early levothyroxine treatment and outcome
Resistance to thyroid hormone alpha (RTHα) is a rare disorder that may present with clear hypothyroid features despite normal thyroid-stimulating hormone (TSH) and marginally low free thyroxine (FT4), leading to underrecognition. We report a 12-year-old with a de novo thyroid hormone receptor alpha ( THRA ) variant (c.802G>A, p.Asp268Asn), treated with levothyroxine from the age of 14 months, who showed improved energy, motor milestones, and school performance. This case highlights that children with disproportionate hypothyroid signs and subtle thyroid function test abnormalities warrant early assessment of free triiodothyronine (FT3), timely THRA genetic testing, and a monitored levothyroxine trial, which may benefit milder RTHα phenotypes.
2026-05-12 | Saroglitazar, a novel PPAR-α/γ agonist, modulates thyroid hormone homeostasis through hepatic UGT expression in wistar rats.
PPAR agonists are promising therapeutic agents approved for managing dyslipidemia and insulin resistance, and emerging evidence suggests they may also affect thyroid hormone metabolism by modulating hepatic enzymes and transporters. We aimed to determine whether dual PPAR activation via saroglitazar modulates hepatic enzymes involved in thyroid hormone clearance, thereby bridging metabolic regulation with thyroid function. To investigate this possibility, female rats were dosed orally with saroglitazar (3, 10, or 30 mg/kg/day) for 28 days. Serum T4, T3, and TSH levels were measured using high-sensitivity immunoassays, and hepatic UGT isoforms and thyroid gene expression were assessed by qPCR. Saroglitazar modestly increased T4 and slightly reduced T3, while serum TSH remained stable, suggestive of a well-compensated HPT axis under the study conditions. Mechanistically, saroglitazar markedly induced hepatic UGT1A1 and UGT1A6, key enzymes in T4 glucuronidation and triggered compensatory upregulation of thyroid-specific genes (TSH, TPO, thyroglobulin, and the TSH receptor). Histological analysis revealed no adverse changes in the liver, thyroid, or pituitary glands. Overall, our findings indicate that saroglitazar modulates thyroid hormone homeostasis in rodents primarily via PPAR-mediated peripheral metabolism and intrinsic thyroidal compensation without central HPT disruption; these adaptive changes are rodent-specific due to the lack of thyroxine-binding globulin and unlikely to translate to humans.
2026-01-01 | The Role of Transdermal 3,5-Diiodo-L-Thyronine (T2) in Hypothyroid Metabolic Recovery: A Formulation Rationale and Consumer Case Series
Weight loss resistance remains one of the most prevalent and clinically frustrating complaints among hypothyroid patients, persisting in a substantial proportion of individuals despite normalization of serum thyroid-stimulating hormone (TSH) on levothyroxine (T4) monotherapy. Conventional thyroid hormone replacement corrects circulating thyroxine deficits but fails to address the downstream mitochondrial metabolic impairment that underlies depressed basal metabolic rate (BMR) in these patients. 3,5-Diiodo-L-thyronine (T2), once considered a biologically inert byproduct of thyroid hormone deiodination, has emerged in the past two decades as a potent, rapid-acting stimulator of mitochondrial respiration with a distinct mechanism of action from its parent hormones T4 and triiodothyronine (T3). T2 exerts its metabolic effects primarily through direct, non-genomic activation of cytochrome c oxidase (Complex IV) and upregulation of mitochondrial uncoupling proteins (UCPs), resulting in increased lipid oxidation and thermogenesis without proportional activation of nuclear thyroid hormone receptors (TR-alpha and TR-beta). This receptor selectivity profile confers a meaningful clinical advantage: T2 stimulates basal metabolic rate while exhibiting substantially lower potential for cardiac overstimulation and TSH suppression compared with T3. Transdermal delivery of T2 bypasses hepatic first-pass metabolism and gastrointestinal degradation, offering pharmacokinetic advantages including sustained systemic release and more consistent steady-state serum concentrations. This white paper presents the formulation rationale for a transdermal 3,5-Diiodo-L-thyronine product, including the biophysical mechanism of action, pharmacokinetic basis for transdermal delivery, clinical application framework, and an observational consumer case series detailing outcomes in weight-loss-resistant hypothyroid individuals utilizing the formulation in real-world settings.
2025-08-05 | Multigenerational thyroid hormone resistance due to THRβ mutation.
Resistance to thyroid hormone (RTH) is a rare genetic disorder caused by mutations in the thyroid hormone receptors α or β (THRα, THRβ) genes, leading to impaired tissue responsiveness to thyroid hormones. While its systemic effects are well-documented, the cardiac manifestations of RTH, including hypertrophic and dilated cardiomyopathy (DCM), arrhythmias, and heart failure, are often underrecognized, particularly in cases of treatment refractory heart failure. This case report aims to highlight the importance of cardiological awareness in diagnosing and managing RTH-related cardiomyopathy. We report the case of a 50-year-old Caucasian female with a confirmed variant c.1357C > A, p.P453T mutation in the THRβ gene, presenting with recurrent goitre, hypothyroidism, and progressive cardiovascular complications. Her clinical course was marked by episodes of angina-like symptoms, atrial fibrillation, left heart failure, and severe pulmonary oedema, eventually progressing to DCM with an ejection fraction below 30%. Despite optimal guideline-directed medical therapy, her cardiac condition deteriorated, necessitating orthotopic heart transplantation. Genetic testing confirmed the same mutation in her mother, brother, and two sons, highlighting the autosomal dominant inheritance of the disease. Thyroidectomy and lifelong levothyroxine therapy, combined with post-transplant immunosuppression, further complicated her management, underscoring the systemic interplay of RTH with cardiac function. This case emphasizes the rarity and clinical significance of RTH as a potential aetiology in refractory cardiac failure. Cardiologists should maintain a high index of suspicion for thyroid dysfunction in unexplained or treatment-resistant cardiomyopathy, particularly when associated with familial thyroid disorders or arrhythmias. Early diagnosis and a multidisciplinary approach involving endocrinology and cardiology are essential for improving outcomes and tailored therapeutic strategies for patients with RTH-related cardiomyopathy.
proteins
2024-05-15 | Clinical Characteristics of Children with THRA Mutations: Variable Phenotype and Good Response to Recombinant Human Growth Hormone Therapy.
Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases. Three patients (P1, P2, and P3) from unrelated families presented to their endocrinologists with short stature and abnormalities in thyroid function results. P1 showed hypoactivity and mild thyroid-stimulating hormone (TSH) elevation. P2 presented with a mild developmental delay and a hormonal profile initially interpreted as central hypothyroidism. Patient P3 had severe symptoms, including hypotonia, developmental delay, normal TSH, hypercholesterolemia, severe hypertriglyceridemia, high amylase levels, and mild pericardial effusion. All the patients had low free thyroxine (FT4) levels, mild constipation, and short stature. The patients underwent exome sequencing analysis that identified three different heterozygous variants in the THRA gene (P1 and P2 had missense variants, and P3 had a stop codon variant). All patients were treated with levothyroxine replacement, improving their clinical symptoms, such as constipation, and neurological symptoms. P1 and P2 were also treated with the recombinant human growth hormone (rhGH). The improvements in growth velocity and height standard deviation scores (SDS) were remarkable. Notably, P1 had a total height gain of 2.5 SDS, reaching an adult height within the normal range. THRA gene defects can lead to growth disorders with different phenotypes. Children with THRA mutations can benefit from adequate treatment with levothyroxine and may respond well to rhGH treatment.
2021-12-13 | Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha.
Thyroid hormone signaling plays an essential role in muscle development and function, in the maintenance of muscle mass, and in regeneration after injury, via activation of thyroid nuclear receptor alpha (THRA). A mouse model of resistance to thyroid hormone carrying a frame-shift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury. The expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA-PV mice and it is known to negatively regulate myogenesis. Here, we report that in murine myoblasts COUP-TFII interacts with THRA and modulates THRA binding to thyroid response elements (TREs). Silencing of COUP-TFII expression restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts. Moreover, COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice.
2020-05-19 | CREG1 stimulates brown adipocyte formation and ameliorates diet-induced obesity in mice.
Increased formation of brown and beige adipocytes is critical for adaptive thermogenesis to maintain homeothermy in cold or to circumvent diet-induced obesity (DIO). Cellular repressor of adenovirus early region 1A-stimulated genes 1 (CREG1) exhibits the ability to stimulate brown adipogenesis, including the induction of uncoupling protein 1 (UCP1), in vitro. Thus, we aimed to clarify whether CREG1 promotes brown adipocyte formation and inhibits DIO at the whole-animal level. In mouse brown adipose tissue (BAT), CREG1 expression was markedly increased in cold but was decreased under thermoneutrality, suggesting CREG1 involvement in BAT thermogenesis. Moreover, in BAT and white adipose tissue, expression of UCP1 and fibroblast growth factor-21 and browning were both significantly higher in adipocyte P2-Creg1-transgenic (Tg) mice than in wild-type (WT) littermates. Following stimulation with a β3-adrenergic agonist, energy consumption was elevated in the Tg mice, which showed increased resistance to DIO and improvement of obesity-associated complications including fatty liver relative to WT mice. The CREG1 stimulatory effect on brown adipogenesis was confirmed in Tg-BAT primary cultures. It was also found that CREG1 binds to retinoid X receptor α, which interacts with thyroid hormone receptor for brown adipogenesis. Our findings demonstrate that CREG1 stimulates brown adipocyte formation and browning, ameliorating obesity and its related pathology in vivo.-Hashimoto, M., Kusudo, T., Takeuchi, T., Kataoka, N., Mukai, T., Yamashita, H. CREG1 stimulates brown adipocyte formation and ameliorates diet-induced obesity in mice.
2018-06-06 | Thyroid Hormone Receptor Alpha is Essential to Maintain the Satellite Cell Niche During Skeletal Muscle Injury and Sarcopenia of Aging.
Myopathic changes are commonly described in hypothyroid and hyperthyroid patients, including muscular atrophy and weakness. Satellite cells (SCs) play a major role in skeletal muscle maintenance and regeneration after injury. A mouse model of resistance to thyroid hormone-TRα1PV demonstrated impaired skeletal muscle regeneration after injury with significant reduction of SCs, suggesting that exhaustion of the SC pool contributes to the impaired regeneration. To test this hypothesis, SC activation and proliferation were analyzed in vivo in response to skeletal muscle injury and during aging. SCs of TRα1PV male mice were analyzed four days after cardiotoxin-induced muscle injury, and they were compared to wild-type (WT) male animals. TRα-knockdown C2C12 myoblasts were injected into injured skeletal muscle, and four days after transplantation, the in vivo behavior was compared to control C2C12 myoblasts. Skeletal muscle regeneration was compared in younger and older TRα1PV and WT animals. The total number of SCs in skeletal muscle of TRα1PV mice was significantly lower than control, both before and shortly after muscle injury, with significant impairment of SC activation, consistent with SC pool exhaustion. TRα-knockdown myoblasts showed impaired in vivo proliferation and migration. TRα1PV mice had skeletal muscle loss and significant impairment in skeletal muscle regeneration with aging. This translated to a significant reduction of the SC pool with aging compared to WT mice. TRα plays an important role in the maintenance of the SC pool. Impaired skeletal muscle regeneration in TRα1PV mice is associated with insufficient SC activation and proliferation, as well as the progressive loss of the SC pool with aging. Regulation of the SC pool and SC proliferation provides a therapeutic target to enhance skeletal muscle regeneration and possibly slow age-associated sarcopenia.
1997-02-13 | A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators.
The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone beta receptor (TR beta) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic alpha-helix at the carboxyl terminus of TR beta and the position of the homologous residue in the crystal structure of TR alpha indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone alpha promoter by this mutant, suggests that the amphipathic alpha-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.
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