RESUMO
Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.
Assuntos
Cromossomos Humanos Par 15 , Elementos Facilitadores Genéticos , MicroRNAs , Repetições de Microssatélites , Mutação , Tireotropina , Animais , Feminino , Humanos , Masculino , Cromossomos Humanos Par 15/genética , MicroRNAs/genética , Repetições de Microssatélites/genética , Linhagem , Primatas/genética , Glândula Tireoide/metabolismo , Tireotropina/genéticaRESUMO
CONTEXT: Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high thyroid hormone (TH) levels shown to be detrimental to a normal fetus (NlFe) but not to an affected fetus (AfFe). However, no information is available about differences in placental TH regulators. OBJECTIVE: To investigate whether there are differences in placentas associated with a NlFe compared with an AfFe, we had the unique opportunity to study placentas from 2 pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. METHODS: Sections of placentas were collected and frozen at -80 °C after term delivery of a NlFe and an AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. Expression of following genes was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. RESULTS: The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the TH transporters MCT10, LAT1 and LAT2, and THRA. CONCLUSION: We present the first study of the effect of the fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of TH regulators in the placenta.
Assuntos
Genes erbA , Placenta , Feminino , Gravidez , Humanos , Placenta/metabolismo , Receptores beta dos Hormônios Tireóideos , Hormônios Tireóideos/metabolismo , Feto/metabolismo , GenótipoRESUMO
BACKGROUND: Graves' disease (GD) and papillary thyroid cancer (PTC) can be concomitant. The existence of a link between these entities has long been investigated, but a clear correlation hasn't been established. We report a case of GD resistant to medical treatment in which surgery revealed unsuspected PTC and we aim to study the prevalence of PTC in Graves' disease, its clinical characteristics and review of the literature. CASE PRESENTATION: Report of a 32 yo man who presented with weight loss and was found to be biochemically hyperthyroid. Antibodies were positive. Incremental doses of methimazole provided no improvement in thyroid tests. Hypervascularity and a spongiform nodule were noted on ultrasound. Thyroid uptake and scan showed 70.2% uptake. Thyroidectomy was performed due to inadequate therapeutic response. Pathology revealed PTC with extrathyroidal extension and positive lymph nodes. A retrospective review (2000-2021) and literature review of PTC in GD was performed. Clinical data were reviewed. Statistical analysis was calculated to identify correlations. 243 GD patients had total thyroidectomy at an academic center, 50 (20%) had PTC, 14% were microcarcinomas. 76% of cases were less than 55yo, 82% female, 78% stage 1, PTC diagnosis was incidental in 48%, hyperthyroidism was difficult to treat in 10% and only 2% had recurrence of PTC. There was no correlation between demographic or clinical data. CONCLUSIONS: Evidence is controversial with some studies showing GD does not affect PTC prognosis. PTC may not be well recognized in GD, pre-operative assessment should consider risk of cancer.
Assuntos
Doença de Graves , Hipertireoidismo , Neoplasias da Glândula Tireoide , Feminino , Doença de Graves/complicações , Doença de Graves/patologia , Doença de Graves/cirurgia , Humanos , Hipertireoidismo/complicações , Masculino , Estudos Retrospectivos , Câncer Papilífero da Tireoide/complicações , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , TireoidectomiaRESUMO
We report a 10-month-old girl with familial congenital hypothyroidism harboring a novel heterozygous pathogenic variant in the paired DNA-binding domain of PAX8 (NM_003466:c.110T>C:p.Leu37Pro). Genotype-phenotype correlation revealed complete penetrance of this PAX8 defect in this family, in which the affected father and half-brother carry the same mutation. This deleterious variant has not been reported in any of the available databases [MAFgnomAD = 0, dbSNP (-)], and the amino acid leucine at position 37 is highly conserved across species. Establishing the molecular diagnosis expands our knowledge on the cause of thyroid dysgenesis and provides a guide for counseling and early treatment.
Assuntos
Hipotireoidismo Congênito , Disgenesia da Tireoide , Hipotireoidismo Congênito/genética , Feminino , Humanos , Lactente , Masculino , Mutação , Fator de Transcrição PAX8/genética , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Disgenesia da Tireoide/genéticaRESUMO
Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/ - double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.
Assuntos
Deficiência Intelectual Ligada ao Cromossomo X , Transportadores de Ácidos Monocarboxílicos , Simportadores , Animais , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/terapia , Camundongos , Transportadores de Ácidos Monocarboxílicos/administração & dosagem , Transportadores de Ácidos Monocarboxílicos/deficiência , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hipotonia Muscular , Atrofia Muscular , Mutação , Sorogrupo , Simportadores/administração & dosagem , Simportadores/deficiência , Simportadores/genética , Simportadores/metabolismo , Tri-Iodotironina/metabolismoRESUMO
We report a patient with congenital hypothyroidism due to athyreosis complicated by a heterozygous thyroid hormone receptor beta (THRß) gene mutation (R320L), resulting in a severe resistance to thyroid hormone beta phenotype. The proband inherited the mutant allele from his father, presenting a very mild phenotype. While the precise reason for this discrepancy remains unknown, we postulate the possibility of de novo mutation and mosaicism in the father. Correlating thyrotropin (TSH) with free thyroxine (fT4) allowed us to predict the amount of fT4 required to normalize the proband's TSH, which supported the treatment with high dose of levothyroxine.
Assuntos
Hipotireoidismo Congênito , Disgenesia da Tireoide , Síndrome da Resistência aos Hormônios Tireóideos , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/genética , Humanos , Mutação , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/tratamento farmacológico , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hormônios Tireóideos/uso terapêutico , Tireotropina/uso terapêutico , Tiroxina/uso terapêuticoRESUMO
Background: L-triiodothyronine (LT3) has been increasingly used in combination with levothyroxine in the treatment of hypothyroidism. A metal coordinated form of LT3, known as poly-zinc-liothyronine (PZL), avoided in rats the typical triiodothyronine (T3) peak seen after oral administration of LT3. Objectives: To evaluate in healthy volunteers (i) the pharmacokinetics (PK) of PZL-derived T3 after a single dose, (ii) the pharmacodynamics of PZL-derived T3, (iii) incidence of adverse events, and (iv) exploratory analysis of the sleep patterns after LT3, PZL, or placebo (PB) administration. Methods: Twelve healthy volunteers 18-50 years of age were recruited for a Phase 1, double-blind, randomized, single-dose PB-controlled, crossover study to compare PZL against LT3 or PB. Subjects were admitted three separate times to receive a randomly assigned capsule containing PB, 50 µg LT3, or 50 µg PZL, and were observed for 48 hours. A 2-week washout period separated each admission. Results: LT3-derived serum T3 levels exhibited the expected profile, with a Tmax at 2 hours and return to basal levels by 24-36 hours. PZL-derived serum T3 levels exhibited â¼30% lower Cmax that was 1 hour delayed and extended into a plateau that lasted up to 6 hours. This was followed by a lower but much longer plateau; by 24 hours serum T3 levels still exceeded ½ of Cmax. Thyrotropin levels were similarly reduced in both groups. Conclusion: PZL possesses the necessary properties to achieve a much improved T3 PK. PZL is on track to provide hypothyroid patients with stable levels of serum T3.
Assuntos
Tri-Iodotironina/administração & dosagem , Tri-Iodotironina/farmacocinética , Zinco/administração & dosagem , Adolescente , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Terapia de Reposição Hormonal , Humanos , Hipotireoidismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Chronic arsenic exposure via drinking water is associated with diabetes in human pop-ulations throughout the world. Arsenic is believed to exert its diabetogenic effects via multiple mechanisms, including alterations to insulin secretion and insulin sensitivity. In the past, acute arsenicosis has been thought to be partially treatable with selenium supplementation, though a potential interaction between selenium and arsenic had not been evaluated under longer-term exposure models. The purpose of the present study was to explore whether selenium status may augment arsenic's effects during chronic arsenic exposure. To test this possibility, mice were exposed to arsenic in their drinking water and provided ad libitum access to either a diet replete with selenium (Control) or deficient in selenium (SelD). Arsenic significantly improved glucose tolerance and decreased insulin secretion and ß-cell function in vivo. Dietary selenium deficiency resulted in similar effects on glucose tolerance and insulin secretion, with significant interactions between arsenic and dietary conditions in select insulin-related parameters. The findings of this study highlight the complexity of arsenic's metabolic effects and suggest that selenium deficiency may interact with arsenic exposure on ß-cell-related physiological parameters.
Assuntos
Arsenitos/toxicidade , Glicemia/efeitos dos fármacos , Deficiências Nutricionais/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/sangue , Selênio/deficiência , Compostos de Sódio/toxicidade , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Deficiências Nutricionais/sangue , Deficiências Nutricionais/etiologia , Dieta , Modelos Animais de Doenças , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BLRESUMO
Background: Mutations of the thyroid hormone (TH)-specific cell membrane transporter, monocarboxylate transporter 8 (MCT8), produce an X-chromosome-linked syndrome of TH deficiency in the brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia, and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia, and increased metabolism, associated with high serum levels of the active TH, T3). Treatment in infancy and childhood with TH analogues that reduce serum triiodothyronine (T3) corrects hypermetabolism, but has no effect on the psychoneuromotor deficits. Studies of brain from a 30-week-old MCT8-deficient embryo indicated that brain abnormalities were already present during fetal life. Methods: A carrier woman with an affected male child (MCT8 A252fs268*), pregnant with a second affected male embryo, elected to carry the pregnancy to term. We treated the fetus with weekly 500 µg intra-amniotic instillation of levothyroxine (LT4) from 18 weeks of gestation until birth at 35 weeks. Thyroxine (T4), T3, and thyrotropin (TSH) were measured in the amniotic fluid and maternal serum. Treatment after birth was continued with LT4 and propylthiouracil. Follow-up included brain magnetic resonance imaging (MRI) and neurodevelopmental evaluation, both compared with the untreated brother. Results: During intrauterine life, T4 and T3 in the amniotic fluid were maintained above threefold to twofold the baseline and TSH was suppressed by 80%, while maternal serum levels remained unchanged. At birth, the infant serum T4 was 14.5 µg/dL and TSH <0.01 mU/L compared with the average in untreated MCT8-deficient infants of 5.1 µg/ and >8 mU/L, respectively. MRI at six months of age showed near-normal brain myelination compared with much reduced in the untreated brother. Neurodevelopmental assessment showed developmental quotients in receptive language and problem-solving, and gross motor and fine motor function ranged from 12 to 25 at 31 months in the treated boy and from 1 to 7 at 58 months in the untreated brother. Conclusions: This is the first demonstration that prenatal treatment improved the neuromotor and neurocognitive function in MCT8 deficiency. Earlier treatment with TH analogues that concentrate in the fetus when given to the mother may further rescue the phenotype.
Assuntos
Antitireóideos/uso terapêutico , Terapias Fetais/métodos , Deficiência Intelectual Ligada ao Cromossomo X/tratamento farmacológico , Hipotonia Muscular/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Propiltiouracila/uso terapêutico , Tiroxina/uso terapêutico , Adulto , Líquido Amniótico , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico por imagem , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/diagnóstico por imagem , Hipotonia Muscular/fisiopatologia , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/fisiopatologia , Gravidez , Simportadores/genética , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismoRESUMO
Background: Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptive in nonthyroidal illness such as fasting or acute illness. However, DIO1 gene defects have not been reported in humans. Methods: Genetic analysis was performed using whole-exome sequencing in members of two unrelated families presenting with abnormal serum thyroid function tests. Plasmid constructs containing the two pathogenic DIO1 variants were used for in vitro studies assessing the kinetics of their enzymatic activity. Thyroid function tests were measured in Dio1 heterozygous-null mice. Results: We report the novel identification and characterization of two missense DIO1 pathogenic variants (resulting in p.Asn94Lys and p.Met201Ile) in two unrelated families presenting with abnormal TH metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. These characteristic in vivo parameters are also present in Dio1 heterozygous-null mice. Kinetic studies of the resulting mutant D1 proteins demonstrate two- to threefold higher Km indicating lower substrate affinity and slower enzyme velocity. Conclusions: We report the identification and characterization of two missense DIO1 pathogenic variants identified in families with abnormal TH metabolism. This is the first demonstration of inherited D1 deficiency in humans.
Assuntos
Iodeto Peroxidase/genética , Mutação de Sentido Incorreto , Tri-Iodotironina/metabolismo , Adolescente , Animais , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Células HEK293 , Hereditariedade , Humanos , Iodeto Peroxidase/metabolismo , Cinética , Masculino , Camundongos Knockout , Fenótipo , Especificidade por Substrato , Sequenciamento do ExomaRESUMO
Resistance to thyroid hormone alpha (RTHα) is caused by mutations in thyroid hormone receptor α (THRA). Little is known about the natural history and treatment of RTHα, and diagnosis before the age of 1 year has not been previously reported. A de novo heterozygous THRA mutation (pC380SfsX9) was identified in a 10-month-old female investigated for developmental delay, hypotonia, macrocephaly, and severe constipation. Treatment with levothyroxine was accompanied by an appropriate rise in thyroxine (T4), triiodothyronine (T3), as well as decrease in thyrotropin levels and in the T3/T4 ratio with a trend toward normalization of peripheral markers of thyroid hormone action. THRA pC380SfsX9 results in extreme RTHα.
Assuntos
Receptores alfa dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/tratamento farmacológico , Tiroxina/uso terapêutico , Constipação Intestinal/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Diagnóstico Precoce , Intervenção Médica Precoce , Feminino , Humanos , Lactente , Megalencefalia/fisiopatologia , Hipotonia Muscular/fisiopatologia , Mutação , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/fisiopatologiaRESUMO
CONTEXT: Selenocysteine insertion sequence binding protein 2 (SECISBP2, SBP2) is an essential factor for selenoprotein synthesis. Individuals with SBP2 defects have characteristic thyroid function test (TFT) abnormalities resulting from deficiencies in the selenoenzymes deiodinases. Eight families with recessive SBP2 gene mutations have been reported to date. We report 2 families with inherited defect in thyroid hormone metabolism caused by 4 novel compound heterozygous mutations in the SBP2 gene. CASE DESCRIPTIONS: Probands 1 and 2 presented with growth and developmental delay. Both had characteristic TFT with high T4, low T3, high reverse T3, and normal or slightly elevated TSH. The coding region of the SBP2 gene was sequenced and analysis of in vitro translated wild-type and mutant SBP2 proteins was performed. Sequencing of the SBP2 gene identified novel compound heterozygous mutations resulting in mutant SBP2 proteins E679D and R197* in proband 1, and K682Tfs*2 and Q782* in proband 2. In vitro translation of the missense E679D demonstrated all four isoforms, whereas R197* had only 2 shorter isoforms translated from downstream ATGs, and Q782*, K682Tfs*2 expressed isoforms with truncated C-terminus. Reduction in serum glutathione peroxidase enzymatic activity was also demonstrated in both probands. CONCLUSIONS: We report 2 additional families with mutations in the SBP2 gene, a rare inherited condition manifesting global selenoprotein deficiencies. Report of additional families with SBP2 deficiency and their evaluation over time is needed to determine the full spectrum of clinical manifestations in SBP2 deficiency and increase our understanding of the role played by SBP2 and selenoproteins in health and disease.
Assuntos
Proteínas de Ligação a RNA/genética , Selenoproteínas/deficiência , Doenças da Glândula Tireoide/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Testes de Função Tireóidea , Hormônios Tireóideos/sangue , Adulto JovemRESUMO
Nonautoimmune hyperthyroidism caused by activating mutations in the GNAS gene is a rare condition. In this study, we report a five-year-old girl diagnosed with nonautoimmune hyperthyroidism and tall stature harboring a somatic mosaic gain-of-function mutation in the GNAS gene (NM_080425.3: c.2530C>T;p.Arg844Cys previously reported as NM_000516.5:c.601C>T;p.Arg201Cys) and referred to thereafter as R201C, in three of four quadrants of the thyroid gland. Provision of a molecular diagnosis may avoid unnecessary complete ablation of the thyroid gland.
Assuntos
Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Hipertireoidismo/congênito , Mutação , Glândula Tireoide/metabolismo , Pré-Escolar , Cromograninas/metabolismo , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Humanos , Hipertireoidismo/genética , Hipertireoidismo/metabolismoRESUMO
CONTEXT: Congenital hypothyroidism (CH) is due to dyshormonogenesis in 10% to 15% of subjects worldwide but accounts for 60% of CH cases in the Sudan. OBJECTIVE: To investigate the molecular basis of CH in Sudanese families. DESIGN: Clinical phenotype reporting and serum thyroid hormone measurements. Deoxyribonucelic acid extraction for whole-exome sequencing and Sanger sequencing. SETTING: University research center. PATIENTS: Twenty-six Sudanese families with CH. INTERVENTION: Clinical evaluation, thyroid function tests, genetic sequencing, and analysis. Our samples and information regarding samples from the literature were used to compare TG (thyroglobulin) and TPO (thyroid peroxidase) mutation rates in the Sudanese population with all populations. RESULTS: Mutations were found in dual-oxidase 1 (DUOX1), dual-oxidase 2 (DUOX2), iodotyrosine deiodinase (IYD), solute-carrier (SLC) 26A4, SLC26A7, SLC5A5, TG, and TPO genes. The molecular basis of the CH in 7 families remains unknown. TG mutations were significantly higher on average in the Sudanese population compared with the average number of TG mutations in other populations (P < 0.05). CONCLUSIONS: All described mutations occur in domains important for protein structure and function, predicting the CH phenotype. Genotype prediction based on phenotype includes low or undetectable thyroglobulin levels for TG gene mutations and markedly higher thyroglobulin levels for TPO mutations. The reasons for higher incidence of TG gene mutations include gene length and possible positive genetic selection due to endemic iodine deficiency.
Assuntos
Autoantígenos/genética , Hipotireoidismo Congênito/genética , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Mutação , Tireoglobulina/genética , Adolescente , Criança , Pré-Escolar , Hipotireoidismo Congênito/epidemiologia , Oxidases Duais/genética , Família , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Prevalência , Sudão/epidemiologiaRESUMO
Mutations in the cell membrane thyroid hormone (TH) transporter monocarboxylate transporter (MCT) 8 produce severe neuropsychomotor defects and characteristic thyroid function test (TFT) abnormalities. Two children with mild neurological phenotypes and normal TFTs were found to harbor MCT8 gene variants of unknown significance (VUS), MCT8-R388Q that occurred de novo, and MCT8-Q212E. Normal TH transport and action in fibroblasts of MCT8-R388Q was demonstrated in a novel nonradioactive functional assay measuring the intracellular TH availability after L-T3 treatment. No genotype-phenotype correlation was found in additional family members carrying MCT8-Q212E. For the field of MCT8 deficiency, it is important to assess the significance of MCT8 gene VUS.
Assuntos
Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/genética , Atrofia Muscular/genética , Mutação , Simportadores/genética , Criança , Humanos , Masculino , Hipotonia Muscular/sangue , Atrofia Muscular/sangue , Linhagem , Fenótipo , Hormônios Tireóideos/sangue , Sequenciamento do ExomaRESUMO
Selenocysteine insertion sequence-binding protein 2, SBP2 (SECISBP2), is required for selenoprotein synthesis. Partial SBP2 deficiency syndrome manifests characteristic thyroid function tests. The Sbp2 deficiency mouse model, Sbp2 inducible conditional knockout (iCKO), replicates this thyroid phenotype and was used for pathophysiologic investigations. As selenoproteins have an antioxidative role in thyroid gland function, their deficiencies have potential to affect thyroid hormone (TH) synthesis. Sbp2 iCKO mice had larger thyroids relative to body weight and increased thyroidal thyroxine (T4) and triiodothyronine (T3) content while 5' deiodinases enzymatic activities were decreased. Possible mechanisms for the discrepancy between the increased thyroidal T3 and normal circulating T3 were investigated in dynamic experiments. Treatment with bovine thyroid-stimulating hormone (TSH) resulted in increased delta T4 in Sbp2 iCKO mice, indicating increased availability of preformed thyroidal TH. Next, the recovery of TH levels was evaluated after withdrawal of chemical suppression. At one day, Sbp2 iCKO mice had higher serum and thyroidal T3 concomitant with lower TSH, confirming increased capacity of TH synthesis in Sbp2 deficiency. Decreased TH secretion was ruled out as serum and thyroidal TH were high in Sbp2 iCKO mice. Treatment with a low-iodine diet also ruled out thyroidal secretion defect as both serum levels and thyroidal TH content similarly declined over time in Sbp2-deficient mice compared to wild-type (Wt) mice. This study provides evidence for unsuspected changes in the thyroid gland that contribute to the thyroid phenotype of Sbp2 deficiency, with increased thyroidal T4 and T3 content in the setting of increased TH synthesis capacity contributing to the circulating TH levels while thyroidal secretion is preserved.
Assuntos
Proteínas de Ligação a RNA/metabolismo , Selenoproteínas/metabolismo , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Bovinos , Feminino , Masculino , Camundongos Knockout , Fenótipo , Proteínas de Ligação a RNA/genética , Testes de Função Tireóidea , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/sangue , Tireotropina/sangue , Tireotropina/metabolismo , Tireotropina/farmacologia , Tiroxina/sangue , Tiroxina/metabolismo , Tri-Iodotironina/sangue , Tri-Iodotironina/metabolismoRESUMO
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.
Assuntos
RNA Mensageiro/metabolismo , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina Reversa/metabolismo , Tri-Iodotironina/metabolismo , Adolescente , Família , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Técnicas In Vitro , Fatores de Transcrição Kruppel-Like/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/genética , Mutação , Cultura Primária de Células , Índice de Gravidade de Doença , Síndrome da Resistência aos Hormônios Tireóideos/genética , Tri-Iodotironina/farmacologiaRESUMO
Background: Evidence for transgenerational epigenetic inheritance in humans is still controversial, given the requirement to demonstrate persistence of the phenotype across three generations. A previous study showed that exposure of human and mouse embryos to high maternal thyroid hormone (TH) concentrations not only affects the newborns but also subsequently reduces thyrotroph sensitivity to TH during adult life. The current investigation set out to determine if this epigenetic effect is transmitted by humans not exposed in utero to high TH levels to their offspring. Methods: The study took advantage of the high frequency of intrauterine exposure to high TH in the Azorean wild-type population born to healthy mothers with high TH levels because of a heterozygous TH receptor beta gene mutation. Wild-type individuals from F2 (second) and F3 (third) generations were studied, whose parents and grandparents, respectively, were not exposed to high maternal TH levels. Twenty-six individuals belonging to 17 nuclear families were tested for their sensitivity to TH using their thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) after administration of liothyronine (LT3). Results: Preservation of reduced sensitivity to TH (RSTH) was found in descendants of males but not of females with likewise RSTH. In F2, offspring of fathers but not of mothers exposed to high TH levels had RSTH (TRH-stimulated TSH of 6.39 ± 0.63 vs 1.58 ± 0.41 mIU/L [p < 0.001], respectively, after treatment with LT3). In F3, whose parents nor themselves were exposed to TH excess during their fetal life, descendants of fathers and not mothers had RSTH (TRH-stimulated TSH of 4.60 ± 0.61 vs 1.37 ± 0.23 mIU/L [p < 0.01], respectively, after pretreatment with LT3). Conclusions: Since intrauterine total body and gonadal exposure to elevated TH can potentially affect only the F1 and F2, respectively, the results obtained from F3 confirm a true inheritance of an epigenetic effect, scarcely observed in humans. While the exact mechanism underlying the inheritance of this epigenetic effect remains unknown, it correlates with type 3 deiodinase overexpression demonstrated in pituitary glands of mice born to dams with high TH. This enzyme inactivates TH, and is encoded by an imprinted gene with specific parent of origin expression.
Assuntos
Epigênese Genética , Mutação de Sentido Incorreto , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores beta dos Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Adolescente , Adulto , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Gravidez , Receptores beta dos Hormônios Tireóideos/metabolismo , Adulto JovemRESUMO
Dyshormonogenic congenital hypothyroidism (CH) generally results from biallelic defects in thyroid hormone synthesis genes. Whole exome sequencing allows easier identification of multiple gene defects. Two Sudanese families with CH resulting from oligogenic defects identified by whole exome sequencing are presented. In family 1, the proposita with CH and goiter was heterozygous for three TPO, one TG, and one DUOX2 mutations, including three novel variants inherited from both parents. In family 2, two brothers with psychomotor delay and goiter were homozygous for digenic mutations in the DUOX2 and DUOX1 genes, while their asymptomatic parents were heterozygous. Accumulation of pathogenic mutations may contribute to CH.