The Experts below are selected from a list of 168 Experts worldwide ranked by ideXlab platform
Alexandra M Dumitrescu - One of the best experts on this subject based on the ideXlab platform.
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Role of the Thyroid Gland in Expression of the Thyroid Phenotype of Sbp2-Deficient Mice.
Endocrinology, 2019Co-Authors: Haruki Fujisawa, Xiao-hui Liao, Manassawee Korwutthikulrangsri, Alexandra M DumitrescuAbstract: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.
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a novel homozygous selenocysteine insertion sequence binding protein 2 SECISBP2 sbp2 gene mutation in a turkish boy
Thyroid, 2018Co-Authors: Gonul Catli, Haruki Fujisawa, Ozgur Kirbiyik, Mizuho S Mimoto, Pinar Gencpinar, Taha Resid Ozdemir, Bumin Dundar, Alexandra M DumitrescuAbstract:SECISBP2 is an essential factor in selenoprotein synthesis, and its mutations result in a multiorgan syndrome, including abnormal thyroid hormone metabolism. A 10-year-old obese Turkish boy born to consanguineous parents presented with high thyroxine, low triiodothyronine, high reverse triiodothyronine, and normal or slightly elevated thyrotropin. He also had attention-deficit disorder and muscle weakness but no delay in growth or bone age. Sequencing of genomic DNA revealed a novel c.800_801insA, p.K267Kfs*2 mutation, homozygous in the proband and heterozygous in both parents and his brother. Studies showed reduction in several selenoproteins in serum and fibroblasts.
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Table, Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism and Action
2015Co-Authors: Alexandra M Dumitrescu, Samuel RefetoffAbstract:Defects along the pathways leading to TH action can manifest as impaired sensitivity to TH. Six steps are presumed to be required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps four distinct phenotypes have been identified in humans. The clinical, laboratory, genetic and molecular characteristics of these defects are the subject of this chapter. The first defect, recognized almost 50 years ago, produces reduced sensitivity to TH and was given the acronym RTH, for resistance to thyroid hormone. Its major cause, found in more than 3,000 individuals, is mutations in the TH receptor s (THRB) gene. More recently mutations in the THRA gene were found to produce a different phenotype owing to the distinct tissue distribution of this TH receptor. Two other gene mutations, affecting TH action, but acting at different sites were identified in the last 10 years. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 320 males. A defect of the intracellular metabolism of TH, identified in 11 members from 9 families, is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. Knowledge of the molecular mechanisms involved in mediation of TH action allows the recognition of the phenotypes caused by genetic defects in the involved pathways. While these defects have opened the avenue for novel insights into thyroid physiology, they continue to pose therapeutic challenges. For complete coverage of this and related areas in Endocrinology, visit the free online webtextbook, www.endotext.org. Resistance to thyroid hormone (RTH), a syndrome of reduced responsiveness of target tissues to thyroid hormone (TH) was identified in 1967 (1). An early report proposed various mechanisms including defects in TH transport, metabolism and action (2). However, with the identification of TH receptor beta (THRB) gene mutations 22 years later (3,4), the term RTH become synonymous with defects of this gene (5). Subsequent discoveries of genetic defects that reduce the effectiveness of TH through altered cell membrane transport (6,7) and metabolism (8) have broadened the definition of TH hyposensitivity to encompass all defects that could interfere with the biological activity of a chemically intact hormone secreted in normal or even excess amounts. In this revised chapter, we cover all syndromes resulting from impaired sensitivity to TH, using the recently proposed nomenclature (9) (see Table 1). Table 1.Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
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IMPAIRED SENSITIVITY TO THYROID HORMONE: Defects of Transport,
2015Co-Authors: Alexandra M Dumitrescu, Samuel RefetoffAbstract:Defects along the pathways leading to TH action can manifest as impaired sensitivity to TH. Six steps are presumed to be required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps four distinct phenotypes have been identified in humans. The clinical, laboratory, genetic and molecular characteristics of these defects are the subject of this chapter. The first defect, recognized almost 50 years ago, produces reduced sensitivity to TH and was given the acronym RTH, for resistance to thyroid hormone. Its major cause, found in more than 3,000 individuals, is mutations in the TH receptor s (THRB) gene. More recently mutations in the THRA gene were found to produce a different phenotype owing to the distinct tissue distribution of this TH receptor. Two other gene mutations, affecting TH action, but acting at different sites were identified in the last 10 years. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 320 males. A defect of the intracellular metabolism of TH, identified in 11 members from 9 families, is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. Knowledge of the molecular mechanisms involved in mediation of TH action allows the recognition of the phenotypes caused by genetic defects in the involved pathways. While these defects have opened the avenue for novel insights into thyroid physiology, they continue to pose therapeutic challenges. For complete coverage of this and related areas in Endocrinology, visit the free online webtextbook, www.endotext.org. Resistance to thyroid hormone (RTH), a syndrome of reduced responsiveness of target tissues to thyroid hormone (TH) was identified in 1967 (1). An early report proposed various mechanisms including defects in TH transport, metabolism and action (2). However, with the identification of TH receptor beta (THRB) gene mutations 22 years later (3,4), the term RTH become synonymous with defects of this gene (5). Subsequent discoveries of genetic defects that reduce the effectiveness of TH through altered cell membrane transport (6,7) and metabolism (8) have broadened the definition of TH hyposensitivity to encompass all defects that could interfere with the biological activity of a chemically intact hormone secreted in normal or even excess amounts. In this revised chapter, we
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The syndromes of reduced sensitivity to thyroid hormone.
Biochimica et biophysica acta, 2012Co-Authors: Alexandra M Dumitrescu, Samuel RefetoffAbstract:Background Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified. Scope of review The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. Major conclusions Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH. General significance Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. This article is part of a Special Issue entitled Thyroid hormone signaling.
Samuel Refetoff - One of the best experts on this subject based on the ideXlab platform.
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Table, Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism and Action
2015Co-Authors: Alexandra M Dumitrescu, Samuel RefetoffAbstract:Defects along the pathways leading to TH action can manifest as impaired sensitivity to TH. Six steps are presumed to be required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps four distinct phenotypes have been identified in humans. The clinical, laboratory, genetic and molecular characteristics of these defects are the subject of this chapter. The first defect, recognized almost 50 years ago, produces reduced sensitivity to TH and was given the acronym RTH, for resistance to thyroid hormone. Its major cause, found in more than 3,000 individuals, is mutations in the TH receptor s (THRB) gene. More recently mutations in the THRA gene were found to produce a different phenotype owing to the distinct tissue distribution of this TH receptor. Two other gene mutations, affecting TH action, but acting at different sites were identified in the last 10 years. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 320 males. A defect of the intracellular metabolism of TH, identified in 11 members from 9 families, is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. Knowledge of the molecular mechanisms involved in mediation of TH action allows the recognition of the phenotypes caused by genetic defects in the involved pathways. While these defects have opened the avenue for novel insights into thyroid physiology, they continue to pose therapeutic challenges. For complete coverage of this and related areas in Endocrinology, visit the free online webtextbook, www.endotext.org. Resistance to thyroid hormone (RTH), a syndrome of reduced responsiveness of target tissues to thyroid hormone (TH) was identified in 1967 (1). An early report proposed various mechanisms including defects in TH transport, metabolism and action (2). However, with the identification of TH receptor beta (THRB) gene mutations 22 years later (3,4), the term RTH become synonymous with defects of this gene (5). Subsequent discoveries of genetic defects that reduce the effectiveness of TH through altered cell membrane transport (6,7) and metabolism (8) have broadened the definition of TH hyposensitivity to encompass all defects that could interfere with the biological activity of a chemically intact hormone secreted in normal or even excess amounts. In this revised chapter, we cover all syndromes resulting from impaired sensitivity to TH, using the recently proposed nomenclature (9) (see Table 1). Table 1.Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
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IMPAIRED SENSITIVITY TO THYROID HORMONE: Defects of Transport,
2015Co-Authors: Alexandra M Dumitrescu, Samuel RefetoffAbstract:Defects along the pathways leading to TH action can manifest as impaired sensitivity to TH. Six steps are presumed to be required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps four distinct phenotypes have been identified in humans. The clinical, laboratory, genetic and molecular characteristics of these defects are the subject of this chapter. The first defect, recognized almost 50 years ago, produces reduced sensitivity to TH and was given the acronym RTH, for resistance to thyroid hormone. Its major cause, found in more than 3,000 individuals, is mutations in the TH receptor s (THRB) gene. More recently mutations in the THRA gene were found to produce a different phenotype owing to the distinct tissue distribution of this TH receptor. Two other gene mutations, affecting TH action, but acting at different sites were identified in the last 10 years. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 320 males. A defect of the intracellular metabolism of TH, identified in 11 members from 9 families, is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. Knowledge of the molecular mechanisms involved in mediation of TH action allows the recognition of the phenotypes caused by genetic defects in the involved pathways. While these defects have opened the avenue for novel insights into thyroid physiology, they continue to pose therapeutic challenges. For complete coverage of this and related areas in Endocrinology, visit the free online webtextbook, www.endotext.org. Resistance to thyroid hormone (RTH), a syndrome of reduced responsiveness of target tissues to thyroid hormone (TH) was identified in 1967 (1). An early report proposed various mechanisms including defects in TH transport, metabolism and action (2). However, with the identification of TH receptor beta (THRB) gene mutations 22 years later (3,4), the term RTH become synonymous with defects of this gene (5). Subsequent discoveries of genetic defects that reduce the effectiveness of TH through altered cell membrane transport (6,7) and metabolism (8) have broadened the definition of TH hyposensitivity to encompass all defects that could interfere with the biological activity of a chemically intact hormone secreted in normal or even excess amounts. In this revised chapter, we
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The syndromes of reduced sensitivity to thyroid hormone.
Biochimica et biophysica acta, 2012Co-Authors: Alexandra M Dumitrescu, Samuel RefetoffAbstract:Background Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified. Scope of review The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. Major conclusions Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH. General significance Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. This article is part of a Special Issue entitled Thyroid hormone signaling.
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Syndromes of reduced sensitivity to thyroid hormone : genetic defects in hormone receptors, cell transporters and deiodination
Best practice & research. Clinical endocrinology & metabolism, 2007Co-Authors: Samuel Refetoff, Alexandra M DumitrescuAbstract:At least six major steps are required for secreted thyroid hormone (TH) to exert its action on target tissues. Mutations interfering with three of these steps have been so far identified. The first recognized defect, which causes resistance to TH, involves the TH receptor β gene and has been given the acronym RTH. Occurring in ∼1 per 40,000 newborns, more than 1000 affected subjects, from 339 families, have been identified. The gene defect remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced sensitivity to TH were recently identified. One, producing severe psychomotor defects in > 100 males from 26 families, is caused by mutations in the cell-membrane transporter of TH, MCT8 ; the second, affecting the intracellular metabolism of TH in four individuals from two families, is caused by mutations in the SECISBP2 gene, which is required for the synthesis of selenoproteins, including TH deiodinases.
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Mutations in SECISBP2 result in abnormal thyroid hormone metabolism
Nature Genetics, 2005Co-Authors: Alexandra M Dumitrescu, Xiao-hui Liao, Mohamed S Y Abdullah, Joaquin Lado-abeal, Fathia Abdul Majed, Lars C Moeller, Gerard Boran, Lutz Schomburg, Roy E Weiss, Samuel RefetoffAbstract:Incorporation of selenocysteine (Sec), through recoding of the UGA stop codon, creates a unique class of proteins. Mice lacking tRNA^Sec die in utero ^ 1 , but the in vivo role of other components involved in selenoprotein synthesis is unknown, and Sec incorporation defects have not been described in humans. Deiodinases (DIOs) are selenoproteins involved in thyroid hormone metabolism. We identified three of seven siblings with clinical evidence of abnormal thyroid hormone metabolism. Their fibroblasts showed decreased DIO2 enzymatic activity not linked to the DIO2 locus. Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2 ). An unrelated child with a similar phenotype was compound heterozygous with respect to mutations in SECISBP2 . Because SBP2 is epistatic to selenoprotein synthesis, these defects had a generalized effect on selenoproteins. Incomplete loss of SBP2 function probably causes the mild phenotype.
Sandra Seeher - One of the best experts on this subject based on the ideXlab platform.
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The RNA-binding protein SECISBP2 differentially modulates UGA codon reassignment and RNA decay.
Nucleic acids research, 2016Co-Authors: Noelia Fradejas-villar, Sandra Seeher, Bradley A. Carlson, Christine B. Anderson, Michael Doengi, Dolph L. Hatfield, Ulrich Schweizer, Michael T. HowardAbstract:Dual-assignment of codons as termination and elongation codons is used to expand the genetic code. In mammals, UGA can be reassigned to selenocysteine during translation of selenoproteins by a mechanism involving a 3΄ untranslated region (UTR) selenocysteine insertion sequence (SECIS) and the SECIS-binding protein SECISBP2. Here, we present data from ribosome profiling, RNA-Seq and mRNA half-life measurements that support distinct roles for SECISBP2 in UGA-redefinition and mRNA stability. Conditional deletions of the SECISBP2 and Trsp (tRNASec) genes in mouse liver were compared to determine if the effects of SECISBP2 loss on selenoprotein synthesis could be attributed entirely to the inability to incorporate Sec. As expected, tRNASec depletion resulted in loss of ribosome density downstream of all UGA-Sec codons. In contrast, the absence of SECISBP2 resulted in variable effects on ribosome density downstream of UGA-Sec codons that demonstrate gene-specific differences in Sec incorporation. For several selenoproteins in which loss of SECISBP2 resulted in greatly diminished mRNA levels, translational activity and Sec incorporation efficiency were shown to be unaffected on the remaining RNA. Collectively, these results demonstrate that SECISBP2 is not strictly required for Sec incorporation and has a distinct role in stabilizing mRNAs that can be separated from its effects on UGA-redefinition.
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SECISBP2 is essential for embryonic development and enhances selenoprotein expression
Antioxidants & Redox Signaling, 2014Co-Authors: Sandra Seeher, Yassin Mahdi, Eva K Wirth, Tarik Atassi, Doreen Braun, Bradley A. Carlson, M. KleinAbstract:Abstract Aims: The selenocysteine insertion sequence (SECIS)-binding protein 2 (SECISBP2) binds to SECIS elements located in the 3′-untranslated region of eukaryotic selenoprotein mRNAs. Selenoproteins contain the rare amino acid selenocysteine (Sec). Mutations in SECISBP2 in humans lead to reduced selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display myopathy, hearing impairment, male infertility, increased photosensitivity, mental retardation, and ataxia. Mouse models are needed to understand selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes. Results: Unlike tRNA[Ser]Sec-deficient embryos, homozygous SECISBP2-deleted embryos implant, but fail before gastrulation. Heterozygous inactivation of SECISBP2 reduced the amount of selenoprotein expressed, but did not affect the thyroid hormone axis or growth. Conditional deletion of SECISBP2 in hepatocytes significantly decreased selenoprotein ...
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Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice.
The Biochemical journal, 2014Co-Authors: Sandra Seeher, Yassin Mahdi, Eva K Wirth, Bradley A. Carlson, Dolph L. Hatfield, Angela C. Miniard, Donna M. Driscoll, Ulrich SchweizerAbstract:SECISBP2 [SECIS (selenocysteine insertion sequence)-binding protein 2] binds to SECIS elements located in the 3′-UTR region of eukaryotic selenoprotein mRNAs. It facilitates the incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of SECISBP2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of SECISBP2 (CamK-Cre; SECISBP2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical PV (parvalbumin)+ interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus and striatum. In situ hybridization for Gad67 (glutamic acid decarboxylase 67) confirmed the reduction of GABAergic (where GABA is γ-aminobutyric acid) interneurons. Because of the obvious movement phenotype involving a broad dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49% respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations.
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Targeted deletion of SECISBP2 reduces, but does not abrogate, selenoprotein expression and leads to striatal interneuron loss.
Free Radical Biology and Medicine, 2014Co-Authors: Sandra Seeher, Ulrich SchweizerAbstract:Selenoproteins contain the amino acid selenocysteine (Sec). The Sec insertion sequence (SECIS)-binding protein 2 (SECISBP2) binds to SECIS elements in the 3'-UTR of eukaryotic selenoprotein mRNAs. Mutations in SECISBP2 in humans lead to reduced selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display mental retardation and ataxia. Mouse models are needed to understand selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes. Homozygous SECISBP2 deletion is embryonic lethal. Conditional deletion of SECISBP2 in hepatocytes significantly decreased selenoprotein expression and reduced the abundance of many, but not all, selenoprotein mRNAs. Regarding selenoprotein expression, compensatory Nrf2-dependent gene expression, or embryonic development, phenotypes were always milder in SECISBP2- than in tRNA(Sec)-deficient mice. Neuron-specific inactivation of SECISBP2 reduced cerebral expression of selenoproteins, but allowed to study the development of cortical PVpos interneurons, which are known to depend on selenoproteins. Cre expression spares the cerebellum of these mice, why we suspected that basal ganglia dysfunction may cause the obvious movement phenotype. We observed for the first time that the number of PVpos neurons was reduced by 50% in the caudate putamen of a selenoprotein-deficient mouse model. In situ hybridization for Gad67 showed that selenoprotein deficiency selectively reduced the number of PVpos GABAergic interneurons. We propose that the striatal neuron loss likely causes the movement disorder. The most striking novel finding of this work is the selective damage of PVpos/Gad67pos neurons in the striatum. The second key finding is that selenoprotein expression in hepatocytes and neurons is less dependent on SECISBP2 than on tRNA(Sec). This implies the possibility of SECISBP2-independent selenoprotein expression, albeit on a reduced level.
Ulrich Schweizer - One of the best experts on this subject based on the ideXlab platform.
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Selenium and Neurodevelopment
Molecular and Integrative Toxicology, 2018Co-Authors: Noelia Fradejas-villar, Ulrich SchweizerAbstract:Brain is a privileged organ regarding selenium accumulation and metabolism. The discovery of a neurological phenotype in selenoprotein P knockout mouse provided a new perspective on the function of selenoproteins in brain. Since then, genetic studies in mice have revealed that some selenoproteins are indispensable to normal brain function. Neurodegeneration of GABAergic interneurons (PV+ neurons and Purkinje cells in cerebellum) was observed in Trsp and SECISBP2 knockout mice. Gpx4 knockout mice showed a similar phenotype, which could indicate that Gpx4 is necessary for maintenance or development of GABAergic interneurons. Similarly, SelT has a protective role for dopaminergic neurons and Txnrd1 is involved in radial glia development.
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The RNA-binding protein SECISBP2 differentially modulates UGA codon reassignment and RNA decay.
Nucleic acids research, 2016Co-Authors: Noelia Fradejas-villar, Sandra Seeher, Bradley A. Carlson, Christine B. Anderson, Michael Doengi, Dolph L. Hatfield, Ulrich Schweizer, Michael T. HowardAbstract:Dual-assignment of codons as termination and elongation codons is used to expand the genetic code. In mammals, UGA can be reassigned to selenocysteine during translation of selenoproteins by a mechanism involving a 3΄ untranslated region (UTR) selenocysteine insertion sequence (SECIS) and the SECIS-binding protein SECISBP2. Here, we present data from ribosome profiling, RNA-Seq and mRNA half-life measurements that support distinct roles for SECISBP2 in UGA-redefinition and mRNA stability. Conditional deletions of the SECISBP2 and Trsp (tRNASec) genes in mouse liver were compared to determine if the effects of SECISBP2 loss on selenoprotein synthesis could be attributed entirely to the inability to incorporate Sec. As expected, tRNASec depletion resulted in loss of ribosome density downstream of all UGA-Sec codons. In contrast, the absence of SECISBP2 resulted in variable effects on ribosome density downstream of UGA-Sec codons that demonstrate gene-specific differences in Sec incorporation. For several selenoproteins in which loss of SECISBP2 resulted in greatly diminished mRNA levels, translational activity and Sec incorporation efficiency were shown to be unaffected on the remaining RNA. Collectively, these results demonstrate that SECISBP2 is not strictly required for Sec incorporation and has a distinct role in stabilizing mRNAs that can be separated from its effects on UGA-redefinition.
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Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2016Co-Authors: Ulrich Schweizer, Noelia Fradejas-villarAbstract:Selenocysteine is the 21st proteinogenic amino acid in mammals. The human genome contains 25 genes encoding selenoproteins, and their significance for human health is increasingly recognized through the identification of patients with inborn errors in selenoprotein biosynthetic factors or in individual selenoproteins. Mutations in selenoprotein N (SEPN1) lead to a spectrum of disorders collectively called SEPN1-related myopathy, and mutations in glutathione peroxidase 4 (GPX4) cause respiratory failure and bone defects, and mutations in thioredoxin reductase 2 (TXNRD2) are associated with familial glucocorticoid deficiency. Pathogenic mutations in selenocysteine synthase (SEPSECS) cause neurodevelopmental disorders, but also other factors epistatic to selenoprotein biosynthesis, such as SECIS-binding protein 2 (SECISBP2) and tRNA[Ser]Sec, are known to cause complex disorders. Mutations in the latter 2 genes involve impaired metabolism and action of thyroid hormones, which lead to delayed bone growth and maturation. Mutations in SECISBP2 sometimes affect nervous system development, muscle, inner ear, skin, and immune system function, underlining the significance of selenoproteins for the organism. Mouse models helped to delineate the functions of selenoproteins and explain pathomechanisms. For brevity, this review is focused on human genetic disorders associated with selenoprotein deficiency and only briefly touches on health effects of nutritional selenium deficiency.-Schweizer, U., Fradejas-Villar, N. Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism.
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Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice.
The Biochemical journal, 2014Co-Authors: Sandra Seeher, Yassin Mahdi, Eva K Wirth, Bradley A. Carlson, Dolph L. Hatfield, Angela C. Miniard, Donna M. Driscoll, Ulrich SchweizerAbstract:SECISBP2 [SECIS (selenocysteine insertion sequence)-binding protein 2] binds to SECIS elements located in the 3′-UTR region of eukaryotic selenoprotein mRNAs. It facilitates the incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of SECISBP2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of SECISBP2 (CamK-Cre; SECISBP2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical PV (parvalbumin)+ interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus and striatum. In situ hybridization for Gad67 (glutamic acid decarboxylase 67) confirmed the reduction of GABAergic (where GABA is γ-aminobutyric acid) interneurons. Because of the obvious movement phenotype involving a broad dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49% respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations.
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Targeted deletion of SECISBP2 reduces, but does not abrogate, selenoprotein expression and leads to striatal interneuron loss.
Free Radical Biology and Medicine, 2014Co-Authors: Sandra Seeher, Ulrich SchweizerAbstract:Selenoproteins contain the amino acid selenocysteine (Sec). The Sec insertion sequence (SECIS)-binding protein 2 (SECISBP2) binds to SECIS elements in the 3'-UTR of eukaryotic selenoprotein mRNAs. Mutations in SECISBP2 in humans lead to reduced selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display mental retardation and ataxia. Mouse models are needed to understand selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes. Homozygous SECISBP2 deletion is embryonic lethal. Conditional deletion of SECISBP2 in hepatocytes significantly decreased selenoprotein expression and reduced the abundance of many, but not all, selenoprotein mRNAs. Regarding selenoprotein expression, compensatory Nrf2-dependent gene expression, or embryonic development, phenotypes were always milder in SECISBP2- than in tRNA(Sec)-deficient mice. Neuron-specific inactivation of SECISBP2 reduced cerebral expression of selenoproteins, but allowed to study the development of cortical PVpos interneurons, which are known to depend on selenoproteins. Cre expression spares the cerebellum of these mice, why we suspected that basal ganglia dysfunction may cause the obvious movement phenotype. We observed for the first time that the number of PVpos neurons was reduced by 50% in the caudate putamen of a selenoprotein-deficient mouse model. In situ hybridization for Gad67 showed that selenoprotein deficiency selectively reduced the number of PVpos GABAergic interneurons. We propose that the striatal neuron loss likely causes the movement disorder. The most striking novel finding of this work is the selective damage of PVpos/Gad67pos neurons in the striatum. The second key finding is that selenoprotein expression in hepatocytes and neurons is less dependent on SECISBP2 than on tRNA(Sec). This implies the possibility of SECISBP2-independent selenoprotein expression, albeit on a reduced level.
Erik Schoenmakers - One of the best experts on this subject based on the ideXlab platform.
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Human Disorders Affecting the Selenocysteine Incorporation Pathway Cause Systemic Selenoprotein Deficiency.
Antioxidants & redox signaling, 2020Co-Authors: Erik Schoenmakers, Krishna ChatterjeeAbstract:Significance: Generalized selenoprotein deficiency has been associated with mutations in SECISBP2, SEPSECS, and TRU-TCA1-1, 3 factors that are crucial for incorporation of the amino acid selenocyst...
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Identification of Genetic Disorders Causing Disruption of Selenoprotein Biosynthesis
Methods in molecular biology (Clifton N.J.), 2017Co-Authors: Erik Schoenmakers, Krishna ChatterjeeAbstract:Disorders of selenoprotein biosynthesis in humans, due to mutations in three genes (SECISBP2, TRU-TCA1-1, and SEPSECS) involved in the selenocysteine insertion pathway, have been described. Patients with SECISBP2 and TRU-TCA1-1 defects manifest a multisystem disorder with a biochemical signature of abnormal thyroid function tests due to the impaired activity of deiodinase selenoenzymes, myopathic features linked to SEPN1 deficiency and phenotypes resulting from increased levels of reactive oxygen species attributable to lack of antioxidant selenoenzymes. In patients harboring SEPSECS mutations, severe, progressive, cerebello-cerebral atrophy (pontocerebellar hypoplasia type 2D) dominates the phenotype and it is not known whether the disorder is associated with thyroid dysfunction.
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Mutations in Humans That Adversely Affect the Selenoprotein Synthesis Pathway
Selenium, 2016Co-Authors: Erik Schoenmakers, Nadia Schoenmakers, Krishna ChatterjeeAbstract:Human mutations have been described in three genes implicated in the selenocysteine insertion pathway (SECISBP2, TRU-TCA1-1 and SEPSECS), which result in impaired synthesis of multiple selenoproteins. Mutations in these genes result in decreased gene expression and/or generate defective protein or RNA products; however, in all cases the preservation of some residual function is presumed, since selenoprotein expression is not completely abrogated. Patients harbouring SEPSECS mutations present with progressive cerebello-cerebral atrophy as the predominant phenotype, whereas this has not been associated with SECISBP2 and TRU-TCA1-1 defects. In contrast, patients with mutations in the latter two genes manifest a multisystem disorder with a thyroid hormone biochemical signature secondary to loss of selenoprotein deiodinases, myopathic features due to SEPN1 deficiency and phenotypes attributable to elevated levels of reactive oxygen species as a consequence of lack of antioxidant selenoenzymes. The progressive nature of most reported phenotypes may be explained by cumulative oxidative damage over time, which may also mediate the development of additional pathologies.
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Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans
The Journal of clinical investigation, 2010Co-Authors: Erik Schoenmakers, L. Papp, Nadia Schoenmakers, Odelia Rajanayagam, Raja Padidela, Rainer Doffinger, Maura Agostini, Catherine Mitchell, Lourdes Ceron-gutierrez, Claudia PrevostoAbstract:Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence–binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation–induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.
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mutations in the selenocysteine insertion sequence binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans
Faculty of Health, 2010Co-Authors: Erik Schoenmakers, L. Papp, Nadia Schoenmakers, Odelia Rajanayagam, Raja Padidela, Lourdes Cerongutierrez, Rainer Doffinger, Maura Agostini, Catherine Mitchell, Claudia PrevostoAbstract:Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.