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Raymond F. Burk - One of the best experts on this subject based on the ideXlab platform.
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selenoprotein gene nomenclature
Journal of Biological Chemistry, 2016Co-Authors: Raymond F. Burk, Brigelius Flohe Regina, Sergi Castellano, Elspeth A Bruford, Elias S J Arner, Bradley A. Carlson, Vadim N. Gladyshev, Marla J Berry, Laurent ChavatteAbstract:Abstract The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.
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selenoprotein gene nomenclature
Journal of Biological Chemistry, 2016Co-Authors: Raymond F. Burk, Brigelius Flohe Regina, Sergi Castellano, Elspeth A Bruford, Elias S J Arner, Bradley A. Carlson, Vadim N. Gladyshev, Marla J Berry, Laurent ChavatteAbstract:Abstract The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.
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production of selenoprotein p sepp1 by hepatocytes is central to selenium homeostasis
Journal of Biological Chemistry, 2012Co-Authors: Kristina E Hill, Amy K Motley, Sen Wu, Teri D Stevenson, John F. Atkins, Virginia P. Winfrey, Mario R Capecchi, Raymond F. BurkAbstract:Abstract Sepp1 is a widely expressed extracellular protein that in humans and mice contains 10 selenocysteine residues in its primary structure. Extra-hepatic tissues take up plasma Sepp1 for its selenium via apolipoprotein E receptor-2 (apoER2)-mediated endocytosis. The role of Sepp1 in the transport of selenium from liver, a rich source of the element, to peripheral tissues was studied using mice with selective deletion of Sepp1 in hepatocytes (Sepp1c/c/alb-cre+/− mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1c/c mice (controls) and increased urinary selenium excretion, decreasing whole-body and tissue selenium concentrations. Under selenium-deficient conditions, Sepp1c/c/alb-cre+/− mice accumulated selenium in the liver at the expense of extra-hepatic tissues, severely worsening clinical manifestations of dietary selenium deficiency. These findings are consistent with there being competition for metabolically available hepatocyte selenium between the synthesis of selenoproteins and the synthesis of selenium excretory metabolites. In addition, selenium deficiency down-regulated the mRNA of the most abundant hepatic selenoprotein, glutathione peroxidase-1 (Gpx1), to 15% of the selenium-replete value, while reducing Sepp1 mRNA, the most abundant hepatic selenoprotein mRNA, only to 61%. This strongly suggests that Sepp1 synthesis is favored in the liver over Gpx1 synthesis when selenium supply is limited, directing hepatocyte selenium to peripheral tissues in selenium deficiency. We conclude that production of Sepp1 by hepatocytes is central to selenium homeostasis in the organism because it promotes retention of selenium in the body and effects selenium distribution from the liver to extra-hepatic tissues, especially under selenium-deficient conditions.
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long isoform mouse selenoprotein p sepp1 supplies rat myoblast l8 cells with selenium via endocytosis mediated by heparin binding properties and apolipoprotein e receptor 2 apoer2
Journal of Biological Chemistry, 2012Co-Authors: Suguru Kurokawa, Kristina E Hill, Hayes W Mcdonald, Raymond F. BurkAbstract:In vivo studies have shown that selenium is supplied to testis and brain by apoER2-mediated endocytosis of Sepp1. Although cultured cell lines have been shown to utilize selenium from Sepp1 added to the medium, the mechanism of uptake and utilization has not been characterized. Rat L8 myoblast cells were studied. They took up mouse Sepp1 from the medium and used its selenium to increase their glutathione peroxidase (Gpx) activity. L8 cells did not utilize selenium from Gpx3, the other plasma selenoprotein. Neither did they utilize it from Sepp1Δ240–361, the isoform of Sepp1 that lacks the selenium-rich C-terminal domain. To identify Sepp1 receptors, a solubilized membrane fraction was passed over a Sepp1 column. The receptors apoER2 and Lrp1 were identified in the eluate by mass spectrometry. siRNA experiments showed that knockdown of apoER2, but not of Lrp1, inhibited 75Se uptake from 75Se-labeled Sepp1. The addition of protamine to the medium or treatment of the cells with chlorate also inhibited 75Se uptake. Blockage of lysosome acidification did not inhibit uptake of Sepp1 but did prevent its digestion and thereby utilization of its selenium. These results indicate that L8 cells take up Sepp1 by an apoER2-mediated mechanism requiring binding to heparin sulfate proteoglycans. The presence of at least part of the selenium-rich C-terminal domain of Sepp1 is required for uptake. RT-PCR showed that mouse tissues express apoER2 in varying amounts. It is postulated that apoER2-mediated uptake of long isoform Sepp1 is responsible for selenium distribution to tissues throughout the body.
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optimization of selenoprotein p and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement a placebo controlled double blind study of selenomethionine supplementation in selenium deficient chinese subjects
The American Journal of Clinical Nutrition, 2010Co-Authors: Kristina E Hill, Amy K Motley, Ping Li, Jiayuan Xu, Dingyou Zhou, Li Wang, Daniel W Byrne, Raymond F. BurkAbstract:Background: The intake of selenium needed for optimal health has not been established. Selenoproteins perform the functions of selenium, and the selenium intake needed for their full expression is not known. Objective: This study sought to determine the intake of selenium required to optimize plasma selenoprotein P (SEPP1) and to compare SEPP1 with other plasma selenium biomarkers. Design:A 40-wkplacebo-controlled, double-blind studyofselenium repletion was carried out in 98 healthy Chinese subjects who had a daily dietary selenium intake of 14 lg. Fourteen subjects each were assigned randomly to daily dose groups of 0, 21, 35, 55, 79, 102, and 125 l gS e asL-selenomethionine. Plasma glutathione peroxidase (GPX) activity, SEPP1, and selenium were measured. A biomarker was considered to be optimized when its valuewas not different from the mean value of the subjects receiving larger supplements. Results: The SEPP1 concentration was optimized at 40 wk by the 35-lg supplement, which indicated that 49 lg/d could optimize it. GPX activity was optimized by 21 lg (total ingestion: 35 lg/d). The selenium concentration showed no tendency to become optimized. Conclusions: The present results indicate that SEPP1 concentration is the best plasma biomarker studied for assessing optimal expression of all selenoproteins, because its optimization required a larger intake of selenium than did GPX activity. On the basis of the selenium intake needed for SEPP1 optimization with adjustments for body weight and individual variation, ’75 lg Se/d as selenomethionine is postulated to allow full expression of selenoproteins in US residents. This trial was registered at clinicaltrials.gov as NCT00428649. Am J Clin Nutr doi: 10.3945/ajcn.2010.29642.
Alain Lescure - One of the best experts on this subject based on the ideXlab platform.
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Increased Muscle Stress-Sensitivity Induced by Selenoprotein N Inactivation in Mouse: A Mammalian
2016Co-Authors: Model For Sepn-related Myopathy, Alain Krol, Pascale Guicheney, Ana Ferreiro, Alain LescureAbstract:Selenium is an essential trace element and selenoprotein N (SelN) was the first selenium-containing protein shown to be directly involved in human inherited diseases. Mutations in the SEPN1 gene, encoding SelN, cause a group of muscular disorders characterized by predominant affection of axial muscles. SelN has been shown to participate in calcium and redox homeostasis, but its pathophysiological role in skeletal muscle remains largely unknown. To address SelN function in vivo, we generated a SEPN1-null mouse model by gene targeting. The SEPN12/2 mice had normal growth and lifespan, and were macroscopically indistinguishable from wild-type littermates. Only minor defects were observed in muscle morphology and contractile properties in SelN-deficient mice in basal conditions. However, when subjected to challenging physical exercise and stress conditions (forced swimming test), SEPN12/2 mice developed an obvious phenotype, characterized by limited motility and body rigidity during the swimming session, as well as a progressive curvature of the spine and predominant alteration of paravertebral muscles. This induced phenotype recapitulates the distribution of muscle involvement in patients with SEPN1-Related Myopathy, hence positioning this new animal model as a valuable tool to dissect the role of SelN i
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ral ssBioMed CentBMC Developmental Biology Open AcceResearch article
2015Co-Authors: Mathieu Rederstorff, Alain Lescure, Alain Krol, Shahragim Tajbakhsh, Valérie Allam, Pascale GuicheneyAbstract:Background: In humans, mutations in the SEPN1 gene, encoding selenoprotein N (SelN), are involved in early onset recessive neuromuscular disorders, referred to as SEPN1-related-myopathies. The mechanisms behind these pathologies are poorly understood since the function of SelN remains elusive. However, previous results obtained in humans and more recently in zebrafish pointed to a potential role for SelN during embryogenesis. Using qRT-PCR, Western blot and whole mount in situ hybridization, we characterized in detail the spatio-temporal expression pattern of the murine SEPN1 gene during development, focusing particularly on skeletal muscles. Results: In whole embryos, SEPN1 transcripts were detected as early as E5.5, with expression levels peaking at E12.5, and then strongly decreasing until birth. In isolated tissues, only mild transcriptional variations were observed during development, whereas a striking reduction of th
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Selenoprotein N in skeletal muscle: from diseases to function
Journal of Molecular Medicine, 2012Co-Authors: Perrine Castets, Alain Lescure, Pascale Guicheney, Valérie AllamandAbstract:Selenoprotein N (SelN) deficiency causes several inherited neuromuscular disorders collectively termed SEPN1 -related myopathies, characterized by early onset, generalized muscle atrophy, and muscle weakness affecting especially axial muscles and leading to spine rigidity, severe scoliosis, and respiratory insufficiency. SelN is ubiquitously expressed and is located in the membrane of the endoplasmic reticulum; however, its function remains elusive. The predominant expression of SelN in human fetal tissues and the embryonic muscle phenotype reported in mutant zebrafish suggest that it is involved in myogenesis. In mice, SelN is also mostly expressed during embryogenesis and especially in the myotome, but no defect was detected in muscle development and growth in the SEPN1 knock-out mouse model. By contrast, we recently demonstrated that SelN is essential for muscle regeneration and satellite cell maintenance in mice and humans, hence opening new avenues regarding the pathomechanism(s) leading to SEPN1 -related myopathies. At the cellular level, recent data suggested that SelN participates in oxidative and calcium homeostasis, with a potential role in the regulation of the ryanodine receptor activity. Despite the recent and exciting progress regarding the physiological function(s) of SelN in muscle tissue, the pathogenesis leading to SEPN1 -related myopathies remains largely unknown, with several unsolved questions, and no treatment available. In this review, we introduce SelN, its properties and expression pattern in zebrafish, mice, and humans, and we discuss its potential roles in muscle tissue and the ensuing clues for the development of therapeutic options.
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Satellite cell loss and impaired muscle regeneration in selenoprotein N deficiency.
Human Molecular Genetics, 2011Co-Authors: Perrine Castets, Mathieu Rederstorff, Maud Beuvin, Arnaud Ferry, Alain Krol, Anne T. Bertrand, Fabien Le Grand, Marie Castets, Guillaume Chazot, Alain LescureAbstract:Selenoprotein N (SelN) deficiency causes a group of inherited neuromuscular disorders termed SEPN1-related myopathies (SEPN1-RM). Although the function of SelN remains unknown, recent data demonstrated that it is dispensable for mouse embryogenesis and suggested its involvement in the regulation of ryanodine receptors and/or cellular redox homeostasis. Here, we investigate the role of SelN in satellite cell (SC) function and muscle regeneration, using the SEPN1(-/-) mouse model. Following cardiotoxin-induced injury, SelN expression was strongly up-regulated in wild-type muscles and, for the first time, we detected its endogenous expression in a subset of mononucleated cells by immunohistochemistry. We show that SelN deficiency results in a reduced basal SC pool in adult skeletal muscles and in an imperfect muscle restoration following a single injury. A dramatic depletion of the SC pool was detected after the first round of degeneration and regeneration that totally prevented subsequent regeneration of SEPN1(-/-) muscles. We demonstrate that SelN deficiency affects SC dynamics on isolated single fibres and increases the proliferation of SEPN1(-/-) muscle precursors in vivo and in vitro. Most importantly, exhaustion of the SC population was specifically identified in muscle biopsies from patients with mutations in the SEPN1 gene. In conclusion, we describe for the first time a major physiological function of SelN in skeletal muscles, as a key regulator of SC function, which likely plays a central role in the pathophysiological mechanism leading to SEPN1-RM.
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Selenoprotein N: Its Role in Disease
Selenium, 2011Co-Authors: Alain Lescure, Valérie Allamand, David Grunwald, Perrine Castets, Michael T HowardAbstract:Selenoprotein N is among the newly identified selenoproteins, initially discovered in silico with no known molecular function. It has become the focus of attention because mutations in the selenoprotein N gene are linked to a group of muscle disorders, now referred as SEPN1-related myopathies. An emerging view arising from recent findings is that the loss of selenoprotein N leads to cellular sensitivity to oxidative stress and loss of calcium homeostasis. Studies of animal models for SEPN1-Related Myopathies revealed the fate of sensitized muscle may depend on stresses to which it is subjected, and defects in the function of selenoprotein N-deficient muscle progenitor cells during development in zebrafish embryos or during muscle regeneration in fully developed mouse muscle. Dysfunction of these different processes raises significant questions regarding which of the phenotypic manifestations of SEPN1-Related Myopathies are initiated by events during development and which are progressive in nature arising from dysfunction of mature muscle.
Valérie Allamand - One of the best experts on this subject based on the ideXlab platform.
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Selenoprotein N in skeletal muscle: from diseases to function
Journal of Molecular Medicine, 2012Co-Authors: Perrine Castets, Alain Lescure, Pascale Guicheney, Valérie AllamandAbstract:Selenoprotein N (SelN) deficiency causes several inherited neuromuscular disorders collectively termed SEPN1 -related myopathies, characterized by early onset, generalized muscle atrophy, and muscle weakness affecting especially axial muscles and leading to spine rigidity, severe scoliosis, and respiratory insufficiency. SelN is ubiquitously expressed and is located in the membrane of the endoplasmic reticulum; however, its function remains elusive. The predominant expression of SelN in human fetal tissues and the embryonic muscle phenotype reported in mutant zebrafish suggest that it is involved in myogenesis. In mice, SelN is also mostly expressed during embryogenesis and especially in the myotome, but no defect was detected in muscle development and growth in the SEPN1 knock-out mouse model. By contrast, we recently demonstrated that SelN is essential for muscle regeneration and satellite cell maintenance in mice and humans, hence opening new avenues regarding the pathomechanism(s) leading to SEPN1 -related myopathies. At the cellular level, recent data suggested that SelN participates in oxidative and calcium homeostasis, with a potential role in the regulation of the ryanodine receptor activity. Despite the recent and exciting progress regarding the physiological function(s) of SelN in muscle tissue, the pathogenesis leading to SEPN1 -related myopathies remains largely unknown, with several unsolved questions, and no treatment available. In this review, we introduce SelN, its properties and expression pattern in zebrafish, mice, and humans, and we discuss its potential roles in muscle tissue and the ensuing clues for the development of therapeutic options.
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Selenoprotein N: Its Role in Disease
Selenium, 2011Co-Authors: Alain Lescure, Valérie Allamand, David Grunwald, Perrine Castets, Michael T HowardAbstract:Selenoprotein N is among the newly identified selenoproteins, initially discovered in silico with no known molecular function. It has become the focus of attention because mutations in the selenoprotein N gene are linked to a group of muscle disorders, now referred as SEPN1-related myopathies. An emerging view arising from recent findings is that the loss of selenoprotein N leads to cellular sensitivity to oxidative stress and loss of calcium homeostasis. Studies of animal models for SEPN1-Related Myopathies revealed the fate of sensitized muscle may depend on stresses to which it is subjected, and defects in the function of selenoprotein N-deficient muscle progenitor cells during development in zebrafish embryos or during muscle regeneration in fully developed mouse muscle. Dysfunction of these different processes raises significant questions regarding which of the phenotypic manifestations of SEPN1-Related Myopathies are initiated by events during development and which are progressive in nature arising from dysfunction of mature muscle.
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selenoprotein function and muscle disease
Biochimica et Biophysica Acta, 2009Co-Authors: Alain Lescure, Valérie Allamand, Mathieu Rederstorff, Alain Krol, Pascale GuicheneyAbstract:The crucial role of the trace element selenium in livestock and human health, in particular in striated muscle function, has been well established but the underlying molecular mechanisms remain poorly understood. Over the last decade, identification of the full repertoire of selenium-containing proteins has opened the way towards a better characterization of these processes. Two selenoproteins have mainly been investigated in muscle, namely SelW and SelN. Here we address their involvement in muscle development and maintenance, through the characterization of various cellular or animal models. In particular, mutations in the SEPN1 gene encoding selenoprotein N (SelN) cause a group of neuromuscular disorders now referred to as SEPN1-related myopathy. Recent findings on the functional consequences of these mutations suggest an important contribution of SelN to the regulation of oxidative stress and calcium homeostasis. Importantly, the conclusions of these experiments have opened new avenues of investigations that provide grounds for the development of therapeutic approaches.
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a mutation in the SEPN1 selenocysteine redefinition element sre reduces selenocysteine incorporation and leads to SEPN1 related myopathy
Human Mutation, 2009Co-Authors: Baijayanta Maiti, Valérie Allamand, P Richard, S Arbogast, Mark W Moyle, Christine B Anderson, Pascale GuicheneyAbstract:Mutations in SEPN1 result in a spectrum of early-onset muscle disorders referred to as SEPN1-related myopathy. The SEPN1 gene encodes selenoprotein N (SelN), which contains the amino acid selenocysteine (Sec). Incorporation of Sec occurs due to redefinition of a UGA codon during translation. Efficient insertion requires a Sec insertion sequence (SECIS) in the 3′UTR and, for at least a subset of selenoprotein genes, a Sec redefinition element (SRE) located adjacent to the UGA codon. We report the effect of three novel and one previously reported point mutation in the SelN SRE element on Sec insertion efficiency. Notably, the previously reported mutation c.1397G>A (p.R466Q), which weakens the secondary structure of the SRE element, reduces Sec insertion efficiency and SelN RNA levels. Muscle from patients with this mutation have negligible levels of SelN protein. This data highlights the importance of the SRE element during SelN expression and illustrates a novel molecular mechanism by which point mutations may lead to SEPN1-related myopathy. Hum Mutat 0, 1–6, 2008. © 2008 Wiley-Liss, Inc.
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Selenoprotein N is dynamically expressed during mouse development and detected early in muscle precursors.
BMC Developmental Biology, 2009Co-Authors: Perrine Castets, Alain Lescure, Valérie Allamand, Mathieu Rederstorff, Alain Krol, Svetlana Maugenre, Corine Gartioux, Shahragim Tajbakhsh, Pascale GuicheneyAbstract:BACKGROUND: In humans, mutations in the SEPN1 gene, encoding selenoprotein N (SelN), are involved in early onset recessive neuromuscular disorders, referred to as SEPN1-related-myopathies. The mechanisms behind these pathologies are poorly understood since the function of SelN remains elusive. However, previous results obtained in humans and more recently in zebrafish pointed to a potential role for SelN during embryogenesis. Using qRT-PCR, Western blot and whole mount in situ hybridization, we characterized in detail the spatio-temporal expression pattern of the murine SEPN1 gene during development, focusing particularly on skeletal muscles. RESULTS: In whole embryos, SEPN1 transcripts were detected as early as E5.5, with expression levels peaking at E12.5, and then strongly decreasing until birth. In isolated tissues, only mild transcriptional variations were observed during development, whereas a striking reduction of the protein expression was detected during the perinatal period. Furthermore, we demonstrated that SEPN1 is expressed early in somites and restricted to the myotome, the sub-ectodermal mesenchyme and the dorsal root ganglia at mid-gestation stages. Interestingly, SEPN1 deficiency did not alter somitogenesis in embryos, suggesting that SelN is dispensable for these processes in mouse. CONCLUSION: We characterized for the first time the expression pattern of SEPN1 during mammalian embryogenesis and we demonstrated that its differential expression is most likely dependent on major post-transcriptional regulations. Overall, our data strongly suggest a potential role for selenoprotein N from mid-gestation stages to the perinatal period. Interestingly, its specific expression pattern could be related to the current hypothesis that selenoprotein N may regulate the activity of the ryanodine receptors.
Pascale Guicheney - One of the best experts on this subject based on the ideXlab platform.
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Increased Muscle Stress-Sensitivity Induced by Selenoprotein N Inactivation in Mouse: A Mammalian
2016Co-Authors: Model For Sepn-related Myopathy, Alain Krol, Pascale Guicheney, Ana Ferreiro, Alain LescureAbstract:Selenium is an essential trace element and selenoprotein N (SelN) was the first selenium-containing protein shown to be directly involved in human inherited diseases. Mutations in the SEPN1 gene, encoding SelN, cause a group of muscular disorders characterized by predominant affection of axial muscles. SelN has been shown to participate in calcium and redox homeostasis, but its pathophysiological role in skeletal muscle remains largely unknown. To address SelN function in vivo, we generated a SEPN1-null mouse model by gene targeting. The SEPN12/2 mice had normal growth and lifespan, and were macroscopically indistinguishable from wild-type littermates. Only minor defects were observed in muscle morphology and contractile properties in SelN-deficient mice in basal conditions. However, when subjected to challenging physical exercise and stress conditions (forced swimming test), SEPN12/2 mice developed an obvious phenotype, characterized by limited motility and body rigidity during the swimming session, as well as a progressive curvature of the spine and predominant alteration of paravertebral muscles. This induced phenotype recapitulates the distribution of muscle involvement in patients with SEPN1-Related Myopathy, hence positioning this new animal model as a valuable tool to dissect the role of SelN i
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whole body muscle magnetic resonance imaging in SEPN1 related myopathy shows a homogeneous and recognizable pattern
Muscle & Nerve, 2015Co-Authors: Karolina Hankiewicz, Pascale Guicheney, Ana Ferreiro, Robe Carlie, Leila Lazaro, Javie Linzoai, Christine Arnerias, David Gomezandres, Daniela Avilasmirnow, Dominique P GermaiAbstract:Introduction: The aim of this study was to delineate the spectrum of muscle involvement in patients with a myopathy due to mutations in SEPN1 (SEPN1-RM). Methods: Whole-body magnetic resonance imaging (WBMRI) was used in 9 patients using T1-weighted turbo spin–echo (T1-TSE) sequences and short tau inversion recovery (STIR) in 5 patients. Results: Analysis of signal and volume abnormalities by T1-TSE sequences in 109 muscles showed a homogeneous pattern characterized by a recognizable combination of atrophy and signal abnormalities in selected muscles of the neck, trunk, pelvic girdle, and lower limbs. Severe wasting of sternocleidomastoid muscle and atrophy of semimembranosus were detected. Selective paraspinal, gluteus maximus, and thigh muscle involvement was also observed. The lower leg was less constantly affected. Conclusions: WBMRI scoring of altered signal and atrophy in muscle can be represented by heatmaps and is associated with a homogeneous, recognizable pattern in SEPN1-RM, distinct from other genetic muscle diseases. Muscle Nerve 52: 728–735, 2015
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ral ssBioMed CentBMC Developmental Biology Open AcceResearch article
2015Co-Authors: Mathieu Rederstorff, Alain Lescure, Alain Krol, Shahragim Tajbakhsh, Valérie Allam, Pascale GuicheneyAbstract:Background: In humans, mutations in the SEPN1 gene, encoding selenoprotein N (SelN), are involved in early onset recessive neuromuscular disorders, referred to as SEPN1-related-myopathies. The mechanisms behind these pathologies are poorly understood since the function of SelN remains elusive. However, previous results obtained in humans and more recently in zebrafish pointed to a potential role for SelN during embryogenesis. Using qRT-PCR, Western blot and whole mount in situ hybridization, we characterized in detail the spatio-temporal expression pattern of the murine SEPN1 gene during development, focusing particularly on skeletal muscles. Results: In whole embryos, SEPN1 transcripts were detected as early as E5.5, with expression levels peaking at E12.5, and then strongly decreasing until birth. In isolated tissues, only mild transcriptional variations were observed during development, whereas a striking reduction of th
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Selenoprotein N in skeletal muscle: from diseases to function
Journal of Molecular Medicine, 2012Co-Authors: Perrine Castets, Alain Lescure, Pascale Guicheney, Valérie AllamandAbstract:Selenoprotein N (SelN) deficiency causes several inherited neuromuscular disorders collectively termed SEPN1 -related myopathies, characterized by early onset, generalized muscle atrophy, and muscle weakness affecting especially axial muscles and leading to spine rigidity, severe scoliosis, and respiratory insufficiency. SelN is ubiquitously expressed and is located in the membrane of the endoplasmic reticulum; however, its function remains elusive. The predominant expression of SelN in human fetal tissues and the embryonic muscle phenotype reported in mutant zebrafish suggest that it is involved in myogenesis. In mice, SelN is also mostly expressed during embryogenesis and especially in the myotome, but no defect was detected in muscle development and growth in the SEPN1 knock-out mouse model. By contrast, we recently demonstrated that SelN is essential for muscle regeneration and satellite cell maintenance in mice and humans, hence opening new avenues regarding the pathomechanism(s) leading to SEPN1 -related myopathies. At the cellular level, recent data suggested that SelN participates in oxidative and calcium homeostasis, with a potential role in the regulation of the ryanodine receptor activity. Despite the recent and exciting progress regarding the physiological function(s) of SelN in muscle tissue, the pathogenesis leading to SEPN1 -related myopathies remains largely unknown, with several unsolved questions, and no treatment available. In this review, we introduce SelN, its properties and expression pattern in zebrafish, mice, and humans, and we discuss its potential roles in muscle tissue and the ensuing clues for the development of therapeutic options.
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selenoprotein function and muscle disease
Biochimica et Biophysica Acta, 2009Co-Authors: Alain Lescure, Valérie Allamand, Mathieu Rederstorff, Alain Krol, Pascale GuicheneyAbstract:The crucial role of the trace element selenium in livestock and human health, in particular in striated muscle function, has been well established but the underlying molecular mechanisms remain poorly understood. Over the last decade, identification of the full repertoire of selenium-containing proteins has opened the way towards a better characterization of these processes. Two selenoproteins have mainly been investigated in muscle, namely SelW and SelN. Here we address their involvement in muscle development and maintenance, through the characterization of various cellular or animal models. In particular, mutations in the SEPN1 gene encoding selenoprotein N (SelN) cause a group of neuromuscular disorders now referred to as SEPN1-related myopathy. Recent findings on the functional consequences of these mutations suggest an important contribution of SelN to the regulation of oxidative stress and calcium homeostasis. Importantly, the conclusions of these experiments have opened new avenues of investigations that provide grounds for the development of therapeutic approaches.
Kristina E Hill - One of the best experts on this subject based on the ideXlab platform.
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production of selenoprotein p sepp1 by hepatocytes is central to selenium homeostasis
Journal of Biological Chemistry, 2012Co-Authors: Kristina E Hill, Amy K Motley, Sen Wu, Teri D Stevenson, John F. Atkins, Virginia P. Winfrey, Mario R Capecchi, Raymond F. BurkAbstract:Abstract Sepp1 is a widely expressed extracellular protein that in humans and mice contains 10 selenocysteine residues in its primary structure. Extra-hepatic tissues take up plasma Sepp1 for its selenium via apolipoprotein E receptor-2 (apoER2)-mediated endocytosis. The role of Sepp1 in the transport of selenium from liver, a rich source of the element, to peripheral tissues was studied using mice with selective deletion of Sepp1 in hepatocytes (Sepp1c/c/alb-cre+/− mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1c/c mice (controls) and increased urinary selenium excretion, decreasing whole-body and tissue selenium concentrations. Under selenium-deficient conditions, Sepp1c/c/alb-cre+/− mice accumulated selenium in the liver at the expense of extra-hepatic tissues, severely worsening clinical manifestations of dietary selenium deficiency. These findings are consistent with there being competition for metabolically available hepatocyte selenium between the synthesis of selenoproteins and the synthesis of selenium excretory metabolites. In addition, selenium deficiency down-regulated the mRNA of the most abundant hepatic selenoprotein, glutathione peroxidase-1 (Gpx1), to 15% of the selenium-replete value, while reducing Sepp1 mRNA, the most abundant hepatic selenoprotein mRNA, only to 61%. This strongly suggests that Sepp1 synthesis is favored in the liver over Gpx1 synthesis when selenium supply is limited, directing hepatocyte selenium to peripheral tissues in selenium deficiency. We conclude that production of Sepp1 by hepatocytes is central to selenium homeostasis in the organism because it promotes retention of selenium in the body and effects selenium distribution from the liver to extra-hepatic tissues, especially under selenium-deficient conditions.
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long isoform mouse selenoprotein p sepp1 supplies rat myoblast l8 cells with selenium via endocytosis mediated by heparin binding properties and apolipoprotein e receptor 2 apoer2
Journal of Biological Chemistry, 2012Co-Authors: Suguru Kurokawa, Kristina E Hill, Hayes W Mcdonald, Raymond F. BurkAbstract:In vivo studies have shown that selenium is supplied to testis and brain by apoER2-mediated endocytosis of Sepp1. Although cultured cell lines have been shown to utilize selenium from Sepp1 added to the medium, the mechanism of uptake and utilization has not been characterized. Rat L8 myoblast cells were studied. They took up mouse Sepp1 from the medium and used its selenium to increase their glutathione peroxidase (Gpx) activity. L8 cells did not utilize selenium from Gpx3, the other plasma selenoprotein. Neither did they utilize it from Sepp1Δ240–361, the isoform of Sepp1 that lacks the selenium-rich C-terminal domain. To identify Sepp1 receptors, a solubilized membrane fraction was passed over a Sepp1 column. The receptors apoER2 and Lrp1 were identified in the eluate by mass spectrometry. siRNA experiments showed that knockdown of apoER2, but not of Lrp1, inhibited 75Se uptake from 75Se-labeled Sepp1. The addition of protamine to the medium or treatment of the cells with chlorate also inhibited 75Se uptake. Blockage of lysosome acidification did not inhibit uptake of Sepp1 but did prevent its digestion and thereby utilization of its selenium. These results indicate that L8 cells take up Sepp1 by an apoER2-mediated mechanism requiring binding to heparin sulfate proteoglycans. The presence of at least part of the selenium-rich C-terminal domain of Sepp1 is required for uptake. RT-PCR showed that mouse tissues express apoER2 in varying amounts. It is postulated that apoER2-mediated uptake of long isoform Sepp1 is responsible for selenium distribution to tissues throughout the body.
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optimization of selenoprotein p and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement a placebo controlled double blind study of selenomethionine supplementation in selenium deficient chinese subjects
The American Journal of Clinical Nutrition, 2010Co-Authors: Kristina E Hill, Amy K Motley, Ping Li, Jiayuan Xu, Dingyou Zhou, Li Wang, Daniel W Byrne, Raymond F. BurkAbstract:Background: The intake of selenium needed for optimal health has not been established. Selenoproteins perform the functions of selenium, and the selenium intake needed for their full expression is not known. Objective: This study sought to determine the intake of selenium required to optimize plasma selenoprotein P (SEPP1) and to compare SEPP1 with other plasma selenium biomarkers. Design:A 40-wkplacebo-controlled, double-blind studyofselenium repletion was carried out in 98 healthy Chinese subjects who had a daily dietary selenium intake of 14 lg. Fourteen subjects each were assigned randomly to daily dose groups of 0, 21, 35, 55, 79, 102, and 125 l gS e asL-selenomethionine. Plasma glutathione peroxidase (GPX) activity, SEPP1, and selenium were measured. A biomarker was considered to be optimized when its valuewas not different from the mean value of the subjects receiving larger supplements. Results: The SEPP1 concentration was optimized at 40 wk by the 35-lg supplement, which indicated that 49 lg/d could optimize it. GPX activity was optimized by 21 lg (total ingestion: 35 lg/d). The selenium concentration showed no tendency to become optimized. Conclusions: The present results indicate that SEPP1 concentration is the best plasma biomarker studied for assessing optimal expression of all selenoproteins, because its optimization required a larger intake of selenium than did GPX activity. On the basis of the selenium intake needed for SEPP1 optimization with adjustments for body weight and individual variation, ’75 lg Se/d as selenomethionine is postulated to allow full expression of selenoproteins in US residents. This trial was registered at clinicaltrials.gov as NCT00428649. Am J Clin Nutr doi: 10.3945/ajcn.2010.29642.
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selenoprotein p expression functions and roles in mammals
Biochimica et Biophysica Acta, 2009Co-Authors: Raymond F. Burk, Kristina E HillAbstract:Selenoprotein P (Sepp1) is a secreted protein that is made up of 2 domains. The larger N-terminal domain contains 1 selenocysteine residue in a redox motif and the smaller C-terminal domain contains the other 9 selenocysteines. Sepp1 isoforms of varying lengths occur but quantitation of them has not been achieved. Hepatic synthesis of Sepp1 affects whole-body selenium content and the liver is the source of most plasma Sepp1. ApoER2, a member of the lipoprotein receptor family, binds Sepp1 and facilitates its uptake into the testis and retention of its selenium by the brain. Megalin, another lipoprotein receptor, facilitates uptake of filtered Sepp1 into proximal tubule cells of the kidney. Thus, Sepp1 serves in homeostasis and distribution of selenium. Mice with deletion of Sepp1 suffer greater morbidity and mortality from infection with Trypanosoma congolense than do wild-type mice. Mice that express only the N-terminal domain of Sepp1 have the same severity of illness as wild-type mice, indicating that the protective function of Sepp1 against the infection resides in the N-terminal (redox) domain. Thus, Sepp1 has several functions. In addition, plasma Sepp1 concentration falls in selenium deficiency and, therefore, it can be used as an index of selenium nutritional status.
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megalin mediates selenoprotein p uptake by kidney proximal tubule epithelial cells
Journal of Biological Chemistry, 2008Co-Authors: Gary E. Olson, Virginia P. Winfrey, Kristina E Hill, Raymond F. BurkAbstract:Abstract Selenoprotein P (Sepp1) contains most of the selenium in blood plasma, and it is utilized by the kidney, brain, and testis as a selenium source for selenoprotein synthesis. We recently demonstrated that apolipoprotein E receptor-2 (ApoER2) is required for Sepp1 uptake by the testis and that deletion of ApoER2 reduces testis and brain, but not kidney, selenium levels. This study examined the kidney Sepp1 uptake pathway. Immunolocalization experiments demonstrated that Sepp1 passed into the glomerular filtrate and was specifically taken up by proximal tubule epithelial cells. Neither the C terminus selenocysteine-rich domain of Sepp1 nor ApoER2 was required for Sepp1 uptake by proximal tubules. Tissue ligand binding assays using cryosections of Sepp1-/- kidneys revealed that the proximal tubule epithelium contained Sepp1-binding sites that were blocked by the receptor-associated protein, RAP, an inhibitor of lipoprotein receptor-ligand interactions. Ligand blotting assays of kidney membrane preparations fractionated by SDS-PAGE revealed that Sepp1 binds megalin, a lipoprotein receptor localized to the proximal tubule epithelium. Immunolocalization analyses confirmed the in vivo co-localization of Sepp1 and megalin in wild type kidneys and demonstrated the absence of proximal tubule Sepp1 uptake in megalin null mice. These results demonstrate that kidney selenium homeostasis is mediated by a megalin-dependent Sepp1 uptake pathway in the proximal tubule.
