The Experts below are selected from a list of 159 Experts worldwide ranked by ideXlab platform
Aymeric Chartier - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Dysfunction Reveals the Role of mRNA Poly(A) Tail Regulation in Oculopharyngeal Muscular Dystrophy Pathogenesis
PLoS Genetics, 2015Co-Authors: Aymeric Chartier, Pierre Klein, Stéphanie Pierson, Nicolas Barbezier, Teresa Gidaro, François Casas, Steven Carberry, Paul Dowling, Laurie Maynadier, Maëlle BellecAbstract:Oculopharyngeal muscular dystrophy (OPMD), a Late-Onset Disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-reguLated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correLates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-reguLated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative Disorders that involve mitochondrial dysfunction.
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Prevention of oculopharyngeal muscular dystrophy by muscular expression of Llama single-chain intrabodies in vivo
Human molecular genetics, 2009Co-Authors: Aymeric Chartier, Vered Raz, Silvère M. Van Der Maarel, C. Theo Verrips, Ellen Sterrenburg, Martine SimoneligAbstract:Oculopharyngeal muscular dystrophy (OPMD) is a Late Onset Disorder characterized by progressive weakening of specific muscles. It is caused by short expansions of the N-terminal polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1), and it belongs to the group of protein aggregation diseases, such as Huntington's, Parkinson's and Alzheimer diseases. Mutant PABPN1 forms nuclear aggregates in diseased muscles in both patients and animal models. Intrabodies are antibodies that are modified to be expressed intracellularly and target specific antigens in subcellular locations. They are commonly generated by artificially linking the variable domains of antibody heavy and light chains. However, natural single-chain antibodies are produced in Camelids and, when engineered, combined the advantages of being single-chain, small sized and very stable. Here, we determine the in vivo efficiency of Llama intrabodies against PABPN1, using the established Drosophila model of OPMD. Among six anti-PABPN1 intrabodies expressed in muscle nuclei, we identify one as a strong suppressor of OPMD muscle degeneration in Drosophila, leading to nearly complete rescue. Expression of this intrabody affects PABPN1 aggregation and restores muscle gene expression. This approach promotes the identification of intrabodies with high therapeutic value and highlights the potential of natural single-chain intrabodies in treating protein aggregation diseases.
Theo Stijnen - One of the best experts on this subject based on the ideXlab platform.
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calculating risk changes after negative mutation test outcomes for autosomal dominant hereditary Late Onset Disorders
Heredity, 2006Co-Authors: Benno Bonke, Arend Tibben, D Lindhout, Theo StijnenAbstract:We demonstrate, in a specific scenario, the effect of negative test results from relatives in families at risk for an autosomal dominant hereditary Late-Onset Disorder. A hypothetical pedigree, of a family at risk of Huntington's disease, was used to demonstrate the consequences for the risk status of various family members in the case where relatives have been tested, and found to be mutation negative. We argue that accurate assessment of conditional probabilities in clinical genetics is important for individuals at risk for hereditary Disorders with Mendelian transmission patterns; our formulae offer the opportunity -- when simplifying assumptions are met -- to determine the changed risk status of individuals in such cases.
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Favourable mutation test outcomes for individuals at risk for Huntington disease change the perspectives of first-degree relatives
Human genetics, 2002Co-Authors: Benno Bonke, Arend Tibben, Dick Lindhout, Theo StijnenAbstract:In mutation testing for Huntington disease, an autosomal dominant hereditary Late-Onset Disorder, unfavourable test outcomes in at-risk individuals provide important information about other family members at risk. On the other hand, common counselling practice considers favourable outcomes as non-informative for at-risk relatives, except for the offspring of the tested individual. We shall show, however, that favourable outcomes also change the perspectives for the tested individual's first-degree relatives at risk. In the case of a (prospective) parent originally at 50% risk, and with n equalling the number of children or fetuses identified as non-carriers, the probability of being a non-carrier equals 2 n /(2 n +1) for the at-risk parent, providing that none of the offspring of this parent has been identified as a carrier. Likewise, the probability of being a non-carrier equals (2 n+1 +1)/(2 n+1 +2) for the (future) siblings of the tested individual. These changes in probabilities are important for individuals who are considering prenatal or presymptomatic DNA-testing for autosomal dominant hereditary Late-Onset Disorders, such as Huntington disease and hereditary forms of cancer (BRCA1/2, FAP, HNPCC). Consequences can be far reaching in the case of pregnancies, where the risk of miscarriage after a prenatal test is 1%–2%. Parents initially at 50% risk may consider not having a prenatal test in successive pregnancies, knowing that favourable test results in previous pregnancies have considerably reduced their personal risk.
Maëlle Bellec - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Dysfunction Reveals the Role of mRNA Poly(A) Tail Regulation in Oculopharyngeal Muscular Dystrophy Pathogenesis
PLoS Genetics, 2015Co-Authors: Aymeric Chartier, Pierre Klein, Stéphanie Pierson, Nicolas Barbezier, Teresa Gidaro, François Casas, Steven Carberry, Paul Dowling, Laurie Maynadier, Maëlle BellecAbstract:Oculopharyngeal muscular dystrophy (OPMD), a Late-Onset Disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-reguLated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correLates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-reguLated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative Disorders that involve mitochondrial dysfunction.
Andrew M Schaefer - One of the best experts on this subject based on the ideXlab platform.
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identification of a novel heterozygous guanosine monophosphate reductase gmpr variant in a patient with a Late Onset Disorder of mitochondrial dna maintenance
Clinical Genetics, 2020Co-Authors: Ewen W Sommerville, Ilaria Dalla Rosa, Masha M Rosenberg, Francesco Bruni, Kyle Thompson, Mariana C Rocha, Emma L Blakely, Gavin Falkous, Andrew M SchaeferAbstract:Autosomal dominant progressive external ophthalmoplegia (adPEO) is a Late-Onset, Mendelian mitochondrial Disorder characterised by paresis of the extraocular muscles, ptosis, and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Although dominantly inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remains challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase-deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G>C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G>C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells, and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the 19th locus for PEO and highlights the complexities of uncovering disease mechanisms in Late-Onset PEO phenotypes.
Francesco Bruni - One of the best experts on this subject based on the ideXlab platform.
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identification of a novel heterozygous guanosine monophosphate reductase gmpr variant in a patient with a Late Onset Disorder of mitochondrial dna maintenance
Clinical Genetics, 2020Co-Authors: Ewen W Sommerville, Ilaria Dalla Rosa, Masha M Rosenberg, Francesco Bruni, Kyle Thompson, Mariana C Rocha, Emma L Blakely, Gavin Falkous, Andrew M SchaeferAbstract:Autosomal dominant progressive external ophthalmoplegia (adPEO) is a Late-Onset, Mendelian mitochondrial Disorder characterised by paresis of the extraocular muscles, ptosis, and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Although dominantly inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remains challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase-deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G>C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G>C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells, and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the 19th locus for PEO and highlights the complexities of uncovering disease mechanisms in Late-Onset PEO phenotypes.
