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Littérature scientifique sur le sujet « Mitochondrial disease, gene discovery »

Auteur : Grafiati
Publié le 9 mars 2023
Mis à jour le 10 mars 2023

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Articles de revues sur le sujet "Mitochondrial disease, gene discovery"

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Sato, Shigeto, et Nobutaka Hattori. « Genetic Mutations and Mitochondrial Toxins Shed New Light on the Pathogenesis of Parkinson's Disease ». Parkinson's Disease 2011 (2011) : 1–7. http://dx.doi.org/10.4061/2011/979231.

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The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD.
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Candelise, Niccolò, Illari Salvatori, Silvia Scaricamazza, Valentina Nesci, Henri Zenuni, Alberto Ferri et Cristiana Valle. « Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis : An Update on a Lasting Relationship ». Metabolites 12, no 3 (9 mars 2022) : 233. http://dx.doi.org/10.3390/metabo12030233.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu–Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial “metabolic threshold”, which may appear pivotal in ALS pathogenesis.
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McBride, Heidi M. « Parkin mitochondria in the autophagosome ». Journal of Cell Biology 183, no 5 (24 novembre 2008) : 757–59. http://dx.doi.org/10.1083/jcb.200810184.

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Narendra et al. (see p. 795 of this issue) have made an exciting new discovery that links the fields of mitochondrial quality control and the genetics of Parkinson's disease (PD). Through an elegant series of high-resolution imaging experiments, they are the first to provide evidence that the PARK2 gene product Parkin is selectively recruited to damaged or uncoupled mitochondria. This recruitment leads to the clearance of the organelles through the autophagosome, demonstrating a primary function for Parkin in the regulation of mitochondrial turnover. This work significantly increases our understanding of PD and provides a new framework for the development of therapeutic interventions.
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Napier, Ian, Prem Ponka et Des R. Richardson. « Iron trafficking in the mitochondrion : novel pathways revealed by disease ». Blood 105, no 5 (1 mars 2005) : 1867–74. http://dx.doi.org/10.1182/blood-2004-10-3856.

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AbstractIt is well known that iron (Fe) is transported to the mitochondrion for heme synthesis. However, only recently has the importance of this organelle for many other facets of Fe metabolism become widely appreciated. Indeed, this was stimulated by the description of human disease states that implicate mitochondrial Fe metabolism. In particular, studies assessing various diseases leading to mitochondrial Fe loading have produced intriguing findings. For instance, the disease X-linked sideroblastic anemia with ataxia (XLSA/A) is due to a mutation in the ATP-binding cassette protein B7 (ABCB7) transporter that is thought to transfer [Fe-S] clusters from the mitochondrion to the cytoplasm. This and numerous other findings suggest the mitochondrion is a dynamo of Fe metabolism, being vital not only for heme synthesis but also for playing a critical role in the genesis of [Fe-S] clusters. Studies examining the disease Friedreich ataxia have suggested that a mutation in the gene encoding frataxin leads to mitochondrial Fe loading. Apart from these findings, the recently discovered mitochondrial ferritin that may store Fe in ring sideroblasts could also regulate the level of Fe needed for heme and [Fe-S] cluster synthesis. In this review, we suggest a model of mitochondrial Fe processing that may account for the pathology observed in these disease states.
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Kalvala, Anil Kumar, Islauddin Khan, Chayanika Gundu et Ashutosh Kumar. « An Overview on ATP Dependent and Independent Proteases Including an Anterograde to Retrograde Control on Mitochondrial Function ; Focus on Diabetes and Diabetic Complications ». Current Pharmaceutical Design 25, no 23 (30 septembre 2019) : 2584–94. http://dx.doi.org/10.2174/1381612825666190718153901.

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Mitochondria are the central power stations of the cell involved with a myriad of cell signalling pathways that contribute for whole health status of the cell. It is a well known fact that not only mitochondrial genome encodes for mitochondrial proteins but there are several other mitochondrial specific proteins encoded by nuclear genome which regulate plethora of cell catabolic and anabolic process. Anterograde pathways include nuclear gene encoded proteins and their specific transport into the mitochondria and regulation of mitochondrial homeostasis. The retrograde pathways include crosstalk between the mitochondria and cytoplasmic proteins. Indeed, ATP dependent and independent proteases are identified to be very critical in balancing anterograde to retrograde signalling and vice versa to maintain the cell viability or cell death. Different experimental studies conducted on silencing the genes of these proteases have shown embryonic lethality, cancer cells death, increased hepatic glucose output, insulin tolerance, increased protein exclusion bodies, mitochondrial dysfunction, and defect in mitochondrial biogenesis, increased inflammation, Apoptosis etc. These experimental studies included from eubacteria to eukaryotes. Hence, many lines of theories proposed these proteases are conservative from eubacteria to eukaryotes. However, the regulation of these proteases at gene level is not clearly understood and still research is warranted. In this review, we articulated the origin and regulation of these proteases and the cross talk between the nucleus and mitochondria vice versa, and highlighted the role of these proteases in diabetes and diabetic complications in human diseases.
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Insolera, Ryan, Péter Lőrincz, Alec J. Wishnie, Gábor Juhász et Catherine A. Collins. « Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons ». PLOS Genetics 17, no 8 (12 août 2021) : e1009731. http://dx.doi.org/10.1371/journal.pgen.1009731.

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A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.
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Meyrick, Jonathan, Renae J. Stefanetti, Linda Errington, Robert McFarland, Gráinne S. Gorman et Nichola Z. Lax. « Model systems informing mechanisms and drug discovery : a systematic review of POLG-related disease models ». Wellcome Open Research 8 (20 janvier 2023) : 33. http://dx.doi.org/10.12688/wellcomeopenres.18637.1.

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Introduction Pathogenic variants in the gene encoding the catalytic subunit of DNA polymerase gamma (POLG), comprise an important single-gene cause of inherited mitochondrial disorders. Clinical manifestations are now recognised as an array of overlapping clinical features rather than discrete syndromes as originally conceptualised. Animal and cellular models have been used to address numerous scientific questions, from basic science to the development and assessment of novel therapies. Here, we sought to perform a systematic review of the existing models used in mitochondrial research and their effectiveness in recapitulating POLG-related disease. Methods Four databases were searched from inception to May 31, 2022: MEDLINE, Scopus, Web of Science, and Cochrane Review. Original articles available in English, reporting the use of a model system designed to recapitulate POLG­-related disease, or related pathogenicity, were eligible for inclusion. Risk of bias and the methodological quality of articles were assessed by an adapted version of the Cochrane Risk of Bias Tool, with the quality of evidence synthesized across each model. Results A total of 55 articles, including seven model organisms (Human, yeast [Saccharomyces cerevisiae and Schizosaccharomyces pombe], Drosophila, Mouse, Nematoda, and Zebrafish) with 258 distinct variants were included. Of these, 66% (N=38) of articles recapitulated mitochondrial DNA (mtDNA) depletion and 42% (N=23) recapitulated POLG-related disease. Thirty-three percent of articles (N=18/55) utilised tissue-specific models of POLG-related dysfunction, while 13% (N=7) investigated the effect of potential therapeutics in POLG-related mitochondrial disorders. Discussion The available evidence supporting the ability of models for POLG-related disease to recapitulate molecular mechanisms and phenotype is limited, inconsistent and of poor methodologic quality. Further success in examining and translating novel therapies into effective treatments will be enhanced by the availability of more robust models that better recapitulate the entire spectrum of POLG-related disease. PROSPERO registration: CRD42021234883
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DiMauro, Salvatore. « A Brief History of Mitochondrial Pathologies ». International Journal of Molecular Sciences 20, no 22 (12 novembre 2019) : 5643. http://dx.doi.org/10.3390/ijms20225643.

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The history of “mitochondrial pathologies”, namely genetic pathologies affecting mitochondrial metabolism because of mutations in nuclear DNA-encoded genes for proteins active inside mitochondria or mutations in mitochondrial DNA-encoded genes, began in 1988. In that year, two different groups of researchers discovered, respectively, large-scale single deletions of mitochondrial DNA (mtDNA) in muscle biopsies from patients with “mitochondrial myopathies” and a point mutation in the mtDNA gene for subunit 4 of NADH dehydrogenase (MTND4), associated with maternally inherited Leber’s hereditary optic neuropathy (LHON). Henceforth, a novel conceptual “mitochondrial genetics”, separate from mendelian genetics, arose, based on three features of mtDNA: (1) polyplasmy; (2) maternal inheritance; and (3) mitotic segregation. Diagnosis of mtDNA-related diseases became possible through genetic analysis and experimental approaches involving histochemical staining of muscle or brain sections, single-fiber polymerase chain reaction (PCR) of mtDNA, and the creation of patient-derived “cybrid” (cytoplasmic hybrid) immortal fibroblast cell lines. The availability of the above-mentioned techniques along with the novel sensitivity of clinicians to such disorders led to the characterization of a constantly growing number of pathologies. Here is traced a brief historical perspective on the discovery of autonomous pathogenic mtDNA mutations and on the related mendelian pathology altering mtDNA integrity.
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Vizziello, Maria, Linda Borellini, Giulia Franco et Gianluca Ardolino. « Disruption of Mitochondrial Homeostasis : The Role of PINK1 in Parkinson’s Disease ». Cells 10, no 11 (4 novembre 2021) : 3022. http://dx.doi.org/10.3390/cells10113022.

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The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.
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Maier, Dieter, Carol L. Farr, Burkhard Poeck, Anuradha Alahari, Marion Vogel, Susanne Fischer, Laurie S. Kaguni et Stephan Schneuwly. « Mitochondrial Single-stranded DNA-binding Protein Is Required for Mitochondrial DNA Replication and Development in Drosophila melanogaster ». Molecular Biology of the Cell 12, no 4 (avril 2001) : 821–30. http://dx.doi.org/10.1091/mbc.12.4.821.

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The discovery that several inherited human diseases are caused by mtDNA depletion has led to an increased interest in the replication and maintenance of mtDNA. We have isolated a new mutant in thelopo (low power) gene fromDrosophila melanogaster affecting the mitochondrial single-stranded DNA-binding protein (mtSSB), which is one of the key components in mtDNA replication and maintenance.lopo 1 mutants die late in the third instar before completion of metamorphosis because of a failure in cell proliferation. Molecular, histochemical, and physiological experiments show a drastic decrease in mtDNA content that is coupled with the loss of respiration in these mutants. However, the number and morphology of mitochondria are not greatly affected. Immunocytochemical analysis shows that mtSSB is expressed in all tissues but is highly enriched in proliferating tissues and in the developing oocyte.lopo 1 is the first mtSSB mutant in higher eukaryotes, and its analysis demonstrates the essential function of this gene in development, providing an excellent model to study mitochondrial biogenesis in animals.
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Thèses sur le sujet "Mitochondrial disease, gene discovery"

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GHEZZI, DANIELE. « Identification and characterization of nuclear genes responsible for human mitochondrial disorders : fastkd2, responsible for a neurological disease associated with cox defiency and sdhaf1, encoding a complex II assembly, mutated in SDH-defective leukoencephalopaty ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2009. http://hdl.handle.net/10281/7657.

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My researches during the DIMET project have been focused on the discovery of new genes responsible for mitochondrial disorders and the characterization of their role. Recent epidemiological studies show that mitochondrial disorders have an incidence of 1:5000. These disorders are very heterogeneous and hence the diagnosis is difficult. Moreover mitochondrial dysfunctions are now clearly related to a wide range of disease conditions (i.e. neurodegeneration and cancer). The majority of the inherited mitochondrial disorders, especially those with onset in infancy or childhood, are due to nuclear genes encoding proteins targeted to mitochondria. While identification of mutations in mitochondrial DNA has become relatively easy thank to the feasibility to perform the complete sequence analysis of mtDNA, the analysis of genomic DNA is more complicate and therefore the number of nuclear genes associated with mitochondrial diseases is still small. Genome-wide analysis in families with autosomal recessive mitochondrial disorders could help to identify a genomic region to be further investigated. However, about one half/one third of the components of the mitochondrial proteome have yet to be identified, and this lack of information makes the search of candidate genes more difficult. By linkage analysis or homozygosity mapping and prioritization of candidate genes, I studied subjects from multiconsanguineos families characterized by clinical pictures compatible with mitochondrial disorders. In chapter 2, there is the report regarding the discovery of a nonsense mutation in two brothers displaying asymmetric brain atrophy, psychomotor regression and severe complex IV deficiency. The mutated gene codes for a mitochondrial predicted kinase that may have a role in apoptosis. Using the same procedure, I take part in a project, which leads to the identification of the first assembly factor for complex II of the OXPHOS system (Chapter 3). Two different mutations were found in two pedigrees, with affected children characterized by acute psychomotor regression followed by spastic quadriparesis and/or dystonia. The pathogenic role of the mutations was confirmed in cellular and yeast models. Finally, in chapter 4, there is the characterization of a protein, MR-1, already known and responsible for a movement disorder (PNKD, Paroxysmal non kinesigenic Dyskinesia). The mutant isoforms were erroneously localized into cytosol or membranes, whereas I demonstrated that they are mitochondrial and that the mutations reported so far in PNKD patients (and a new mutation identify in our study) are in the mitochondrial targeting signal (MTS). Hence PNKD could be considered a mitochondrial disease, due to a novel mechanism based on a deleterious action of the MTS.
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Russel, Oliver Michael. « Development and discovery of treatments for mitochondrial disease ». Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2434.

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Although mitochondrial disorders are the most common inherited form of neuromuscular disease, there are currently limited effective treatments that directly improve mitochondrial function – either by modulation of the effects of mutated genes or by increasing the proportion of healthy mitochondria. In this work, two different approaches were employed to develop treatments for mitochondrial diseases: the design of mitochondrially targeted anti-sense oligonucleotides and the development of a high throughput screen of a unique library of bacterial extracts. The heteroplasmic nature of mitochondrial DNA (mtDNA) enables the use of anti-genomic strategies to specifically prevent the replication, transcription or translation of mutated molecules of mtDNA or mitochondrial mRNA in patients with heteroplasmic mtDNA mutations. In conjunction with an industrial partner (Ugichem GmbH), a mitochondrial targeting oligonucleotide was developed using cell membrane crossing oligomers (CMCOs) – a new class of oligonucleotide with the ability to enter and accumulate within the cytoplasm. By conjugating “mitochondrial targeting” molecules to the CMCOs, translocation to mitochondria was shown, potentially enabling the use of anti-sense therapies in the treatment of mtDNA diseases. To complement the mutation specific approach of anti-sense oligonucleotide therapies a large scale screen was carried out to discover compounds that could cause a general improvement in mitochondrial function. A library of unique bacterial extracts, provided by Demuris Ltd, was screened for effects on mitochondrial biogenesis in HeLa cells. To that end, a high throughput assay, which used fluorescent markers to detect changes in relative mitochondrial mass, was designed and validated using mitochondrially active control compounds. The screen of bacterial extracts discovered several one extract which caused mitochondrial mass to increase 2 fold after 48 hours incubation.
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Menezes, Minal Juliet. « Gene discovery and functional studies of mitochondrial respiratory chain disorders ». Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/12688.

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Mitochondrial respiratory chain disorders (MRCD) are one of the most challenging inborn errors of metabolism to diagnose and treat, because of their phenotypic and genetic heterogeneity, and a paucity of validated therapies. The approach opted to diagnose our MRCD patient cohort was using next generation sequencing (NGS) technology, and in particular whole exome sequencing (WES). Using our research pipeline we were able to identify novel YARS2 variants in patients with a tissue specific MRCD. Novel disease gene discoveries (CYC1 and MRPS7) causing MRCD were identified using the WES approach, and the functional studies implemented confirmed the pathogenicity of the newly identified variants. Advances in NGS technologies lead to the identification of a novel mtDNA mutation in the MT_ND3 gene and therefore rapid genetic diagnosis of a patient with Leigh disease allowing timely acceptance into a Phase 2B clinical trial. Using WES, two patients initially suspected to have a mitochondrial myopathy were diagnosed with congenital myasthenia resulting in the successful treatment for one patient. Through the research presented in this thesis, we were able to gain more knowledge about the disease mechanisms of MRCDs, and we hope that these findings will be instrumental in research towards future therapy of MRCD.
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Oellrich, Anika. « Supporting disease candidate gene discovery based on phenotype mining ». Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648355.

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Best, Heather Annette. « Gene discovery and mechanism of disease in the myopathies ». Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18940.

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Congenital myopathy and muscular dystrophy are two groups of inherited muscle diseases characterised by muscle weakness, and sub-classified by hallmark pathological features within a skeletal muscle biopsy. In order to understand the pathogenesis of inherited muscle disorders, and develop or apply therapies based on mechanistic insight, one must elucidate deep knowledge of the associated gene, genetic variant and the function of the encoded protein. This thesis focuses on three aspects of gene discovery in the inherited myopathies: (1) Identification of a novel variant and phenotype for a known disease gene; (2) understanding the functional role of a recently identified disease gene in skeletal muscle biology and disease; and (3) discovering a novel disease gene for congenital myopathy. We identified the first recessive variant within ACTA1 (encoding α-skeletal actin) as the genetic cause of congenital muscular dystrophy with rigid spine. This case uniquely describes recessive ACTA1 variants where α-skeletal actin protein is expressed. The unique clinical and histological presentation expands the spectrum of ACTA1 disease, and will help guide clinical care and future genetic diagnoses. Our team identified LMOD3 (leiomodin-3) as a novel disease gene for severe nemaline myopathy (NM). KLHL40 (encoding kelch-like family member 40) is another disease gene for severe NM. A recent study suggests mouse Klhl40 protects mouse Lmod3 protein from proteasome-mediated degradation, with the mechanistic basis of KLHL40-NM resulting from secondary loss of LMOD3. We investigated the regulation of human LMODs by human KLHL40, and unexpectedly found evidence that disputes the central paradigm that KLHL40 protects LMOD3 from proteasome-mediated degradation. We identified PYROXD1 as a new genetic cause of early-onset congenital myopathy. We provide the first characterisation of PYROXD1 as a nuclear-cytoplasmic oxidoreductase and our discovery highlights oxidative distress as a core mechanistic pathway in the myopathies. We derived a mouse model of Pyroxd1 deficiency, determining that global loss of mouse Pyroxd1 is embryonic lethal. We subsequently developed a mouse model with skeletal muscle knock-out of Pyroxd1 – as a means to elucidate the role of PYROXD1 in biology and disease.
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Chinnery, Patrick Francis. « The pathogenesis, investigation and management of mitochondrial DNA disease ». Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324935.

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Karicheva, Olga. « Modelling gene therapy for a mitochondrial disease MELAS by exploiting the pathway of RNA mitochondrial import ». Strasbourg, 2010. http://www.theses.fr/2010STRA6115.

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Les mutations de l'ADN mitochondrial sont une cause importante de maladies neuromusculaires humaines incurables. Parmi plusieurs mutations répertoriées, plus de 170 sont localisées dans les gènes codant pour les ARN de transfert (ARNt), dont 29 - dans le gène de l’ARNtLeu(UUR) (MT-TL1). La mutation m. 3243A>G de MT-TL1 a été décrite comme une cause majore du syndrome MELAS (myopathie, encéphalopathie, acidose lactique, accidents vasculaires cérébraux). Cette mutation réduit le niveau d’aminoacylation de l’ARNtLeu(UUR) et mène à l’hypomodification de la position « wobble » de son anticodon, ce qui cause des déficiences de la synthèse protéique dans l'organite et une réduction des activités des complexes de la chaîne respiratoire. L’objectif principal de la thèse a été d’étudier si l’expression des ARNt recombinants dans le noyau de cellules transmitochondriales humaines ayant la mutation MELAS m. 3243A>G et leurs adressage dans les mitochondries puisse améliorer les fonctions mitochondriales des cellules touchées par la mutation. Il a été démontré que l'expression des ARNt recombinants est accompagnée par une amélioration de la synthèse protéique mitochondriale, une augmentation du niveau des protéines codées par l’ADNmt et une restauration partielle de la respiration. Ces résultats démontrent la possibilité d’adresser dans les mitochondries les ARNt au potentiel thérapeutique dont la spécificité d’aminoacylation a été changée, et étendent ainsi l’utilisation de l’approche de l’expression allotopique pour le développement de thérapie génique des maladies mitochondriales
Mutations in human mitochondrial DNA are often associated with incurable human neuromuscular diseases. Among these mutations, more than 170 have been identified in tRNA genes, including 29 in the tRNALeu(UUR) gene (MT-TL1). The m. 3243A>G mutation in MT-TL1 was described as the major cause of the MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). This mutation reduces tRNALeu(UUR) aminoacylation level and leads to a hypomodification of the wobble position of its anticodon, which results in a decreased level of mitochondrial protein synthesis and reduced activities of respiratory chain complexes. The thesis was aimed to test if the allotopic expression of recombinant leucine tRNAs in the nucleus of transmitochondrial cybrid cells carrying MELAS m. 3243A>G mutation and their subsequent targeting into mitochondria can rescue mutation-induced dysfunctions. It was shown that expression of specifically designed recombinant tRNAsLeu is accompanied by a significant improvement of mitochondrial translation, an increase of steadystate level of several mtDNA-encoded protein subunits of respiratory chain, and a partial rescue of respiration. These findings prove the possibility to direct into mitochondria tRNAs with changed aminoacylation specificity possessing potential therapeutic activity, thus extending the potential of allotopic expression as the approach to cure mitochondrial disorders
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Jain, Shushant. « Discovery and characterization of LRRK2 : Gene responsible for PARK8-linked Parkinson Disease ». Thesis, University College London (University of London), 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497530.

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Chen, Yang. « DEVELOPMENT OF COMPUTATIONAL APPROACHES FOR MEDICAL IMAGE RETRIEVAL, DISEASE GENE PREDICTION, AND DRUG DISCOVERY ». Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1435601642.

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Sabri, Amin. « Inherited Retinal Dystrophies : Genomics and Functional Studies in Novel Variant and Disease Gene Discovery ». Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18890.

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Purpose: Inherited retinal dystrophy (IRD) describes a collection of degenerative retinal disorders, with a prevalence of approximately 1 in 3500. Many of the underlying disease genes and their functions are not known. There is progressive degeneration of the photoreceptors which may result in complete blindness at early ages of life. Although mutations in over 250 genes have been described in IRD, diverse clinical features and the genotypic heterogeneity make the application of conventional sequencing methods very limited. The aims of this study were to: identify the underlying disease-causing gene in a cohort of 12 retinitis pigmentosa (RP) families using genomic approaches and targeted gene analysis; identify the underlying candidate disease gene in a family with a novel syndromic retinal dystrophy and investigate the function of the gene using cell-based assays; and to characterise a mouse model of the novel retinal dystrophy syndrome. Methods: Whole exome sequencing using the TruSeq exome enrichment system (Illumina Inc., San Diego, CA, USA), was applied to 12 probands diagnosed with autosomal dominant retinitis pigmentosa (ADRP, n=6) and autosomal recessive retinitis pigmentosa (ARRP, n=6). Pathogenicity was predicted and detected variants were confirmed and segregation determined using Sanger sequencing. In a family with an inherited novel syndromic retinal dystrophy described in the thesis, genomic, cell-based, and animal model approaches were undertaken to identify and understand the function of the novel disease gene. Functional studies were performed in mutant and control human fibroblasts, and transfected HeLa cells. A CRISPR/Cas9 generated mouse model of the disease was investigated using electroretinography (ERG), histology, and immunohistochemistry studies to understand the impact of the detected variant. Results: Pathogenic variants were identified in 4 families with ADRP families. Clear-cut variants were identified in 2 families with ARRP. A novel candidate retinal disease gene, alpha kinase-1 (ALPK1), has been identified in the newly described ROSAH syndrome which analysis from this thesis implicates in centrosome and cilia biology. Analyses in mouse retina showed expression of Alpk1 in the connecting cilium region of the photoreceptors with a possible role in ciliary trafficking. Cell-based assays revealed ALPK1 localisation in the centrosomes and the basal body of the primary cilium. Immunocytochemistry on skin fibroblasts revealed a higher percentage of cells with abnormal numbers of centrosomes in affected individuals. In HeLa cells transfected with the mutant construct, there were a higher number of multinucleated cells, further suggesting abnormality of centrosome biology. ERG studies revealed significant decrease in scotopic and photopic responses in mice with the orthologous mouse mutation, and histology sections showed thinning of the retinal layers. Further immunohistochemistry studies confirmed significant decrease in Tcp1 (ALPK1 binding partner) expression in the inner segment of photoreceptors and aberration of connecting cilium proteins, Ift88 and centrin in the mouse model. Conclusions: Genomic and functional work in this thesis has led to new knowledge with implications for regulation of centrosome biology and impact on ciliary function in the retina. This study highlights benefits of genomic investigation, phenotype-based bioinformatics, and functional studies to gain insight to the pathophysiology of the disease, paving the way for development of therapeutic strategies in the future.
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Livres sur le sujet "Mitochondrial disease, gene discovery"

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Gu, Weikuan, et Yongjun Wang, dir. Gene Discovery for Disease Models. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2011. http://dx.doi.org/10.1002/9780470933947.

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Gene discovery for disease models. Hoboken, N.J : Wiley, 2011.

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Knott, Andrew B., et Ella Bossy-Wetzel. Mitochondrial Changes and Bioenergetics in Neurodegenerative Diseases. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190233563.003.0012.

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Mitochondria are dynamic organelles that are of critical importance for cellular survival and health. Because mitochondria play central roles in energy production and synaptic maintenance, neurons are believed to be particularly vulnerable to mitochondrial dysfunction. The discovery that genetic mutations in genes coding for mitochondrial proteins cause neurodegenerative conditions further hinted at the likelihood that mitochondrial dysfunction is a key pathway of neurodegeneration. Indeed, a wealth of research has identified mitochondrial dysfunction as an early and shared event of all common neurodegenerative diseases, both genetic and sporadic in origin. Specific types of mitochondrial dysfunction that have been observed in most neurodegenerative diseases include bioenergetic failure, increased oxidative stress, mitochondrial DNA mutations, defective calcium handling, impaired mitochondrial dynamics, defective mitophagy, and decreased mitochondrial biogenesis. The search for drugs that successfully target these pathways of mitochondrial dysfunction in neurodegeneration is ongoing.
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Wang, Yongjun, et Weikuan Gu. Gene Discovery for Disease Models. Wiley & Sons, Incorporated, John, 2011.

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Wang, Yongjun, et Weikuan Gu. Gene Discovery for Disease Models. Wiley & Sons, Incorporated, John, 2011.

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Gu, W., Yongjun Wang et Weikuan Gu. Gene Discovery for Disease Models. Wiley & Sons, Incorporated, John, 2011.

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Wang, Yongjun, et Weikuan Gu. Gene Discovery for Disease Models. Wiley & Sons, Incorporated, John, 2011.

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Renton, Alan E., et Alison M. Goate. Genetics of Dementia. Sous la direction de Dennis S. Charney, Eric J. Nestler, Pamela Sklar et Joseph D. Buxbaum. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190681425.003.0051.

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The genetic architecture of dementia is polygenic and complex, with risk alleles spanning frequency–effect size space. Despite significant progress, most genes influencing these disorders await discovery. Known risk loci implicate perturbed pathways that coalesce around recurring mechanistic themes, notably the autophagosome-lysosome system, the cytoskeleton, endocytosis, innate immunity, lipid metabolism, mitochondria, and the ubiquitin-proteasome system. Phenotypic and pathophysiological pleiotropy suggests some conditions form continuous clinicopathogenetic disease spectra blurring classical diagnoses. Future large-scale genome sequencing of global populations will significantly elucidate etiopathogenesis and is likely to reframe nosology. Furthermore integrative prospective cohort studies have the potential to revolutionize our understanding of dementia.
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Carriers : What the Fragile X Gene Reveals about Family, Heredity, and Scientific Discovery. Columbia University Press, 2022.

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OVERCOMING A BAD GENE : The story of the discovery and successful treatment of Phenylketonuria, a genetic disease that causes mental retardation. AuthorHouse, 2004.

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Chapitres de livres sur le sujet "Mitochondrial disease, gene discovery"

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Borrás, Consuelo, Cristina Mas-Bargues, Ana B. Paes et Susana Novella. « Sex Differences in Mitochondrial Antioxidant Gene Expression ». Dans Sex Differences in Heart Disease, 267–84. Cham : Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-58677-5_16.

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Seibel, Peter, Adrian Flierl, Corinna Bachmann et Martina Seibel. « Gene Therapy of Mitochondrial DNA Diseases ». Dans Mitochondrial DNA Mutations in Aging, Disease and Cancer, 395–402. Berlin, Heidelberg : Springer Berlin Heidelberg, 1998. http://dx.doi.org/10.1007/978-3-662-12509-0_20.

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Gu, Weikuan, et Daniel Goldowitz. « Gene Discovery : From Positional Cloning to Genomic Cloning ». Dans Gene Discovery for Disease Models, 1–9. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9780470933947.ch1.

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Lam, Ching-Wan, et Kin-Chong Lau. « Candidate Screening through High-Density SNP Array ». Dans Gene Discovery for Disease Models, 195–214. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9780470933947.ch10.

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Ray, Kunal, Arijit Mukhopadhyay et Mainak Sengupta. « Gene Discovery by Direct Genome Sequencing ». Dans Gene Discovery for Disease Models, 215–33. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9780470933947.ch11.

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Wu, Song, et Wei Zhao. « Candidate Screening through Bioinformatics Tools ». Dans Gene Discovery for Disease Models, 235–60. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9780470933947.ch12.

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Jiao, Yan, et Weikuan Gu. « Using an Integrative Strategy to Identify Mutations ». Dans Gene Discovery for Disease Models, 261–78. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9780470933947.ch13.

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Edderkaoui, Bouchra. « Determination of the Function of a Mutation ». Dans Gene Discovery for Disease Models, 281–301. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9780470933947.ch14.

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Martinez-Valdez, Hector, et Blanca Ortiz-Quintero. « Confirmation of a Mutation by Multiple Molecular Approaches ». Dans Gene Discovery for Disease Models, 303–42. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9780470933947.ch15.

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Zheng, Hongwei, et Yongjun Wang. « Confirmation of a Mutation by MicroRNA ». Dans Gene Discovery for Disease Models, 343–69. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9780470933947.ch16.

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Actes de conférences sur le sujet "Mitochondrial disease, gene discovery"

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Xing, Chunxiao, Shunyao Wu, Fengjing Shao et Rencheng Sun. « Disease gene discovery of single-gene disorders based on complex network ». Dans UCC '16 : 9th International Conference on Utility and Cloud Computing. New York, NY, USA : ACM, 2016. http://dx.doi.org/10.1145/3006299.3006316.

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Hwang, TaeHyun, et Rui Kuang. « A Heterogeneous Label Propagation Algorithm for Disease Gene Discovery ». Dans Proceedings of the 2010 SIAM International Conference on Data Mining. Philadelphia, PA : Society for Industrial and Applied Mathematics, 2010. http://dx.doi.org/10.1137/1.9781611972801.51.

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Bhattacharya, S., A. Basu et TJ Mariani. « An Expression Profiling Data Repository for Lung Disease Gene Discovery. » Dans American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California. American Thoracic Society, 2009. http://dx.doi.org/10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a1890.

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Thompson, Paul, et Sophia Ananiadou. « Extracting Gene-Disease Relations from Text to Support Biomarker Discovery ». Dans DH '17 : International Conference on Digital Health. New York, NY, USA : ACM, 2017. http://dx.doi.org/10.1145/3079452.3079472.

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Xu, Yan, Zhiqiang Chang, Wen Hu, Lili Yu, Huizi DuanMu et Xia Li. « Mining the Relationship between Gene and Disease from Literature ». Dans 2009 Sixth International Conference on Fuzzy Systems and Knowledge Discovery. IEEE, 2009. http://dx.doi.org/10.1109/fskd.2009.42.

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Huang, Justin K., Daniel E. Carlin, Michael K. Yu, Wei Zhang, Jason F. Kreisberg, Pablo Tamayo et Trey Ideker. « Abstract 1310 : Systematic evaluation of gene networks for discovery of disease genes ». Dans Proceedings : AACR Annual Meeting 2018 ; April 14-18, 2018 ; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1310.

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Nguyen, Le B., Sharon Diskin, Hakon Hakonarson, John M. Maris et Hongzhe Li. « Abstract 4743 : Genome-wide gene-centric discovery of disease variants in neuroblastoma ». Dans Proceedings : AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010 ; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-4743.

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Faro, Alberto, Daniela Giordano et Concetto Spampinato. « Discovery and assessment of gene-disease associations by integrated analysis of scientific literature and microarray data ». Dans 2010 10th IEEE International Conference on Information Technology and Applications in Biomedicine (ITAB 2010). IEEE, 2010. http://dx.doi.org/10.1109/itab.2010.5687757.

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Souto, Emília Correia, Carolina Maria Marin, Gustavo Carvalho Costa, Igor Braga Farias, Bruno de Mattos Lombardi Badia, Icaro França Navarro Pinto, Roberta Ismael Lacerda Machado, Paulo Victor Sgobbi de Souza, Wladimir Bocca Vieira de Rezende Pinto et Acary Souza Bulle Oliveira. « Family with atypical Parkinsonism due to CHCHD10 gene mutation ». Dans XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.502.

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Introduction: Parkinson’s disease - PD is the second most common agerelated neurodegenerative disorder. Characterized by a variety of motor and non-motor symptoms that relate to the loss of dopaminergic neurons in the midbrain black substance. Although most cases of PD are sporadic, 5–10% of patients have monogenetic mutations with a description of more than 20 genes for the familial form. Mitochondrial mutation in CHCHD10 has also been reported to be associated with a wide spectrum of neurodegenerative disorders, including PD. Objectives: Description of a rare recently described genetic cause of autosomal dominant parkinsonism. Methodology: Describe the case of a Brazilian woman with atypical parkinsonism due to CHCHD10 pathogenic variant that was followed up in our service. Result: Female, 64 years old. “. He started episodes of imbalance about 5 years ago, with falls, in addition to limb stiffness, worse on the left. 4 years ago, he started myalgia to great efforts with low subsequent tolerance to light effort. 1 year ago with urinary incontinence and choking past of poor performance in physical activities without pre-motor symptoms FAMILY: mother with clinical picture of possible dementia syndrome at age 60, history in the maternal family of myalgia, intolerance to physical exercise and hearing loss in adulthood. EXOMA: presence of variant c.146C > T (p.Ala49Val) in simple heterozygosity without CHCHD10 gene. MRI with thigh muscle hypotrophy in anterior and posterior thigh compartments; slight muscle edema in the legs. Conclusion: Pathogenic variants in the CHCHD10 gene should be considered in cases of atypical parkinsonism, especially in cases of positive familial history of mitochondrial myopathy or dementia.
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Koptyra, Mateusz P., Namrata Choudhari, Zhang Zhe, Mariarita Santi, Angela Waanders et Adam Resnick. « Abstract 2081 : Empowering rare disease cohort biomarker discovery via comparative assessments of gene expression analysis platforms for FFPE pediatric brain tumor specimens ». Dans Proceedings : AACR Annual Meeting 2018 ; April 14-18, 2018 ; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-2081.

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Rapports d'organisations sur le sujet "Mitochondrial disease, gene discovery"

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Olsen, A. S., et C. T. Wake. Inflammatory Bowel Disease Gene Discovery Final Report CRADA No. TC-1335-96. Office of Scientific and Technical Information (OSTI), mars 2018. http://dx.doi.org/10.2172/1430922.

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Harman, Gary E., et Ilan Chet. Discovery and Use of Genes and Gene Combinations Coding for Proteins Useful in Biological Control. United States Department of Agriculture, septembre 1994. http://dx.doi.org/10.32747/1994.7568787.bard.

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The objectives of the research in this proposal were to (A) identify synergy among proteins that provide enhanced activity over single proteins for control of plant pathogenic fungi, (B) clone and characterize genetic sequences coding for proteins with ability to control pathogenic fungi, (C) produce transgenic organisms with enhanced biocontrol ability using genes and gene combinations and determine their efficiency in protecting plants against plant pathogenic fungi. A related objective was to produce disease-resistant plants. Fungal cell wall degrading enzymes from any source are strongly synergistic with any membrane active compound and, further, different classes of cell wall degrading enzymes are also strongly synergistic. We have cloned and sequenced a number of genes from bacterial and fungal sources including five that are structurally unrelated. We have prepared transgenic fungi that are deficient in production of enzymes and useful in mechanistic studies. Others are hyperproducers of specific enzymes that permit us, for the first time, to produce enzymes from T. harzianum in sufficient quantity to conduct tests of their potential use in commercial agriculture. Finally, genes from these studies have been inserted into several species of crop plants were they produce a high level of resistance to several plant pathogenic fungi.
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Sharon, Amir, et Maor Bar-Peled. Identification of new glycan metabolic pathways in the fungal pathogen Botrytis cinerea and their role in fungus-plant interactions. United States Department of Agriculture, 2012. http://dx.doi.org/10.32747/2012.7597916.bard.

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The involvement of glycans in microbial adherence, recognition and signaling is often a critical determinant of pathogenesis. Although the major glycan components of fungal cell walls have been identified there is limited information available on its ‘minor sugar components’ and how these change during different stages of fungal development. Our aim was to define the role of Rhacontaining-glycans in the gray mold disease caused by the necrotrophic fungus B. cinerea. The research was built on the discovery of two genes, Bcdhand bcer, that are involved in formation of UDP-KDG and UDP-Rha, two UDP- sugars that may serve as donors for the synthesis of cell surface glycans. Objectives of the proposed research included: 1) To determine the function of B. cinereaBcDh and BcEr in glycan biosynthesis and in pathogenesis, 2) To determine the expression pattern of BcDH and BcERand cellular localization of their encoded proteins, 3) Characterize the structure and distribution of Rha- containing glycans, 4) Characterization of the UDP-sugar enzymes and potential of GTs involved in glycanrhamnosylation. To address these objectives we generated a series of B. cinereamutants with modifications in the bchdhand bcergenes and the phenotype and sugar metabolism in the resulting strains were characterized. Analysis of sugar metabolites showed that changes in the genes caused changes in primary and secondary sugars, including abolishment of rhamnose, however abolishment of rhamnose synthesis did not cause changes in the fungal phenotype. In contrast, we found that deletion of the second gene, bcer, leads to accumulation of the intermediate sugar – UDP- KDG, and that such mutants suffer from a range of defects including reduced virulence. Further analyses confirmed that UDP-KDG is toxic to the fungus. Studies on mode of action suggested that UDP-KDG might affect integrity of the fungal cell wall, possibly by inhibiting UDP-sugars metabolic enzymes. Our results confirm that bcdhand bcerrepresent a single pathway of rhamnose synthesis in B. cinerea, that rhamnose does not affect in vitro development or virulence of the fungus. We also concluded that UDP-KDG is toxic to B. cinereaand hence UDP-KDG or compounds that inhibit Er enzymes and lead to accumulation of UDP-KDG might have antifungal activity. This toxicity is likely the case with other fungi, this became apparent in a collaborative work with Prof. Bart Thomma of Wageningen University, NETHERLANDS . We have shown the deletion of ER mutant in Verticillium dahlia gave plants resistance to the fungal infection.
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Yogev, David, Ricardo Rosenbusch, Sharon Levisohn et Eitan Rapoport. Molecular Pathogenesis of Mycoplasma bovis and Mycoplasma agalactiae and its Application in Diagnosis and Control. United States Department of Agriculture, avril 2000. http://dx.doi.org/10.32747/2000.7573073.bard.

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Mycoplasma bovis and M. agalactiae are two phylogenetically related mycoplasmas which cause economically significant diseases in their respective bovine or small ruminant hosts. These organisms cause persistent asymptomatic infections that can result in severe outbreaks upon introduction of carrier animals into susceptible herds. Little is known about the mechanisms underlying mycoplasma-host interaction, variation in virulence, or of the factors enabling avoidance of the host immune system. In recent years it has become apparent that the ability of pathogenic microorganisms to rapidly alter surface antigenic structures and to fine tune their antigenicity, a phenomena called antigenic variation, is one of the most effective strategies used to escape immune destruction and to establish chronic infections. Our discovery of a novel genetic system, mediating antigenic variation in M. bovis (vsp) as well as in M. agalactiae (avg) served as a starting point for our proposal which included the following objectives: (i) Molecular and functional characterization of the variable surface lipoproteins (Vsp) system of M. bovis and comparison with the Vsp-counterpart in M. agalactiae (ii) Determination of the role of Vsp proteins in the survival of M. bovis when confronted by host defense factors, (iii) Assessment of Vsp-based genetic and antigenic typing of M. bovis and M. agalactiae for epidemiology of infection and (iv) Improvement of diagnostic tests for M. bovis and M. agalactiae based on the vsp-and vsp-analogous systems. We have carried out an extensive molecular characterization of the vsp system and unravelled the precise molecular mechanism responsible for the generation of surface antigenic variation in M. bovis. Our data clearly demonstrated that the two pathogenic mycoplasma species possess large gene families encoding variable lipoprotein antigens that apparently play an important role in immune evasion and in pathogen-host interaction during infection. Phase variable production of these antigens was found to be mediated by a novel molecular mechanism utilizing double site-specific DNA inversions via an intermediate vsp configuration. Studies in model systems indicate that phase variation of VspA is relevant in interaction between M. bovis and macrophages or monocytes, a crucial stage in pathogenesis. Using an ELISA test with captured VspA as an antigen, phase variation was shown to occur in vivo and under field conditions. Genomic rearrangements in the avg gene family of M. agalactiae were shown to occur in vivo and may well have a role in evasion of host defences and establishment of chronic infection. An epidemiological study indicated that patterns of vsp-related antigenic variation diverge rapidly in an M. bovis infected herd. Marked divergence was also found with avg-based genomic typing of M. agalactiae in chronically infected sheep. However, avg-genomic fingerprints were found to be relatively homogeneous in different animals during acute stages of an outbreak of Contagious Agalactiae, and differ between unrelated outbreaks. These data support the concept of vsp-based genomic typing but indicate the necessity for further refinement of the methodology. The molecular knowledge on these surface antigens and their encoding genes provides the basis for generating specific recombinant tools and serological methods for serodiagnosis and epidemiological purposes. Utilization of these methods in the field may allow differentiating acutely infected herds from chronic herds and disease-free herds. In addition the highly immunogenic nature of these lipoproteins may facilitate the design of protective vaccine against mycoplasma infections.
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Inflammatory bowel disease gene discovery. CRADA final report. Office of Scientific and Technical Information (OSTI), septembre 1997. http://dx.doi.org/10.2172/296882.

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