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1
Meyer, Alayne. "Genotype-phenotype correlations and characterization of medication use in inherited myotonic disorders". The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu155506792600104.
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2
Villeneuve, Josée. "Évaluation du recours au test génétique chez les personnes à risque de la dystrophie myotonique au Saguenay-Lac-St-Jean /". Thèse, Chicoutimi : Université du Québec à Chicoutimi, 2001. http://theses.uqac.ca.
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Brisson, Diane. "Évaluation de la variabilité génotypique et phénotypique, intrafratrie, dans la dystrophie myotonique de Steinert /". Thèse, Ste-Foy : Chicoutimi : Université Laval. Université du Québec à Chicoutimi, 1999. http://theses.uqac.ca.
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4
Novak, Kevin Richard. "Novel Mechanisms Underlying Warm-up and Percussion Myotonia in Myotonia Congenita". Wright State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright1496183981178166.
Testo completo
5
Burge, J. A. "Mechanisms of phenotypic variability in Myotonia Congenita". Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1401157/.
Testo completoAbstract (sommario):
The severity of Myotonia Congenita varies not only across individuals with different CLCN1 genotypes, but also within a pedigree, and can even fluctuate over time within a single individual in response to environmental circumstances. The functional consequences of eight naturally occurring sequence variants in the skeletal muscle chloride channel gene, CLCN1, were examined by whole cell patch-clamp of HEK293T cells expressing the gene product, ClC-1, in order to investigate potential differences in their mechanisms of pathogenicity. G276D and G523D caused complete loss of function, while S289G produced altered kinetics and a marked depolarizing shift of voltage dependence. H369P, A566T and M646T all tested normal in the HEK293T assay despite strong clinical support for pathogenicity. Their mechanism of pathogenicity may rely on muscle-specific processes that are not faithfully recapitulated in HEK293T cells. W118G and P744T were selected as examples of variants for which pathogenicity is unclear from the clinical evidence. The former is present in controls, but over-represented in the Myotonia Congenita population. The latter is present in an individual who also harbours a large deletion in CLCN1. Both variants tested normal in the HEK293T assay. A potent trigger for worsening of myotonia in some female patients is pregnancy. In order to clarify the role of sex hormones in non-genomic modulation of skeletal muscle excitability, the effects of progesterone and oestrogen on endogenous chloride currents through the wildtype ClC-1 of mouse skeletal muscle were tested by whole cell patch clamp. Progesterone and oestrogen rapidly reduced the chloride conductance and shifted its voltage dependence, thus a non-genomic mechanism exists in skeletal muscle linking sex hormones to ClC-1. However the effect was only significant at 500 times the highest physiological concentration encountered in pregnancy. The macroscopic chloride conductance of a membrane expressing wildtype ClC-1 was simulated in Matlab. The simulation improves on published models by recapitulating both time-dependence and voltage-dependence of the channel through a method based on independent representations of the fast and the slow gates. The applicability of the model for the purposes of exploring the effects of specific mutations was assessed by attempting to simulate the currents through S289G channels; the effects of S289G could be mimicked by slowing and inverting the kinetics of the fast gate and shifting the fast gate opening probability to more depolarized potentials. The mechanism of low chloride conductance myotonia and electrical factors likely to impact on its severity are discussed in the context of experiments conducted in a model of myotonic muscle. Slowing of ClC-1 kinetics alone did not produce myotonia, but could lower the threshold for myotonia caused by shifts in voltage dependence. Muscle fibre diameter is an important factor in the propensity to myotonia, which can be driven by asynchrony between surface and t-tubular action potentials in large muscle fibres. Increasing muscle fibre diameter could underly the age-dependence of symptom onset in Myotonia Congenita, and differences in diameter could contribute to phenotypic variability, including male-female differences.
6
Chaiklieng, Sunisa. "Low chloride conductance myotonia - in vitro investigations on muscle stiffness and the warm-up phenomenon". [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-61365.
Testo completo
7
Papponen, H. (Hinni). "The muscle specific chloride channel ClC-1 and myotonia congenita in Northern Finland". Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514286926.
Testo completoAbstract (sommario):
Abstract Functional defects in the muscle specific chloride channel ClC-1 result in reduced chloride conductance and electrical hyperexcitability, which in turn impairs muscle relaxation and leads to myotonia. The gene CLCN 1 codes for ClC-1 in humans, and mutations in CLCN 1 cause the disease known as myotonia congenita. Worldwide over 80 mutations in CLCN1 have been described, but only three were found in patients in Northern Finland. These included two missense mutations and a nonsense mutation. The behavior and localization of the normal and mutated ClC-1 mRNA and protein were analyzed in muscle cell cultures. In intact muscle the ClC-1 protein was seen in the sarcolemma, but after myofiber isolation the protein was located intracellularly. Sarcolemmal localization was restored when myofibers were electrically stimulated or treated with a protein kinase C inhibitor. When mutated ClC-1 proteins were examined in a myofiber cell culture system, retardation in the ER was observed with the two missense mutations. The nonsense mutation did not have an effect on the transport from the ER to the Golgi elements, but the mutated ClC-1 was degraded more rapidly than the wild type ClC-1, at least in myotubes. Both retardation and degradation of the mutated ClC-1 are likely to result in too few channels present at the plasma membrane of the muscle cell to maintain normal physiological function. A very strict quality control in muscle cells was observed. The behavior and survival of multinuclear skeletal muscle cells is dependent on innervation and muscle activity, and the balance between the phosphorylation and dephosphorylation pathways modulates the function of muscle chloride channelsTiivistelmä Lihasspesifisen kloridikanavan ClC-1:n toiminnalliset virheet johtavat alentuneeseen kloridin johtumiseen solukalvon läpi ja lihassolun ylieksitoitumiseen. Tämän seurauksena lihaksen rentoutuminen vaikeutuu ja havaitaan myotoniaa, lihasjäykkyyttä. Pohjoissuomalaisesta potilasmateriaalista tautiin johtavia geenimutaatioita löytyi kolme erilaista. Poikkeuksellista havainnoissa on erilaisten mutaatioiden vähyys, mikä on tyypillistä suomalaiselle tautiperinnölle. Yhteensä tämän kloridikanavan mutaatioita on julkaistu yli 80 erilaista. Tutkiessamme normaalin ja mutatoidun ClC-1 lRNA:n ja proteiinin käyttäytymistä ja sijaintia lihassoluviljelmissä. Havaitsimme eron lihasleikkeiden ja eristettyjen myofiibereiden välillä. Lihasleikkeissä ClC-1 paikantui solun pinnalle sarkolemmalle, mutta eristetyissä myofiibereissä lähinnä solun sisälle. Stimuloimalla eristettyjä myofiibereitä sähkövirralla tai käsittelemällä proteiini kinaasi C inhibiittorilla, saimme kloridikanava-proteiinin siirtymään takaisin solun pinnalle. Proteiinitasolla kuljetuksessa on havaittavissa eroja. Aminohappomuutokseen johtavat pistemutaatiot aiheuttivat proteiinin jäämisen endoplasmiseen kalvostoon, kun taas ennenaikaisen stop-kodonin johdosta lyhentynyt proteiini kuljetetaan eteenpäin Golgin laitteeseen. Myotuubeissa tämä lyhentynyt proteiini kuitenkin hajotettiin nopeammin kuin normaali kloridikanavaproteiini. Sekä kuljetuksen hidastuminen että nopeampi hajotus johtavat tilanteeseen, jossa lihassolun solukalvolla on liian vähän kloridikanavia ylläpitämään lihaksen normaalia fysiologista toimintaa. Monitumaisten lihassolujen laaduntarkkailu havaittiin vielä monitahoisemmaksi kuin yksitumaisilla. Monitumainen lihassolu on riippuvainen hermoärsytyksestä ja lihasaktiivisuudesta. Lisäksi fosforylaatioon liittyvä signalointi on tärkeää ClC-1 proteiinin oikealle paikantumiselle lihassolussa
8
Amior, N. "Developing models to study the mechanisms of weakness and myotonia in Periodic Paralysis". Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10044636/.
Testo completoAbstract (sommario):
Periodic paralysis (PP) is a disorder characterised by episodic attacks of paralysis, caused by mutations of skeletal muscle voltage gated ion channels. Although episodes eventually subside, patients develop progressive muscle weakness and frequently, myopathy. The relationship between this progression and the associated mutations is not understood. I propose that the longer term defect might result from disordered calcium signalling secondary to altered excitability, and its impact on mitochondrial function. I sought models where these aspects of muscle signalling could be studied. These were: A genetic model derived from patients: patient derived fibroblasts were virally transduced with MyoD to generate myoblasts, which were differentiated into myotubes with patient specific gene mutations. A pharmacological model: generated by treating neonatal rat myotube cultures with barium (an inhibitor of potassium channels) and low extracellular potassium to simulate attacks of PP. Treated cultures displayed more frequent spontaneous calcium fluctuations. Mitochondrial membrane potential was not affected by the treatment, but expression of TFAM (mitochondrial transcription factor A; a regulator of mitochondrial transcription and biogenesis) was upregulated, suggesting activation of retrograde signalling pathways. A mouse model: collaborators at MRC Harwell generated mice carrying a mutation (c.1744A > G; p.Ile582Val) equivalent to a novel point mutation in SCN4A, one of the ion channel genes associated with PP. Measurements in vivo established that affected mice show muscle weakness and delayed fatigue during tetanic responses. Calcium handling and mitochondrial function were analysed in single isolated myofibres. Calcium handling was not affected, however mitochondrial membrane potential was reduced in fibres from the PP mice and distribution was also affected, with fewer intermyofibrillar mitochondria, indicating altered mitochondrial bioenergetics. Thus I describe several approaches to investigate mechanisms that cause progressive weakness and myopathy in PP, and assess the relative merits of each approach. Furthermore, results suggest that a shift toward a more oxidative phenotype is taking place.
9
Braida, Claudia. "Molecular analysis of myotonic dystrophy type 1 patients with an unusual molecular diagnosis". Thesis restricted. Connect to e-thesis to view abstract, 2008. http://theses.gla.ac.uk/359/.
Testo completoAbstract (sommario):
Thesis (Ph.D.) - University of Glasgow, 2008.Ph.D. thesis submitted to the Division of Molecular Genetics, Institute of Biomedical and Life Sciences, University of Glasgow, 2008. Includes bibliographical references. Print version also available.
10
Goers, Emily Sarah Marie. "The muscleblind protein family's RNA sequence elements, structural elements and novel binding sites defend through SELEX /". Connect to title online (Scholars' Bank) Connect to title online (ProQuest), 2008. http://hdl.handle.net/1794/9173.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--University of Oregon, 2008.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 93-106). Also available online in Scholars' Bank; and in ProQuest, free to University of Oregon users.
11
Fialho, D. "Clinical, genetic and electrophysiological study of skeletal muscle channelopathies : new insights into myotonia congenita and Andersen-Tawil syndrome". Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18909/.
Testo completoAbstract (sommario):
This thesis examines clinical characteristics, molecular genetic aspects and electrophysiological features of two muscle channelopathies - myotonia congenita (MC) and Andersen-Tawil syndrome (ATS). MC is a muscle stiffness disorder caused by mutations in the skeletal muscle chloride channel gene CLCN1. A detailed genotype-phenotype analysis was undertaken in an initial MC cohort (22 families). A screening strategy for genetic testing was developed and applied to a larger cohort (303 cases). Twenty-three novel mutations and a high proportion of dominant MC predominantly due to four novel mutations clustered in exon 8 were observed. These four mutations were studied in vitro using two-electrode voltage-clamp methods in Xenopus laevis oocytes. Loss of function and clear dominant-negative effect in CO-expression experiments were demonstrated. The Xenopus oocyte expression system was also used to study the non-genomic effect of sex hormones on CLC-1 channels. It is shown that both testosterone and progesterone rapidly and reversibly inhibit wild-type CIC-1 channels by causing a prominent rightward shift in the voltage dependence of their open probability. In contrast, 17 β-estradiol causes only a small shift. These results suggest a possible mechanism to explain how the severity of myotonia congenita may be modulated by sex hormones. The potential modifying effect of the myotonic dystrophy genes DMPK and ZNF9 on the phenotype of MC was investigated. Allele sizes for these genes were measured in more than 400 patients with suspected non-dystrophic myotonia. Four individuals were identified with an intermediate size allele of DMPK and ten individuals tested positive for myotonic dystrophy type 2. ATS is characterised by the triad of periodic paralysis, cardiac arrhythmias and dysmorphic features. A UK cohort with ATS is presented with detailed phenotype-genotype correlation. Novel mutations were found and unusual clinical features including renal tubular defect, CNS involvement, dental and phonation abnormalities were observed.
12
Hawash, Ahmed Alaa. "Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita". Wright State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright1500932300888521.
Testo completo
13
Edin, Joel. "Alternativ splicing i mänsklig sjukdom". Thesis, Linköping University, Linköping University, Department of Physics, Chemistry and Biology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-57545.
Testo completoAbstract (sommario):
Exoner är de sekvenser i DNA vilka rymmer koden för proteiner i människan och i alla andra organismer. Intronerna, vilka utgör utrymmet mellan exoner, består av ickekodande sekvenser och kontrollelement. Exoner tillhörande en gen måste inte alltid inkluderas i den slutliga mRNA produkten, alternativ splicing tillåter exkludering av vissa sekvenser och gör att en gen kan ha mer än en mRNA produkt, därigenom kan en gen koda för flera olika proteiner. Alternativ splicing är ett fält som snabbt utvecklas och dess relevans för många sjukdomar har blivit uppenbar. Detta arbete går igenom ett flertal av dessa sjukdomar för att sammanställa ny forskning och tydliggöra rollen av alternativ splicing i dem. De sjukdomar som undersökts är cystisk fibros, ärftlig frontotemporal dementia, systemisk lupus erythematosus, aniridi, myotonisk dystrofi, amyotrophic lateral sclerosoch familial dysautonomia. Dessa sjukdomar har involvering av alternativ splicing, de genetiska processerna bakom dem är dock mycket olika och kan visa på de många sätt alternativ splicing kan påverka cell och kroppsfunktion. Målet med arbetet är en översiktlig bild av framstegen som gjorts och vilken forskning som nu bedrivs.
14
Stahl, Kristina [Verfasser], e Benedikt [Akademischer Betreuer] Schoser. "Klinische Untersuchung zur Dyslexie bei Myotoner Dystrophie Typ 1 und Bildungsniveau bei Patienten mit Myotonen Dystrophien / Kristina Stahl ; Betreuer: Benedikt Schoser". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1163949051/34.
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15
Machuca-Tzili, Laura E. "Molecular basis of myotonic dystrophy". Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440000.
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16
Winchester, Catherine Louisa. "Expression of myotonic dystrophy candidate proteins". Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265141.
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Coonrod, Leslie, e Leslie Coonrod. "Targeting Myotonic Dystrophy with Small Molecules". Thesis, University of Oregon, 2012. http://hdl.handle.net/1794/12379.
Testo completoAbstract (sommario):
Myotonic dystrophy (DM) is one of the most common forms of muscular dystrophy, characterized by its hallmark symptom myotonia. DM is an autosomal dominant disease caused by a toxic gain of function RNA. The toxic RNA is produced from expanded non-coding CTG/CCTG repeats, and these CUG/CCUG repeats sequester a family of RNA binding proteins. The Muscleblind-like (MBNL) family of RNA binding proteins are sequestered to the expanded CUG/CCUG repeats. The MBNL proteins are regulators of alternative splicing, and their sequestration to the toxic RNA leads to mis-splicing events, which are believed to cause the symptoms observed in DM patients.
A previously reported screen for small molecules used to identify compounds that could disrupt MBNL from binding the toxic CUG repeats found that pentamidine was able to rescue splicing defects associated with DM. Herein, we present a new class of molecules (phenolsulphonphthaleins) that inhibited MBNL1/CUG repeat complex formation in a competitive electrophoretic mobility shift assay (EMSA). Additionally, one of these molecules, bromophenol blue (BPB), acted in a synergistic manner with the previously described inhibitor pentamidine. We also demonstrated that the halogenation of the phenolsulphonphthalein dyes is an important factor for activity. Moreover, we presentant analysis of a series of methylene linker variants of pentamidine that revealed heptamidine (an analog of pentamidine) could reverse splicing defects in a DM1 tissue culture model and rescue myotonia in a DM1 mouse model.
Finally, we report on a new crystal structure of CUG repeats, crystallized in the context of a GAAA tetraloop/receptor which facilitated ordered packing within the crystal. This structure was consistent with previous structures showing that the repeats are essentially A-form RNA, despite having a U-U mismatch every third base pair. We also identified six types of U-U mismatch in the context of the 5'CUG/3'GUC motif, suggesting that the interactions between the uridines are dynamic. This structure also contains the highest resolution GAAA tetraloop/receptor structure (1.95 Å) reported to date.
This dissertation includes previously unpublished co-authored material.
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Wang, Eric T. (Eric Tzy-shi). "Alternative isoform regulation in myotonic dystrophy". Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/70816.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, 2012.Cataloged from PDF version of thesis.
Includes bibliographical references.
Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, affecting more than 1 in 8000 individuals globally. The symptoms of DM are multi-systemic and include myotonia, severe muscle wasting, cardiac arrhythmias, cataracts, gastrointestinal dysfunction, and cognitive deficits. DM is caused by the expansion of CTG or CCTG repeat sequences expressed in noncoding portions of RNA, which sequester or activate RNA splicing factor proteins, leading to widespread deleterious changes in transcriptome isoform usage. We developed a method for studying transcriptomes, RNAseq, which provides a high resolution, digital inventory of gene and isoform expression. By applying RNAseq to human tissues and cell lines, we discovered that essentially 92-94% of all human genes are alternatively spliced, 86% of them with a minor isoform frequency 15% or more. We found that the majority of alternative splicing and alternative polyadenylation and cleavage events are tissue-regulated, and that patterns of these RNA processing events are strongly correlated across tissues, implicating protein factors that may regulate both types of events. We applied this method towards the goal of identifying transcriptome changes occurring in DM, focusing on the Muscleblind-like (MBNL) family of RNA binding proteins, which are functionally inactivated by CUG or CCUG repeats. Using RNAseq to profile tissues and cells depleted of MBNLs, we found that MBNL1 and MBNL2 co-regulate hundreds of redundant targets. MBNL1 UV cross-linking and immunoprecipitation, followed by sequencing (CLIPseq), was used to identify the in vivo transcriptome-wide binding locations of MBNL1, and facilitated the construction of a context-dependent RNA map for MBNL1 splicing regulation. Extensive 3' UTR binding of MBNL1 was found to localize mRNAs to membrane compartments of mouse myoblasts, suggesting a new global function for MBNLs, and additional mechanisms by which MBNL depletion can lead to DM symptoms.
by Eric T. Wang.
Ph.D.
19
Gagnon, Cynthia, e Cynthia Gagnon. "Conséquences fonctionnelles et sociales de la dystrophie myotonique : impacts des facteurs personnels et environnementaux sur la participation sociale". Doctoral thesis, Université Laval, 2007. http://hdl.handle.net/20.500.11794/19703.
Testo completoAbstract (sommario):
But : Le but de ce programme était de décrire et d’expliquer la participation sociale des personnes atteintes de dystrophie myotonique de type 1 (DM1). Méthode : Un échantillon aléatoire de 200 patients atteints de DM1 (phénotype léger (42) ou adulte (158)) a été recruté. La participation et la satisfaction dans la réalisation des habitudes de vie a été évaluée avec la Mesure des Habitudes de Vie (MHAVIE). Les facteurs environnementaux ont été évalués avec la Mesure de la Qualité de l’Environnement. Les facteurs personnels incluant la force musculaire, l’équilibre, la dextérité fine, la fatigue et l’hypersomnolence ont été évalués à l’aide d’instruments standardisés. Résultats : Les participants avec le phénotype adulte ont démontré un niveau de participation significativement inférieur à celui des participants avec le phénotype léger dans 8 des 11 catégories de la MHAVIE. Une restriction de la participation a été rapportée dans les catégories Déplacements, Habitation, Soins personnels, Nutrition, Condition corporelle, Travail, Loisirs, Vie communautaire chez les participants avec le phénotype adulte. La réalisation des habitudes de vie dans la catégorie loisirs était la plus affectée avec 57% des items qui démontraient une restriction de la participation chez 22 à 27% des participants. Les catégories Travail et Loisirs ont eu le plus faible taux de satisfaction. Les prédicteurs d’une atteinte de la participation sociale des quatre domaines les plus touchés soit Habitation, Déplacements, Travail et Loisirs ont été déterminés avec une analyse de régression logistique. Pour les facteurs personnels, la diminution de la force musculaire et une fatigue importante étaient significativement associées à la diminution de la participation sociale. Pour les facteurs environnementaux, la présence d’obstacles liée au support de la famille et l’accès et l’utilisation de la technologie est associée à une plus faible participation. Conclusion : Cette étude a permis de dresser un portrait et de mieux comprendre la participation sociale dans la DM1. Les résultats aideront à mieux définir le processus d’évaluation et la mise en place d’interventions en réadaptation et dans le milieu communautaire.But : Le but de ce programme était de décrire et d’expliquer la participation sociale des personnes atteintes de dystrophie myotonique de type 1 (DM1). Méthode : Un échantillon aléatoire de 200 patients atteints de DM1 (phénotype léger (42) ou adulte (158)) a été recruté. La participation et la satisfaction dans la réalisation des habitudes de vie a été évaluée avec la Mesure des Habitudes de Vie (MHAVIE). Les facteurs environnementaux ont été évalués avec la Mesure de la Qualité de l’Environnement. Les facteurs personnels incluant la force musculaire, l’équilibre, la dextérité fine, la fatigue et l’hypersomnolence ont été évalués à l’aide d’instruments standardisés. Résultats : Les participants avec le phénotype adulte ont démontré un niveau de participation significativement inférieur à celui des participants avec le phénotype léger dans 8 des 11 catégories de la MHAVIE. Une restriction de la participation a été rapportée dans les catégories Déplacements, Habitation, Soins personnels, Nutrition, Condition corporelle, Travail, Loisirs, Vie communautaire chez les participants avec le phénotype adulte. La réalisation des habitudes de vie dans la catégorie loisirs était la plus affectée avec 57% des items qui démontraient une restriction de la participation chez 22 à 27% des participants. Les catégories Travail et Loisirs ont eu le plus faible taux de satisfaction. Les prédicteurs d’une atteinte de la participation sociale des quatre domaines les plus touchés soit Habitation, Déplacements, Travail et Loisirs ont été déterminés avec une analyse de régression logistique. Pour les facteurs personnels, la diminution de la force musculaire et une fatigue importante étaient significativement associées à la diminution de la participation sociale. Pour les facteurs environnementaux, la présence d’obstacles liée au support de la famille et l’accès et l’utilisation de la technologie est associée à une plus faible participation. Conclusion : Cette étude a permis de dresser un portrait et de mieux comprendre la participation sociale dans la DM1. Les résultats aideront à mieux définir le processus d’évaluation et la mise en place d’interventions en réadaptation et dans le milieu communautaire.
Objective: To describe and explain social participation of persons with the adult and mild phenotype of myotonic dystrophy type 1 (DM1). Methods: A random sample of 200 subjects with DM1 (42 mild phenotype, 158 adult phenotype). Level of social participation and satisfaction was assessed with the Assessment of Life Habits (LIFE-H). Environmental factors were assessed with the Measure of the Quality of the Environment. Personal Factors were assessed with standardized instruments including Berg Balance Scale, Krupps Fatigue Severity Scale, and Manual Muscle Testing. Results: Participants with the adult phenotype demonstrated significantly lower participation level than those with the mild phenotype on 8 out of the 11 categories of the LIFE-H. Lower levels of accomplishment were reported in Mobility, Housing, Fitness, Nutrition, Personal Care, Employment, Recreation and Community Life categories among the adult phenotypes. The Recreation category was the most affected category with four out of seven items revealing compromised accomplishment among 22% to 27% of individuals. The lowest satisfaction score was observed in the Employment and Recreation categories. The predictors of the most restricted participation domains being Housing, Mobility, Employment and Recreation were determined with a logistic regression analysis. Participants reported disturbed participation in a large proportion (45-61%) for all domains. Lower extremity strength [OR = 15.4 – 5.5; p < 0.05] and higher fatigue [OR = 6.0 – 2.6; p < 0.05] were significantly present in participants with disturbed participation for all domains. For environmental factors, social support [OR = 3.6 – 2.5; p < 0.05] and public services [OR = 2.8 – 2.4; p < 0.05] were significantly perceived as barriers for participants with disturbed participation for most domains. Conclusion: This doctoral program has permited to better understand social participation in DM1. The results will help to elaborate a more comprehensive evaluation scheme and to develop intervention to promote optimal social participation in this population.
Objective: To describe and explain social participation of persons with the adult and mild phenotype of myotonic dystrophy type 1 (DM1). Methods: A random sample of 200 subjects with DM1 (42 mild phenotype, 158 adult phenotype). Level of social participation and satisfaction was assessed with the Assessment of Life Habits (LIFE-H). Environmental factors were assessed with the Measure of the Quality of the Environment. Personal Factors were assessed with standardized instruments including Berg Balance Scale, Krupps Fatigue Severity Scale, and Manual Muscle Testing. Results: Participants with the adult phenotype demonstrated significantly lower participation level than those with the mild phenotype on 8 out of the 11 categories of the LIFE-H. Lower levels of accomplishment were reported in Mobility, Housing, Fitness, Nutrition, Personal Care, Employment, Recreation and Community Life categories among the adult phenotypes. The Recreation category was the most affected category with four out of seven items revealing compromised accomplishment among 22% to 27% of individuals. The lowest satisfaction score was observed in the Employment and Recreation categories. The predictors of the most restricted participation domains being Housing, Mobility, Employment and Recreation were determined with a logistic regression analysis. Participants reported disturbed participation in a large proportion (45-61%) for all domains. Lower extremity strength [OR = 15.4 – 5.5; p < 0.05] and higher fatigue [OR = 6.0 – 2.6; p < 0.05] were significantly present in participants with disturbed participation for all domains. For environmental factors, social support [OR = 3.6 – 2.5; p < 0.05] and public services [OR = 2.8 – 2.4; p < 0.05] were significantly perceived as barriers for participants with disturbed participation for most domains. Conclusion: This doctoral program has permited to better understand social participation in DM1. The results will help to elaborate a more comprehensive evaluation scheme and to develop intervention to promote optimal social participation in this population.
20
Sabourin, Luc. "Myotonic dystrophy: A study of the expression of the myotonic dystrophy gene in affected tissues and cells". Thesis, University of Ottawa (Canada), 1995. http://hdl.handle.net/10393/9871.
Testo completoAbstract (sommario):
Recently, the molecular basis of myotonic dystrophy(DM) has been characterized as an unstable trinucleotide CTG repeat amplification in the 3' untranslated region of a gene encoding a protien with serine/threonine kinase activity. As a first step towards understanding the molecular mechanisms underlying DM, we have analyzed the amplification of the CTG repeat and the DM kinase (DMK) mRNA steady state levels in tissues and cell lines obtained from normal and congenital DM individuals. We have raised polyclonal antibodies against human DMK fusion protein and undertook DMK protein expression analysis in freshly sampled muscle tissues from normal and DM individuals. Our antibody detected DMK protein isoforms of 72 and 84 kDa, for which the levels and distribution were not significantly altered in tissues from adult and congenital DM patients. In addition, we have demonstrated that the previously reported decrease in DMK mRNA expression in affected tissues may be the result of a significant loss of type I myofibers, which preferentially express DMK. In contrast to previous reports, our results also showed that the mutant DMK allele was clearly transcribed as a high molecular weight mRNA in muscle tissue of a severely affected patient. We have examined DMK expression during muscle differentiation in vitro and subsequently investigated the effect of DMK over-expression on the terminal differentiation of the murine myoblast cell line C2C12. We demonstrated that DMK is up-regulated 2 to 3-fold during skeletal myogenesis and that constitutive over-expression of DMK mRNA in myoblasts caused a marked inhibition of myoblast terminal differentiation. Surprisingly, this activity mapped to the 3'UTR of the DMK transcript.When the DMK 3'UTR was placed downstream of a hygromycin resistance gene, the same inhibition of myogenesis was observed. Over-expression of the DMK 3' UTR in NIH 3T3 fibroblasts did not have any effect on their proliferation, suggesting that the 3' UTR does not prevent cell cycle withdrawal and differentiation by promoting growth. Further characterization of the 3' UTR sequences mediating the observed inhibition of terminal differentiation mapped these elements to a 239 bp conserved segment of the 3' UTR located upsteam of the CTG repeat. Furthermore, the DMK 3' UTR did not have any significant effect on the activity of the myogenic regulator MyoD when co-transfected into 10T1/2 cells along with a reporter construct bearing a muscle specific enhancer element. This suggested that the 3' UTR did not interfere with the ability of MyoD to transactivate muscle-specific genes. However, when the mRNA levels for two early myogenic regulators were analysed, myoblast clones over-expressing the 3' UTR expressed normal levels of MEF-2C, but showed reduced myogenin mRNA levels compared to controls, following the induction of differentiation. In addition, in contrast to controls, myogenin protien levels were found to be unchanged during myogenesis in these clones. These data suggested that over-expression of the DMK 3' UTR may alter the expression of specific mRNAs leading to a delay in terminal differentiation. (Abstract shortened by UMI.)
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Matloka, Magdalena. "MBNL derivatives for therapeutic application in myotonic dystrophy". Electronic Thesis or Diss., Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2019SORUS269.pdf.
Testo completoAbstract (sommario):
Les Dystrophies Myotoniques de type 1 (DM1) et 2 (DM2) sont des maladies neuromusculaires autosomiques dominantes causées par l’expansion anormale de séquences microsatellites C(C)TG situées respectivement dans la région 3’UTR du gène DMPK et le premier intron du gène ZNF9. Les ARNs mutés contenant les expansions de répétitions sont retenus dans le noyau des cellules sous formes d’agrégats riboprotéiques et séquestrent les protéines de liaison à l’ARN de la famille MBNL conduisant à des dérégulations de l’épissage alternatif associés aux symptômes cliniques. Bien que différentes approches thérapeutiques pour la DM soient en développement, il n’existe à ce jour aucune thérapie. Dans ce travail de thèse, nous avons développé une stratégie innovante de thérapie génique basée sur une protéine MBNL1 modifiée. Ce dérivé MBNL∆ agit comme un leurre pour libérer les facteurs MBNL endogènes anormalement séquestrés par les ARN mutés, et restaurer leurs fonctions. Ainsi l’expression de MBNL∆ dans des modèles DM1 permet la correction des anomalies moléculaires et phénotypiques. Nous avons également réalisé différentes optimisations de cet outil dans le but d’accroître ces capacités fonctionnelles. Enfin, nous avons développé un système d’autorégulation basé sur un « senseur d’épissage » dans le but de contrôler l’expression protéique d’un transgène. La preuve de concept de ce système a été faite à l’aide de MBNL∆ et validée dans des modèles DM1. En conclusion, mon travail de thèse a permis d’établir le potentiel d’une approche de thérapie génique pour la DM de type « leurre » basée sur l’ingénierie de protéine de liaison à l’ARNMyotonic dystrophy (DM) is an autosomal neuromuscular disease encompassing two distinct forms, type 1 (DM1) and type 2 (DM2), which are caused by abnormal microsatellite expansions of C(C)TG repeats in the 3’UTR of the DMPK and first intron of ZNF9 genes, respectively. Mutant RNAs carrying expanded repeats are retained in the nucleus as riboprotein aggregates that abnormally sequester MBNL splicing factors leading to alternative splicing misregulations associated with clinical symptoms. Although various therapeutic approaches for DM are under development, there is no effective therapy available so far. In this study, we designed a novel gene therapy strategy with the use of an engineered MBNL RNA-binding protein derivative that acts as a CUGexp-decoy to release sequestered endogenous MBNL factors and restore their proper functions. Expression of the decoy results in the correction of DM1-associated features in both in vitro and in vivo models of the disease. Subsequent optimization processes were applied to the engineered decoy and the most potent derivate that increases its functional capacity was selected for further therapeutic application. Additionally, we developed an autoregulatory system based on a splice-sensor strategy to control transgene product expression and provided a proof-of-concept of its efficacy in both in vitro and in vivo systems. In conclusion, my work establishes the potency of gene therapy treatment for DM and support the use of the decoy-based approach as an alternate or complementary therapeutic intervention for DM
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Tran-Ladam, Hélène. "Mécanismes moléculaires associés aux changements d'épissage de Tau dans une Tauopathie, la dystrophie myotonique de type 1". Thesis, Lille 2, 2010. http://www.theses.fr/2010LIL2S037/document.
Testo completoAbstract (sommario):
La pathologie Tau est une lésion neuronale commune à plus d’une vingtaine de maladies neurodégénératives. Elle correspond à l’agrégation des protéines Tau anormalement modifiées. Les mécanismes moléculaires impliqués dans l’agrégation de Tau demeurent encore mal compris. Toutefois, parmi les différentes hypothèses étiologiques, celle d’une dérégulation de l’épissage alternatif de Tau nous intéresse tout particulièrement. Ici, nous considérons la dystrophie myotonique de type 1 (DM1) comme maladie « modèle » pour étudier cette relation, puisqu’elle présente à la fois une dérégulation de l’épissage alternatif de Tau et des agrégats Tau. La DM1 est la forme adulte la plus fréquente de dystrophie musculaire. Il s’agit d’une maladie héréditaire à transmission autosomale dominante caractérisée par des répétitions CTGn>50 instables localisées dans la région 3’UTR du gène DMPK. Les mécanismes impliqués supposent un gain de fonction toxique des ARN mutés conduisant à une modification de l’épissage alternatif de nombreux transcrits parmi lesquels Tau. Dans ce contexte, nos objectifs étaient 1) de caractériser le défaut d’épissage de Tau dans le cerveau de plusieurs cas DM1 2) de modéliser ce défaut d’épissage afin d'identifier les facteurs trans-régulateurs impliqués et 3) de proposer une approche visant à restaurer un épissage normal. Le défaut d’épissage de Tau a été observé dans tous les cas analysés. Celui de l’exon 10, en revanche, n’a été rapporté que chez deux cas, qui, de façon intéressante, présentaient également une augmentation de l’expression des protéines CELF, décrites comme protéines régulatrices de l’épissage de Tau. Outre les protéines CELF, nous nous sommes également intéressés à MBNL1. MBNL1 est un facteur d’épissage jouant un rôle essentiel dans la physiopathologie de la DM1 où il a été décrit comme séquestré dans les foci. Peu de choses sont connues sur MBNL1 dans le cerveau et sur son rôle sur l’épissage alternatif des transcrits neuronaux. Ici, nous montrons que le niveau d’expression cérébrale de MBNL1 ne varie pas entre les cas DM1 et contrôles. En revanche, nous montrons que son épissage alternatif est dérégulé dans le cerveau. Notre étude de relation entre la structure et la fonction de la protéine suggère que ce changement d’épissage favorise sa séquestration dans les foci en modifiant sa localisation nucléaire, son activité de facteur d’épissage et ses propriétés d’oligomérisation. Le changement d’épissage de MBNL1 n’influence pas celui de Tau. Cependant, sa perte de fonction reproduit un profil d’épissage similaire à celui observé dans les cerveaux DM1. De plus, nous montrons que la surexpression de MBNL1, en présence des répétitions CTG suffit à restaurer un épissage normal de Tau et de plusieurs autres transcrits dérégulés dans la DM1. Enfin, des expériences complémentaires réalisées avec des protéines tronquées non fonctionnelles en tant que facteur d’épissage suggèrent que la restauration d’un profil d’épissage normal dans la DM1 serait due à la saturation des sites de liaisons CUG, ce qui permettrait de libérer les protéines MBNL1 séquestrées. Ces constructions semblent donc présenter un potentiel intérêt pour inverser les changements d’épissage observés dans la DM1 et sont actuellement en cours d’étudesTau pathology is a brain lesion common to more than twenty neurodegenerative disorders. It consists of the abnormal aggregation of the microtubule-associated protein Tau into neurofibrillary tangles. Mechanisms underlying Tau aggregation are not fully understood yet. However, among the different etiological hypothesises, the one of a relationship between Tau mis-splicing and Tau aggregates particularly interests us. Here, we proposed a disease model, being myotonic dystrophy type I (DMI), in which Tau mis-splicing and Tau aggregate occur. DM1 is the most common adult form of muscular dystrophy. It is an inherited autosomal disorder characterised by a dynamic instable CTG repeats (over 50) in the 3’UTR of DMPK gene. DM1 pathogenesis is suggested to result from a RNA toxic gain of function whereby mutant transcripts modify the splicing machinery activity leading thus to a mis-splicing of several pre-mRNA targets including Tau. In this context, our objectives were to 1) characterize Tau mis-splicing in several DM1 brain patients 2) Model it and identify the trans-regulating splicing factors likely involved and 3) Propose a therapeutic approach to reverse it. Tau mis-splicing was always observed for both exons 2 and 3 in human adult DM1 brain and consisted of a reduced inclusion. Tau exon 10 splicing was seldom mis-regulated and associated with an increase of the CELF proteins family. CELF proteins are splicing factors previously described to regulate alternative splicing of Tau exons 2, 3 and 10. In addition to the CELF proteins, we also investigated the potential role of the splicing factor MBNL1, which was shown to play an essential role in DM1 physiopathology through its sequestration by the CUG repeats. MBNL1’s brain expression was ill-defined. Here, we report that MBNL1’s expression level was not altered but its splicing modified in adult DM1 brain. In addition, we provide evidences by a relationship study between the structure and the function of MBNL1 that this mis-splicing event favored its sequestration to the foci by modifying its cell-localization, splicing activity and oligomerization properties. MBNL1 mis-splicing does not influence Tau mis-splicing. However its loss of expression reproduced the mis-splicing of Tau exons 2/3 as observed in DM1 brain. Interestingly, the overexpression of MBNL1 in the presence of the CTG repeats partially restored a normal splicing of Tau as well as several other mis-regulated pre-mRNA targets. Further experiments performed with different molecular constructs lead us to hypothezied that the reversal of the abnormal splicing events observed in DM1 was mediated by a saturation of the CUG binding sites that lead to the release of a free pool of MBNL1, recovering thus its splicing function. This work leads us to design a new molecular tool that might be of interest to reverse the pathological events observed in DM1
23
Bogdanovic, Marko D. "Cerebral Structure and Function in Myotonic Dystrophy". Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501971.
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Li, Xin. "Screening for drugs to treat myotonic dystrophy". Thesis, University of Nottingham, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659218.
Testo completoAbstract (sommario):
Myotonic Dystrophy (DM) is the most common form of muscular dystrophy in adults with an occurrence of about 1 in 8000 people. DM type 1 (DM1) is caused an expanded CTG triplet repeat within the 3' -untranslated region (3' -UTR) of the Myotonic Dystrophy protein kinase (DMPK) gene, while type 2 (DM2) is caused by an expanded CCTG repeat in intron I of the Zinc Finger 9 gene (ZNG9) gene. In DM, the mutant DMPK transcripts are trapped within nucleus and fOlm ribonuclear foci which interact with alternative splicing factors including MBNL and CUG-BP proteins. The abnormal levels of splicing factors lead to splicing defects contributing to the major symptoms of DM. At present, there is no treatment for DM. This study developed a series of screening and validation assays targeting different stages of DM pathophysiology. The subject of this thesis was to identify compounds and small molecules which are able to rescue molecular features of DM as a stat1ing point of therapeutic dmg development for DM. In this study, I have developed a high-throughput screen assay using an in situ hybridization protocol for compounds intenupting nuclear foci in DM patient cell lines. Enzo® Kinase, Phosphatase Inhibitor and NCGC Phatmaceutical Libraries were screened, and four compounds, Hypericin, Ro 31-8220, Gemcitabine and Chromomycin A3, which reduce or remove nuclear foci in DM cells, have been identified. Cyototoxic activities of hit compounds and their effects on molecular features of DM were examined with a series of validation assays. This study demonstrates that Ro 31-8220 alters the ratio of expansion allele of DMPK in the nucleus; Ro 31-8220 and Chromomycin A3 affect alternative splicing of SERCAl in some DMl cell lines, and eliminate or reduce nuclear MBNLl protein foci. The hit compounds identified can be a stat1ing point for dmg development for DM therapy.
25
Klesert, Todd Robert. "The DMAHP/SIX5 gene in myotonic dystrophy /". Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/6355.
Testo completo
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Boland-Freitas, Robert. "Muscle And Nerve Excitability In Myotonic Dystrophy". Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/21289.
Testo completoAbstract (sommario):
Abstract: Myotonic dystrophy is the most common form of muscular dystrophy in adults. Both subtypes, Type 1 (DM1) and Type 2 (DM2), affect multiple body systems. Myotonia and muscle atrophy are common to DM1 and DM2 and contribute to morbidity. The main purpose of this thesis was to elucidate aspects of muscle and nerve function in these conditions. To do this, the neurophysiological techniques of skeletal muscle and axonal excitability assessment, in addition to quantitative sensory thermal thresholds testing were used. Given that relationships between serum electrolyte levels and muscle excitability measures have been found in disease states, in this thesis their assessment was undertaken in healthy individuals. The inter-rater reliability of thermal threshold assessment was also examined, as this method was used to assess small nerve fibre function in DM1 and DM2. Significant muscle excitability differences were found between persons with advanced DM1 and healthy individuals, consistent with sodium-potassium pump dysfunction. Additionally, chloride channel dysfunction was demonstrated in both advanced DM1 and in DM2. It is concluded the technique may merit use as a disease biomarker and aid in diagnosis. Serum electrolyte concentration variation between disease groups and healthy individuals is concluded to be unlikely to account for differences observed between muscle disease and normal groups, despite significant correlations being demonstrated between some measures and ions. Increases in inward rectification, possibly reflecting neural adaptation to muscle weakness, and nodal sodium currents we found on advanced DM1 motor axon excitability. Sensory nerve excitability was not altered, though larger studies of lower limb nerves could increase sensitivity. Perception of thermal change was found to be abnormal in the upper and lower extremities in DM1, consistent with small fibre sensory neuropathy that precedes or occurs in isolation from large fibre nerve dysfunction.
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Antonio, Marie de. "Statistiques et modèles de survie pour améliorer la connaissance d’une maladie rare, la dystrophie myotonique The DM-Scope registry: a rare disease innovative framework bridging the gap between research and medical care Unraveling the myotonic dystrophy type 1 clinical spectrum: a systematic registry-based study - Implications for disease classification". Thesis, Sorbonne université, 2020. http://www.theses.fr/2020SORUS096.
Testo completoAbstract (sommario):
La dystrophie myotonique (DM) est considérée comme l'une des maladies neuromusculaires les plus complexes. Bien que les travaux de recherche de ces 30 dernières années aient permis de mieux comprendre les mécanismes moléculaires sous-jacents, la nature de l'anomalie génétique hors norme, son expression multisystémique et son large spectre clinique ne permettent pas, à l'heure actuelle, une prise en charge optimale des patients. Mon travail a eu pour but d'approfondir les connaissances et de préciser l'histoire naturelle de cette maladie rare. La première partie du manuscrit est consacrée à la présentation de l'observatoire DM-Scope, sur lequel s'appuie tout mon travail de thèse. Après la description du concept, du fonctionnement et de la plateforme de recueil, les caractéristiques de la cohorte DM1, à partir de laquelle les analyses ont été réalisées, sont présentées : spectre clinique couvert, atteinte multisystémique, corrélations génotype/phénotype, interrelations entre les symptômes et comparaison à la dystrophie myotonique de type II (DM2). Ensuite, dans une deuxième partie, nous abordons les avancées majeures obtenues dans les DM grâce à DM-Scope et aux analyses réalisées pendant ma thèse : (i) précision de l'histoire naturelle de la maladie, notamment avec la proposition d'une nouvelle classification ; (ii) mise en exergue de facteurs déterminants du phénotype comme le genre, la taille de la mutation ou les interrelations entre les symptômes. Ces travaux ont conduit à des recommandations de soins, notamment pour la transition enfants-adultes mais aussi la validation de critères d'inclusion importants pour les essais cliniques comme le genre. DM-Scope permet d'accéder à des échantillons biologiques pour des études de recherche fondamentale et valider de nouvelles approches thérapeutiques. Il est aujourd'hui un leader à l'international et un outil incontournable dans la recherche translationnelle dans la DM. Ce concept transférable à n'importe quelle autre population, peut être utilisé pour la prise en charge d’autres maladies rares. Enfin, le développement d'un modèle de survie construit à partir de la cohorte DM de l'observatoire est présenté. Ce modèle a trois spécificités : (i) il est applicable en grande dimension, à des cas comme DM-Scope, où l'on a un nombre important de variables; (ii) il prend en compte les risques compétitifs, lorsque les patients sont exposés simultanément à plusieurs évènements. Dans notre observatoire, l'étude des décès de cause respiratoire est biaisée sans la prise en compte des évènements concurrents tels que le décès de cause cardiaque; (iii) il modélise l'hétérogénéité entre les groupes de patients (effets centres), potentiellement due à une prise en charge différente. L'analyse des données de DM-Scope nécessite cette spécificité issue des modèles à fragilité car l'observatoire est multicentrique (55 centres). Le modèle est transférable et applicable à d'autres données car de plus en plus de bases sont de grandes dimensions, la majorité des analyses de survie ont une censure liée à la survenue de l'événement d'intérêt et les études multicentriques sont de plus en plus communesMyotonic dystrophy (DM) is considered one of the most complex neuromuscular diseases. Although research work over the past 30 years has permitted a better understanding of its underlying molecular mechanisms, the unusual nature of its genetic anomalies, its multisystemic expression and its broad clinical spectrum do not allow, at the moment, optimal patient management. The purpose of my work was to deepen our knowledge of this rare disease and to clarify its natural history. The first part of my manuscript is dedicated to the presentation of the DM-Scope Registry, on which all my thesis work is based. After the description of the concept, the functioning and the data collection platform, the manuscript features the characteristics of the DM1 cohort, from which our analyses were conducted : the clinical spectrum covered, multisystemic impairment, genotype/phenotype correlations, interrelations between symptoms and comparison to myotonic dystrophy type II (DM2). In the second part, we focus on the major progress achieved through the existence of DM-Scope and the analyses conducted during my thesis: (i) detailing the natural history of the disease, in particular proposing a new classification; (ii) highlighting the phenotype’s determining factors such as gender, mutation size, interrelations between symptoms. This work has led to recommendations for care, in particular for the transition from child to adult, but also the validation of important inclusion criteria for clinical trials such as gender. DM-Scope provides access to available biological samples for basic research studies and validates new therapeutic approaches. DM-Scope is now a worldwide leader and an essential tool in translational research in DM. The DM-Scope concept can be transferred to any other population and can be used for care management in other rare diseases. Finally, we present the development of a survival model built from the DM-Scope cohort. This model has three specificities: (i) it is applicable to high dimensional data, in such cases as DM-Scope, where there is a large number of measurements; (ii) it takes into account competitive risks, when patients are simultaneously exposed to several events. In our registry, the study of respiratory-related deaths is biased if competing events such as heart disease deaths are not taken into account ; (iii) it models the heterogeneity between patient groups probably due to divergent care, called \og centres effects \fg{}. DM-Scope data analysis requires such specificity of frailty models due to its multicentric coverage (55 centres). This model can be transferred and applied to other data, considering the following : more and more large-scaled registries are being used ; a majority of survival analyses includes censorship caused by the occurrence of the event of interest ; multicentre studies have become increasingly common
28
Potvin, Lynn. "Étude descriptive de la mortalité dans la dystrophie myotonique au Saguenay-Lac-Saint-Jean /". Thèse, Chicoutimi : Université du Québec à Chicoutimi, 1994. http://theses.uqac.ca.
Testo completoAbstract (sommario):
Mémoire (M.Med.Exp.)-- Université du Québec à Chicoutimi, 1994.Ce mémoire a été réalisé à l'Université du Québec à Chicoutimi dans le cadre du programme de maîtrise en médecine expérimentale (volet génétique) extensionné de l'Université Laval à l'UQAC. CaQCU Document électronique également accessible en format PDF. CaQCU
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Winblad, Stefan. "Myotonic dystrophy type 1 : cognition, personality and emotion /". Göteborg : Göteborg University, Dept. of Psychology, 2006. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=015464022&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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30
Haworth, Christine. "Understanding the pathogenesis of myotonic dystrophy type 1". Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/478/.
Testo completoAbstract (sommario):
To identify the full range of targets and the pathogenic consequences, we sought to mimic the pathogenesis of myotonic dystrophy type 1 with temporal and spatial control: temporal to reproduce the developmental pathogenesis of the congenital form, and spatial to isolate tissue specific pathology. To do this, we attempted to use the Cre-lox system for the conditional expression of an EGFP reporter-linked expanded CUG repeat RNA in the mouse. Expression of the transgene was controlled by Cre excision of a transcriptional stop, placed upstream of the EGFP-expanded repeat open reading frame. The transgenes were constructed and tested successfully, and a normal length repeat transgenic line was established. Unfortunately generation of the expanded repeat line was not successful. The constructs were used to generate cell-culture models of DM1, in both human and murine cells, which mimicked the nuclear foci formation and MBNL1 co-localisation seen in patient cells. Expression of exogenous MBNL1/GFP fusion protein in this model resulted in an increase in the size of foci, indicating that MBNL1 protein is limiting within the cell, and may possibly play a protective role. The murine DM1 cell-culture model was used to investigate the effects of expanded CUG repeat expression on splicing within the transcriptome. The differential effect between 5 and 250 repeat RNA expression using Affymetrix whole transcript and exon arrays was compared. Using whole genome arrays, 6 genes were down-regulated and 128 upregulated. With exon arrays, 58 genes showed alternative exon usage. Six genes were selected for further bioinformatics analysis: MtmR4, which has possible neuromuscular involvement; Kcnk4, Narg1, Ttyh1 and Bptf, potentially related to brain development; and Cacna1c, a promising candidate for heart conductance defects and sudden death.
31
Newman, Emma E. "An investigation into molecular basis of myotonic dystrophy". Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310951.
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Osborne, Robert J. "Caenorhabditis elegans models of myotonic dystrophy type 1". Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408632.
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Fardaei, Majid. "Studies on the molecular mechanism underlying myotonic dystrophy". Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272371.
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Prentl, Katrin. "Ergebnisse der chirurgischen Therapie des Zenker Divertikels Myotomie und Divertikelabtragung versus Myotomie und Diverikulopexie /". [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=96392236X.
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Beaulieu, Daniel. "Inhibition de la différenciation myogénique par un facteur soluble sécrété par des myoblastes dérivés de muscules squelettiques de sujets atteints de la dystrophie myotonique de type 1". Master's thesis, Université Laval, 2006. http://hdl.handle.net/20.500.11794/18661.
Testo completoAbstract (sommario):
La dystrophie myotonique de type 1 (DM1), la maladie neuromusculaire la plus fréquente chez l’adulte, est causée par une expansion de CTG dans la partie 3’ non traduite du gène codant pour la protéine dystrophy myotonic protein kinase, DMPK. La forme adulte de la maladie est caractérisée, notamment, par une faiblesse musculaire, de la myotonie, des cataractes et des troubles cardiaques. La forme congénitale, la forme la plus sévère de la maladie, est caractérisée par de l’hypotonie, une détresse respiratoire aiguë et un retard psychomoteur important. La régénération des fibres musculaires est déficiente dans la forme adulte de DM1, tandis qu’un retard de maturation du système musculaire est observé dans la forme congénitale. A ce jour, les mécanismes moléculaires par lesquels l’expansion de CTG affecte le développement ou la régénération du système musculaire sont inconnus. Des travaux ont démontré que le sérum de mères ayant un enfant atteint de la forme congénitale de la DM1 contient un facteur soluble inhibant la différenciation terminale des myoblastes. Il est encore indéterminé si ce facteur est produit par la mère ou sécrété par le fœtus. Nous avons émis l’hypothèse qu’un facteur soluble était sécrété par les myoblastes prélevés de patients atteints de forme congénitale de la DM1 qui inhibe la différenciation terminale des précurseurs des cellules musculaires. Les résultats obtenus démontrent que les myoblastes DM1 sécrètent un facteur soluble de masse moléculaire inférieure à 30 kDa inhibant la différentiation myogénique. Cet effet est associé une diminution spécifique de la myogenin. L’effet de ce facteur soluble est proportionnel à la longueur de l’expansion des CTG. L’identification et la caractérisation du facteur soluble sécrété spécifiquement par les myoblastes DM1 permettra une meilleure compréhension des mécanismes moléculaires responsable des défauts de développement du système musculaire observés dans la forme congénitale, et des défauts de régénération des fibres musculaires observés dans la forme adulte de la DM1. L’identification de ce facteur soluble est présentement en cours.Myotonic dystrophy (DM1), the most common form of inherited neuromuscular disease in adults, affects 1 in 8000 individuals worldwide. DM1 is an autosomal dominant muscular dystrophy with very variable symptom presentations. Adult onset DM1 is primarily characterized by myotonia, muscle wasting and weakness, but also affects a number of organs and tissues. One characteristic of the disease is the presence of a severe congenital form (CDM1), which differs from the adult form. CDM1 is characterized by a delay in the development of skeletal muscles. This form is associated with hypotonia, respiratory complications and mental retardation. DM1 is caused by the expansion of an unstable CTG trinucleotide repeat in the 3’untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. To date, the mechanisms by which the DM1 mutation affects skeletal muscles development or regeneration are unknown. A previous study demonstrated that serum produced by mothers of children with congenital myotonic dystrophy inhibits myogenic differentiation. In this study, we hypothesized that CDM1 myoblasts secrete a soluble factor that blocks myogenic differentiation. We provide evidence that this soluble factor is produced by DM1 and CDM1 myoblasts which may be involved in their deficiency to fuse. The inhibitory effect is proportional to the length of the CTG repeat expansion. In addition, the delay in muscle differentiation is associated with a specific reduction in myogenin gene expression. We believe that the DM1 mutation triggers the expression of a soluble factor, which is able to block myogenic differentiation. The identification of this soluble factor is presently under investigation.
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Hamilton, Graham. "Identification, isolation and characterisation of the Drosophila othologue of human SIX5". Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252503.
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Barcelo, Juana M. "Analysis of the unstable mutation responsible for myotonic dystrophy". Thesis, University of Ottawa (Canada), 1997. http://hdl.handle.net/10393/9659.
Testo completoAbstract (sommario):
Myotonic dystrophy (DM) is an autosomal dominant genetic disease which affects approximately 1 in 8000 individuals globally. This is a multisystemic disorder which primarily targets muscle tissues. The genetic defect underlying DM is a highly unstable trinucleotide CTG repeat sequence located in the 3$\sp\prime$ untranslated region of a gene encoding a protein with serine/threonine protein kinase activity. The number of CTG repeats in non-DM individuals ranges from 5 to 35, whereas in DM individuals it can range from 50 to over 2000. The mechanism of disease and the role of the kinase are currently unknown. The main characteristics of the mutation are its expanded length and high instability. The instability usually leads to an increase in the number of CTG repeats as the mutant allele is transmitted from one generation to the next. This is seen concurrently with an increase in the severity of the clinical phenotypes through successive generations. The mechanism(s) underlying the unstable behaviour of this mutation have been unknown. I studied several possible elements that might affect the observed instability. These studies were performed on a large number of intergenerational transmissions of the mutant allele in DM patients, as well as on different tissues from the same patients. In vivo studies revealed that both the gender of the transmitting parent and the size of the mutation had a significant effect on its intergenerational dynamics. Instability was also seen in cells that underwent mitosis and meiosis, as well as in patients' cells with very low mitotic activity. In addition, in vitro studies showed instability of this sequence in cells from DM patients which were grown in tissue culture. This instability was seen to not necessarily be associated with the cell-cycle-coupled DNA replication in those cells. Since my previous analyses had ruled out recombination between homologous chromosomes as a major element involved in the instability I focused my studies on tests for the possibility that DNA repair was associated with the instability of this mutation. These analyses revealed that there were breaks or gaps occurring specifically within the mutation. Since breaks and gaps are DNA repair intermediates this suggested that the high instability of this mutation in DM patients was due to repair attempts on the structure adopted by the long arrays of CTG repeats. The results of the previous studies on intergenerational transmissions of the mutation, as well as in vivo and in vitro studies of the unstable properties of this sequence are also compatible with a DNA repair model of repeat instability. These data point the way to a more focused approach to the identification of specific mechanistic pathway's underlying the expansion of this highly unstable CTG repeat in DM. The results of this research may also help in defining the mechanism(s) of expansion of the mutations of an increasing number of human genetic diseases found to be caused by highly unstable trinucleotide repeats.
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Barceló, Juana M. "Analysis of the unstable mutation responsible for myotonic dystrophy". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/nq20990.pdf.
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Truong, Brian. "Myotonic dystrophy : the structure of CUG repeats in solution /". view abstract or download text of file, 2007. http://hdl.handle.net/1794/3958.
Testo completo
40
Udosen, Inyang Udofia. "Development of assays for therapeutic screening in myotonic dystrophy". Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/14282/.
Testo completoAbstract (sommario):
Myotonic dystrophy (DM) is an autosomal dominant inherited multisystemic neuromuscular disease. The molecular mechanism for DM is mediated by toxic RNAs containing expanded repeat units. DMI is caused by a CTG repeat expansion in 3'-UTR of the DMPK gene while DM2 is caused by CCTG repeat in intronl of the ZNF9 gene. The molecular features of DM are formation of RNA foci, co-localisation of MBNL proteins with ribonuclear foci, splicing defects of a subset of pre-mRNAs with elevation ofCUGBPI in DMl. In order to develop therapy for DM, assays were designed based on the molecular characteristics of the disease to screen compounds. Two primary assays were based on disruption of nuclear foci and on correction of misregulated splicing involving intron2 CLCNI. The first part of this report deals with the development of a nuclear foci assay and splicing construct assay. Both assays were optimised in HTS and utilized in screens for molecules that clear nuclear foci from DM cells and correct misregulated splicing in intron2 of CLCNI respectively. High throughput screens of kinase and phosphatase inhibitor libraries using the nuclear foci assay and CLCNI splicing construct assay yielded two positive hits: protein kinase C inhibitors designated in the compound library as D8 (hypericin) and D9 (Ro-31-8220). The second part of this thesis deals with the confirmation of compound hits obtained from the primary screen. I examined two aspects: mutant DMPKtranscript entrapment in nucleus and splicing defects associated with the disease. A BpmJ restriction assay was used to test the effect of compounds on mutant DMPK transcripts showed that both D8 and D9 were unable to release the mutant transcript into the cytoplasm. D8 demonstrated efficacy in reversing spliceopathy in alternative splicing assays of JR, SERCAI MBNLI and MBNL2 while D9 did not have this effect except on MBNLI which showed a very minor efficacy.
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Langlois, Marc-André. "RNA-based gene therapies for myotonic dystrophy type 1". Thesis, Université Laval, 2003. http://www.theses.ulaval.ca/2003/21404/21404.pdf.
Testo completoAbstract (sommario):
La dystrophie myotonique de type 1 (DM1) est une maladie neuromusculaire grave qui engendre une perte d’autonomie des patients et diminue leur espérance de vie. Cette maladie est la plus fréquente des dystrophies musculaires chez l’adulte avec une incidence mondiale d’une personne atteinte sur 15 000. Au Québec, cette maladie est d’une importance particulière, car elle touche une personne sur 500 dans les régions du Saguenay et de Charlevoix. La DM1 est causée par l’expansion du triplet CTG situé dans la région 3’ non-codante de la myotonine protéine kinase (DMPK). Toutefois, il a été démontré que la grande part des symptômes de la maladie seraient liés à l’accumulation nucléaire de l’ARNm de DMPK portant l’expansion. Ces ARNm mutés se lient à des facteurs nucléaires formant des foci dans les noyaux des cellules DM1, engendrant des effets toxiques sur le métabolisme cellulaire et sur l’épissage alternatif de certains ARNm.
Nos travaux avaient comme but premier d’évaluer si la destruction de l’ARNm mutant de DMPK dans des myoblastes provenant de muscle squelettique DM1 permettrait de rétablir certaines fonctions et caractéristiques normales dans ces cellules. Trois technologies à base d’ARNs: les antisens, les ribozymes et les shRNAs ont diminué avec succès ces niveaux d’ARN mutés. Les ARNs antisens et les ribozymes, contrairement aux shRNA, ont permis un ciblage préférentiel des ARNs mutés de DMPK dans le noyau de myoblastes DM1. Ceci permet donc de maintenir un niveau basal de la protéine DMPK dans les myoblastes, un détail important advenant l’utilisation de ces molécules en thérapie génique chez l’humain. En utilisant les ribozymes, nous avons diminué la quantité et l’intensité des foci ce qui a permis de libérer les facteurs cellulaires se liant aux expansions de CUG. Ceci a eu comme effet de corriger un défaut d’épissage alternatif dans le récepteur à l’insuline. En exprimant de longs antisenses à l’ARNm de DMPK par un oncorétrovirus, nous avons constaté une restauration de la fusion cellulaire, de la capture de glucose ainsi qu’une diminution de CUGBP, un facteur d’épissage alternatif. Nous avons également démontré que la surexpression de hnRNP H, un facteur d’épissage liant les expansions de CUG, permettait aussi de diminuer les niveaux de CUGBP et ainsi corriger le défaut d’épissage alternatif du récepteur à l’insuline. Ces résultats démontrent donc pour la première fois le lien direct entre la rétention des ARNs mutés, la déplétion nucléaire d’un facteur d’épissage s’y liant et l’exacerbation de certaines caractéristiques du phénotype DM1. La somme de nos observations a permis deux choses importantes: en premier lieu, d’établir un nouveau modèle détaillé expliquant la pathogenèse de la DM1. En second lieu, nos résultats ont permi de valider la pertinence de détruire spécifiquement les transcrits mutés de DMPK afin de développer une thérapie génique efficace pour la DM1.Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease that ultimately causes loss of mobility and premature death. DM1 is the most common muscular dystrophy in adults with a world wide incidence of 1 affected individual in every 15 000. This disease is of special relevance in the Saguenay and Charlevoix regions in Quebec, where 1 in every 500 individuals is a carrier of the mutation. DM1 is caused by the expansion of an unstable CTG trinucleotide repeat located in 3’UTR of the DMPK (DM protein kinase) gene. However, it has been shown that most DM1 symptoms are related to the nuclear retention of mutant DMPK mRNA. These mutant transcripts bind to nuclear proteins and form foci in DM1 cell nuclei. This is though to be the leading cause of metabolical disruptions and defective alternative splicing of several mRNAs observed in DM1 cells. Our main project objective was to evaluate whether destruction of mutant DMPK mRNA could restore normal phenotype features in DM1 human skeletal myoblasts. The use of three RNA-based approaches: antisense RNAs, ribozymes and shRNAs, all displayed significant reductions in mutant DMPK mRNA. Antisense RNAs and ribozymes, as opposed to shRNAs, allowed specific targeting and destruction of mutant DMPK mRNAs in the nucleus of DM1 myoblasts. This feature thus allows a basal level of DMPK protein expression which is of particular relevance in the advent of developing a gene therapy for DM1. Ribozymes were effective in reducing the number and intensity of foci present in the nucleus of the myoblasts, thus allowing the release of certain CUG-binding proteins. This resulted in restoration of the defective splicing of the insulin receptor mRNA. Antisense RNAs to the DMPK mRNA expressed by an oncoretrovirus restored myoblast fusion, glucose uptake and lowered nuclear levels of CUGBP, an alternative splicing factor. Over expression of hnRNP-H, an alternative splicing factor that we showed could bind to CUG repeats, also reduces expression of CUGBP and restores defective splicing of the insulin receptor. These results reveal for the first time the intricate link between mutant DMPK mRNA nuclear retention, depletion of a CUG-binding protein that is also a splicing factor and exacerbation of related DM1 features. In conclusion, our work has allowed to better define the mechanisms involved in DM1 pathogenesis and has validated the relevance of developing a gene therapy that specifically targets mutant DMPK mRNAs.
Inscrit au Tableau d'honneur de la Faculté des études supérieures
42
Alwazzan, Madawi. "Analysis of genes and their transcripts in myotonic dystrophy". Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301073.
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Russell, Sarah Louise. "Signalling pathways activatedin type 1 myotonic dystrophylens epithelial cells". Thesis, University of East Anglia, 2010. https://ueaeprints.uea.ac.uk/32249/.
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Arya, Sukrat. "The role of muscleblind-like proteins in myotonic dystrophy". Thesis, University of Nottingham, 2014. http://eprints.nottingham.ac.uk/14341/.
Testo completoAbstract (sommario):
Myotonic dystrophy (DM) is a progressive multisystemic genetic disorder which is inherited as an autosomal dominant trait. There are two subtypes of the disorder, DM type 1 and DM type 2. DM type1 is caused by an expansion of a CTG repeat located in the 3' untranslated region of the DMPK gene on chromosome 19q13.3, whereas DM type 2 is caused by a CCTG expansion in intron 1 of ZNF9 gene located on chromosome 3q. The mutant RNAs containing the expanded CTG/CCTG repeats alters the activity of various alternative splicing factors like Muscleblind-like (MBNL) proteins, which are sequestered in the ribonuclear foci in nucleus by the expanded mutant transcripts resulting in a number of splicing defects observed in DM patients. In first part of my thesis, I have assessed the nuclear and cytosolic distribution of MBNL proteins in both normal and DM cells. In both DM1 and DM2 cells the amount of nuclear MBNL1 was found to be at least 50% greater than seen in normal cells. In addition to this, I studied the distribution of MBNL1 protein in nuclear and cytosolic fractions of DM cells before and after treatment with compounds chromomycin A3, gemcitabine, IMOX, RO 31-8220 and hypericin which were highlighted in the primary screen. Treatment with the compounds produced a significant reduction in the proportion of nuclear MBNL1 compared to DMSO treated cells in DM fibroblast and myoblasts. In second part of this thesis I have examined the effect of MBNL1/2 down regulation on both RNA and MBNL1 foci in DM cells. MBNL1 and MBNL2 double knockdown resulted in a 40% increase of nuclear RNA foci than observed in scrambled siRNA treated cells, though a significant reduction was observed in case of MBNL (protein) foci. Also, MBNL 1 and MBNL2 down regulation did not result in the release of mutant transcript from the nucleus to the cytoplasm in KB-Telo MyoD (DM) cells as seen in BpmI restriction polymorphism assay. However, it had a degradative effect on the mutant DMPK transcript.
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Nasser, Khalidah K. "Genetic and symptomatic variations in Myotonic Dystrophy Type 1". Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7874/.
Testo completoAbstract (sommario):
Myotonic dystrophy type 1 (DM1) is an extremely variable genetic disorder showing an autosomal dominant inheritance that is characterised by myotonia, insulin resistance, cardiac conduction defects and cataracts. It is caused by a trinucleotide repeat expansion of CTG sequence located in the 3’-untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19 at q13.3. The severity of symptoms ranges from mild adult onset to severe congenital form. A characteristic clinical feature of DM1 is anticipation phenomenon where disease severity increases and age of onset decreases over successive generations. The DM1 mutation is highly unstable in both the germline and soma, and showed to be an age-dependent, tissue-specific (skeletal muscles comprised the largest allele length of approximately thousand units) and expansion biased. The unaffected level of the repeat sequence falls between ~5-37 repeats whereas the disease associated range starts from ~50 repeats, reaching several thousand units. These properties account for the observed anticipation and contribute toward the tissue-specificity and progressive nature of the symptoms. The manifested phenotypes, symptoms severity and age at onset are extremely variable within and between families. This is mostly accounted for by the progenitor allele length (PAL) passed on from affected parents in addition to the level of somatic instability over time. Though, recent data have shown that additional sequence variations (CCG, CGG variant repeats) within the repeat and immediate flanking DNA are associated with additional symptomatic variation, modified stability and delayed age of onset. Furthermore, individual specific genetic factors have shown to be clustered within and between families as a heritable trait. Therefore, it has been verified that PAL, in addition to individual specific genetic variations are the main modifier of disease onset. More recently, it has been observed that mismatch repair (MMR) genes play a key role in modulating the dynamic of DM1 mutation, and subsequently impact on the age at onset. Therefore, these genes serve as powerful trans-acting modifiers of repeat instability and subsequent severity. Also, sequestration and up-regulation of RNA binding proteins (MBNL1, CELF1 respectively) against the trapped mutant transcripts are the hall mark of DM1 pathogenicity associated with alternative splicing defects that account for the variability of symptoms. Thus, sequence variations within these genes may underlie the genetic and phenotypic variability among DM1 patients. The current diagnostic test for DM1 only provides a qualitative value, and takes no account of the somatic instability and/or the presence of variations within or elsewhere in the genome. Thus, limited prognostic information is delivered to patients and their families. Although more elaborate genotyping approaches that measure the DM1 degree of instability was developed, they remain labour intensive, time consuming and are not suited to routine clinical diagnostics. In this project, we have evaluated the utility of more rapid and higher throughput next generation sequencing (NGS) technologies (Ion PGM and PacBio platforms) to simultaneously sequence the DM1 alleles of the Scottish patients, characterise the immediate flanking variants (5’-extra AAT and 5’-CCG variant repeats), elucidating the possible role of these variants on the DM1 instability, and finally sequencing the potential trans-acting modifiers in a massive customised panel (Ion AmpliSeq). Though, the accurate genotyping of the DM1 allele using NGS method remains challenging and cannot be used at the moment for accurate measurement of allele length. This is due to the sequencing biased nature towards shorter fragments resulting in differences of modal allele length measurement between PacBio and traditional SP-PCR methods. Additionally, Ion PGM platform was not successful at sequencing >20 CTG repeats. To correct for the sequencing biased distribution towards shorter alleles and distinguish between possible somatic variants from sequencing errors, safe sequencing (SafeSeq) method was conducted by tagging each original parental molecule with unique identifier (UID) sequences via PCR followed by sequencing using MiSeq platform. As the UID assignment was successful in tagging different population of repeats lengths, unfortunately we were not able to confidently differentiate between true somatic mutants from possible repeat slippage events in earlier cycles of PCR. Thus, it was decided to modify the incorporation of UID sequences using ligation based approach instead of PCR, and better optimise the method for more accurate results in the future. The identification of the immediate 5’-extra AAT flanking variant of the DM1 allele in a subset of the Scottish DM1 patients with and without CCG variant repeats has led us to speculate the possible presence of a new sub derived DM1 haplotype shared by a recent common ancestor in the Scottish population. In order to address this question, we were able to discriminate the normal allele haplotype of 11-13 repeats from >20 CTG haplotype among 18 DM1 patients whom were previously sequenced by Dr. Saeed Al ghamdi. These data have illustrated the most conserved haplotype around the DM1 allele. Therefore, the corresponding region was included in a customised Ion AmpliSeq sequencing panel for future larger scale haplotype analysis, in order to provide insights about future DM1 prevalence among the Scottish population. The data of this project highlighted the importance of using NGS technologies to characterise the structural pattern of the DM1 allele containing variants that may impact on symptom severity. It also showed the successful sequencing of trans-acting genetic modifiers in massive parallel fashion. Over larger scale analysis, these data could be used for better genotype-phenotype correlation and stratify patients in future clinical trials.
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VAUTIER, CATHERINE. "La motricite de l'oesophage dans la myotonie de steinert". Amiens, 1990. http://www.theses.fr/1990AMIEM067.
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47
Warf, Michael Bryan. "The regulation of alternative splicing associated with Myotonic Dystrophy". Thesis, University of Oregon, 2009. http://hdl.handle.net/1794/10335.
Testo completoAbstract (sommario):
xiv, 78 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number.Myotonic Dystrophy (DM) is a genetic disorder with multisystemic symptoms that is caused by expression (as RNA) of expanded repeats of CTG or CCTG in the genome. It is hypothesized that the protein MBNL1 (M[barbelow]uscleb[barbelow]lin[barbelow]d-l[barbelow]ike-1) is sequestered to the expanded CUG or CCUG RNAs. MBNL1 regulates the alternative splicing of a variety of pre-mRNAs and its mis-localization results in mis-splicing of a subset of pre-mRNAs that are linked to the symptoms found in DM patients. I initially demonstrated that MBNL1 can bind short structured CUG and CCUG repeats with high affinity and specificity in vitro . Next, I was able to determine and articulate the first structure of a binding site of MBNL1 in an endogenous pre-mRNA that it regulates. I found that MBNL1 binds a stem-loop in the cardiac troponin T (cTNT) pre-mRNA. The stem-loop contains two mismatches and resembles both CUG and CCUG repeats. I determined that MBNL1 regulated exon 5 by directly competing with the essential splicing factor U2AF65 for binding upstream of exon 5. When U2AF65 is prevented from binding, factors in the spliceosome can no longer be recruited and the following exon is skipped. Furthermore, I found that MBNL1 and U2AF65 compete by binding mutually exclusive RNA structures. I also characterized a potential therapeutic approach for DM. Current data suggest that if MBNL1 is released from sequestration, disease symptoms may be alleviated. Using a targeted screen of small molecules known to bind structured nucleic acids, I identified the small molecule pentamidine as a compound that disrupted MBNL1 binding to CUG repeats in vitro . I showed in cell culture that pentamidine was able to reverse the mis-splicing of two pre-mRNAs affected in DM. Pentamidine also significantly reduced the formation of RNA foci in tissue culture cells, which are characteristic of DM. MBNL1 was released from the foci in the treated cells. Furthermore, pentamidine partially rescued splicing defects of two pre-mRNAs in mice expressing expanded CUG repeats. This dissertation includes three previously published co-authored publications.
Committee in charge: Kenneth Prehoda, Chairperson, Chemistry; J. Andrew Berglund, Advisor, Chemistry; Victoria DeRose, Member, Chemistry; Peter von Hippel, Member, Chemistry; Alice Barkan, Outside Member, Biology
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Minier, Lisa. "Evaluation de la personnalité, du coping et de la régulation émotionnelle de patients atteints de Dystrophie Myotonique de type 1 (DM1)". Thesis, Paris 10, 2019. http://faraway.parisnanterre.fr/login?URL=http://bdr.parisnanterre.fr/theses/intranet/2019/2019PA100112/2019PA100112.pdf.
Testo completoAbstract (sommario):
Le Dystrophie Myotonique de type 1 (DM1) est une maladie neuromusculaire aux atteintes multiples qui induisent notamment de l’émoussement affectif, de l’apathie, de l’hypersomnolence, de la fatigue, ainsi qu’un déficit de cognition sociale et de théorie de l’esprit. Nous avons évalué les traits de personnalité, le coping et la régulation émotionnelle de 60 patients atteints de DM1. In fine, il s’agissait de proposer, à partir de ces éléments, une prise en charge psychothérapeutique adaptée à leurs besoins. Concernant la personnalité, le résultat le plus frappant concerne la dimension N. Contrairement à ce que nous attendions (des scores élevés du fait de la maladie et de ses répercussions), les patients inclus dans notre échantillon obtiennent des scores similaires à ceux de notre groupe contrôle tout-venant. Nos résultats relatifs au coping témoignent d’une utilisation variée des 10 stratégies que nous avons évaluées. Toutefois, l’apathie et la motivation réduite ressortent comme des obstacles qui limiteraient leur mise en place pour faire face à la DM1. Enfin, l’apathie et la fatigue ne semblent pas influencer la régulation émotionnelle dans notre échantillon. De plus, la stratégie Réévaluation cognitive ne semble pas être impactée par la maladie, ce qui pourrait se révéler un atout important dans la préservation de la qualité de vie des patients malgré la progression de leurs atteintes. En termes de psychothérapie, une Thérapie Comportementale et Cognitive a été développée spécifiquement pour ces patients et apporte des résultats prometteurs. D’autres pistes de psychothérapies pourraient être intéressantes à explorer, notamment la thérapie d’acceptation et d’engagementMyotonic Dystrophy type 1 (DM1) is a neuromuscular disease with multiple impairments leading to blunted affect, apathy, hypersomnia, fatigue, social cognition deficit and theory of mind deficit. In this research, personality traits, coping, and emotion regulation of 60 DM1 patients were assessed. All this information will help us design DM1 adapted psychological care.Regarding personality, our main result is that patients show similar N scores to the healthy control group despite our expectations (high scores in relation with the severity of the disease and its complications). In the light of our coping results, it seems that DM1 patients are using a large variety of coping strategies. However, apathy and reduced motivation constitute obstacles for coping strategies. Finally, apathy and fatigue do not influence emotion regulation in our sample DM1. Furthermore, Cognitive reevaluation strategy seems preserved from the disease’s consequences. This strategy might be an important advantage in the preservation of quality of life in DM1, despite the disease progression. A DM1 specific Cognitive Behavioral Therapy showed promising results. Other psychotherapeutic approaches could be explored, namely Acceptance and Commitment Therapy
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Pinheiro, Philip Mark. "A study of RNA trinucleotide repeats involved in myotonic dystrophy". Thesis, University of Portsmouth, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286084.
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Jimenez, Moreno Aura Cecilia. "Exploring outcome measures for adults with myotonic dystrophy type 1". Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3933.
Testo completoAbstract (sommario):
Myotonic Dystrophy type 1 (DM1) is a multisystem progressive disorder with high heterogeneity. Novel emerging therapies require assessment tools that can effectively assess the effects of an intervention. The Outcome Measures in 5 Myotonic Dystrophy (OMMYD) Consortium has proposed a battery of functional outcome measures (FOM) identified as relevant for clinical trials in DM1. However, due to the variable nature of the disease and a scarcity of resources, there is a lack of systematic research that properly explores the use of these FOM. The current study examined three of these FOM and one extra related to 10 patients’ daily life performance. These are: (1) the ten-meters walk test; (2) the ten-meters walk/run test; (3) the 30-seconds sit and stand test; and, (4) a tri-axial accelerometer. By exploring the reliability, validity and responsiveness of these outcomes, we aimed to establish reference values and standard methodologies that could serve as guidance for clinical trials in DM1. A cohort of DM1 adults 15 screened for the two largest-to-date trials in DM1 (OPTIMSITIC and PHENO-DM1) were examined in relation to a set of pre-specified assessments and disease-burden scores. The results of this thesis supply disease-specific evidence of their validity, reliability and feasibility. The FOM, have shown to be psychometrically robust measures of functionality in DM1 and to be feasible for 20 clinical trials; they can provide a picture of patients’ muscle strength and perceived mobility and participation in life. The accelerometer can objectively quantify joints accelerations when walking at different speeds and summarise a DM1 patient’s habitual physical activity. The final choice of an outcome measure for a clinical trial in DM1 should be guided by disease domain that an intervention 25 is likely to impact on; but, a disease-specific study like this one will reduce the burden of protocol design whilst providing evidence supporting the decision-making process.