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Gaschen, Lorrie. "Cardiomyopathy in dystrophin-deficient hypertrophic feline muscular dystrophy /." [S.l.] : [s.n.], 1998. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Howard, Judith. "Electrodiagnostic evaluation of dystrophin-deficient hypertrophic feline muscular dystrophy /." [S.l.] : [s.n.], 2000. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Coovert, Daniel David. "Analysis of dystrophin in duchenne muscular dystrophy and SMN in spinal muscular atrophy /." The Ohio State University, 1998. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487951595500021.
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Holst, Holst. "The history of muscular dystrophy." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/27477.
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The muscular dystrophies, Duchenne muscular dystrophy being the most common type, are a group for which there is no apparent pathology to the spinal motor neurons concomitant to progressive muscular degeneration. After this fact was established during the nineteenth century through postmortem examination, Charcot divided muscular disease into the "Great Classes" of myopathy and neuropathy. Erb's study of the histopathology brought a further division between the two before death and therefore the muscle biopsy became a tool for differential diagnosis. He also discovered that the response of muscle in myopathy and neuropathy to the application of electric current differed. While the response of myopathic muscle was progressively diminishing and equally so to the application of either galvanic or alternating current, neuropathic muscle maintained its ability to contract upon the application of galvanic current during the course of the disease.
As well as the animating power of the nervous system by way of the anterior nerves, its trophic effect upon the muscle was evident by loss of volume upon interruption of its influence. Even though the absence of a lesion involving the spinal motor neurons or descending motor tracts was a constant in muscular dystrophy, there remained some reluctance to accept myopathy as being independent of the nervous system. According to the maintenance of the contractile response to galvanic current in neuropathy Erb suggested that there was a nerve centre other than that of the anterior cornua of the spinal cord which supplied the trophic influence. When he found histological features which were typical of myopathy in poliomyelitis he was convinced that muscular dystrophy was the result of a trophic disturbance. However, this theory was not sustainable because there was no anatomical evidence for a special trophic centre.
In 1970 McComas again proposed that a neurogenic phenomenon was responsible for the pathogenesis of the muscular dystrophies. It was the re-emergence of a neurogenic hypothesis for muscular dystrophy which was the purpose of my exercise. In order to answer the question as to why a trophic theory reappeared I followed the research and theory regarding muscular dystrophy over time.
The powerful effect of the somatic innervation upon muscle metabolism as determined by cross innervation experiments during the 1960's, set the stage for the reassertion of a trophic disturbance in muscular dystrophy. In addition, the division between myopathy and neuropathy had become less.distinct by 1970 in terms of histology, serum enzymes and the intramuscular innervation. Histological features considered to by typical of myopathy were seen in the biopsies of Charcot-Marie-Tooth disease and Kugelberg-Welander spinal muscular atrophy. As well, abnormally elevated serum levels of creatine phosphokinase which was characteristic of muscular dystrophy, were measured in these neuropathies. Changes in the intramuscular innervation of myotonic dystrophy and the animal model for muscular dystrophy also brought into question the myopathicity of muscular dystrophy.
By 1970 the types of muscular dystrophy had been classified according to clinical and genetic criteria and were thus known to be genetically distinct diseases. A unifying hypothesis is always desireable and therefore, mental deficiency according to clinical assessment in Duchenne and myotonic dystrophy, the latter being an "impure" dystrophy, were considered to be supportive of the neurogenic hypothesis. "Hypertrophic paraplegia of infancy of cerebral origin" was the original title of what became known as Duchenne dystrophy. The frequent occurrence of mental retardation was the foundation of the name but with knowledge concerning the profound influence of the nerve upon the metabolism of the muscle, the alleged cerebral defect in Duchenne dystrophy favoured the neuropathicity of dystrophy even more.<br>Medicine, Faculty of<br>Cellular and Physiological Sciences, Department of<br>Graduate
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Clement, E. "Congenital muscular dystrophy in 2010." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1318071/.
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Congenital Muscular Dystrophies (CMDs) are a heterogeneous group of conditions that usually present in the first months of life with weakness and hypotonia. Extramuscular manifestations are common and may include brain, skin and eye abnormalities. CMDs are relatively rare disorders and despite the major progress made over the last 2 decades in identifying, mapping and investigating these conditions, there remains a lot to be learned. Little is known about the relative frequency of the various forms of CMD in the UK population. Experience had shown that founder mutations are common in different ethnic populations and epidemiological studies performed in other countries are of limited value in this regard. Since 2001, the Dubowitz Neuromuscular Centre (DNC) has been the National Commissioning Group UK Centre for CMD. As such we are in the privileged position to have access to a large number of UK patients with CMD. I analysed a cohort of 214 CMD referrals to the DNC between 2001 and 2008 with a view to reporting the diagnostic outcome and the frequency of the various forms of CMD encountered in our patient population. The second part of the thesis is concerned with the dystroglycanopathies, a recently described group of CMDs associated with aberrant glycosylation of alpha dystroglycan. To date, 7 genes have been identified, some of which give rise to multiple dystroglycanopathy phenotypes. I studied the genotype-phenotype relationship in a large group of dystroglycanopathy patients, reporting new clinical phenotypes and establishing the mutation frequency in this group. I also report in detail the spectrum of MRI brain changes seen in 27 dystroglycanopathy patients. In summary, this work reports the diagnostic outcome in the largest cohort of UK CMD cases studied and refines the genotype-phenotype correlation in patients with dystroglycanopathies.
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Montanaro, Federica. "The role of dystroglycan in muscular dystrophy and synaptogenesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0020/NQ55361.pdf.
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Rabinowitz, Adam Howard. "Antisense therapies for Duchenne muscular dystrophy." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444590.
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Smith, T. J. "Molecular analysis of Duchenne muscular dystrophy." Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233559.
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Hodgson, Shirley V. "Genetic studies in Duchenne muscular dystrophy." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235878.
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Wakefield, Philip M. "Gene therapy for duchenne muscular dystrophy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365743.
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Bakir, Hadil. "Studies on muscular dystrophy associated genes." Thesis, Durham University, 2007. http://etheses.dur.ac.uk/2143/.
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Muscular dystrophy is a collective group of genetic disorder that results in progressive wasting of skeletal muscle. Dysferlin, the gene responsible for Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi Myopathy (MM) was found to be a member of a newly identified protein family named the ferlins. Recent work has suggested that dysferlin is necessary for efficient calcium sensitive membrane resealing therefore is involved in membrane repair, a mechanism which if defective results in progressive muscle wasting. In this project, the involvement of other genes that could possibly be associated with muscular dystrophy is investigated. Myoferlin, a member of the ferlin protein family is highly homologous to dysferlin and is also a plasma membrane protein with six C2 domains and a C-terminus transmembrane domain. To date no disease has been associated with mutations in the myoferlin gene but its high similarity to dysferlin means that it could be a potential muscular dystrophy associated gene. Results obtained from this study strongly suggest that myoferlin like dysferlin is enriched at plasma membrane disruption sites and during myoblast differentiation, two processes which involve the fusion of two opposed bilayers, a process vital in membrane repair. In addition, a fifth member of the ferlin protein family is reported in this project and the primary results obtained are consistent with it being a potential muscular dystrophy associated gene. Finally, a group of MM affected families that were previously excluded for mutations in their dysferlin gene were analysed for muscular dystrophy associated genes other than dysferlin.
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Koppaka, Sisir. "Imaging biomarkers for Duchenne muscular dystrophy." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/106959.
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Thesis: S.M., Massachusetts Institute of Technology, School of Engineering, Center for Computational Engineering, Computation for Design and Optimization Program, 2015.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (pages 75-78).<br>Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood and affects 1 in 3600 male births. The disease is caused by mutations in the dystrophin gene leading to progressive muscle weakness which ultimately results in death due to respiratory and cardiac failure. Accurate, practical, and painless tests to diagnose DMD and measure disease progression are needed in order to test the effectiveness of new therapies. Current clinical outcome measures such as the sixminute walk test and North Star Ambulatory Assessment (NSAA) can be subjective and limited by the patient's degree of effort and cannot be accurately performed in the very young or severely affected older patients. We propose the use of image-based biomarkers with suitable machine learning algorithms instead. We find that force-controlled (precise acquisition at a certain force) and force-correlated (acquisition over a force sweep) ultrasound helps to reduce variability in the imaging process. We show that there is a high degree of inter-operator and intra-operator reliability with this integrated hardware-software setup. We also discuss how other imaging biomarkers, segmentation algorithms to target specific subregions, and better machine learning techniques may provide a boost to the performance reported. Optimizing the ultrasound image acquisition process by maximizing the peak discriminatory power of the images vis-à-vis force applied at the contact force is also discussed. The techniques presented here have the potential for providing a reliable and non-invasive method to discriminate, and eventually track the progression of DMD in patients.<br>by Sisir Koppaka.<br>S.M.
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Tay, Shaun Li Jian. "Duchenne Muscular Dystrophy—Insight and Treatment." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/595055.
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Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by progressive degeneration of muscle fibers and dystrophic changes on muscle biopsy¹. DMD accounts for approximately 50% of all dystrophinopathies, with around 21,000 male babies born with the disease each year², ³, ⁴, ⁵. It is also the most lethal X-linked recessive disorder as phenotypic traits are not immediately present at birth¹¹, ³. Patients usually do not live past their 20's without medical intervention to treat associated respiratory and cardiac dysfunctions¹¹, ³. For these reasons DMD remains one of the greatest threats, amongst a range of pediatric pathologies, to the normalcy of child development and parental care. Although treatment options have shown to mitigate the progression of DMD, most are controversial and costly - the estimated annual treatment cost of DMD per patient is $50,953⁵⁸. In light of this, disease awareness and public health education are critical components for acquiring funds needed for research towards a cure¹². My hope is that through this integrated overview of DMD, the medical layman will better understand the depths of this lethal disease, and how it can be detrimental to both the affected child and his caretaker.
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Wallace, Lindsay M. "Gene Therapy for Facioscapulohumeral Muscular Dystrophy." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338315498.
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Beers, Leanne. "Living With Muscular Dystrophy: Sexual Education." ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/4908.
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Sexual pleasure and intimacy are fundamental and innate human needs. Individuals with physical disabilities often find it difficult to meet these needs because of such factors as impaired mobility and lack of knowledge about sexual health. People with physical disabilities are often seen as asexual and not capable of having sex, and sexuality is often not considered a concern among this population. These misconceptions can result in individuals with physical disabilities not receiving basic sex education or advice and guidance when issues arise. Not receiving this attention may impede disabled individuals' sexual potential and personal relationships. This study's focus was on the unique challenges individuals with muscular dystrophy (MD) face regarding sexual pleasure and intimacy. Humanistic psychology and the human rights theory provided the theoretical framework for this study. Using a qualitative multiple case study approach, 4 individuals with MD were asked what sexual education, if any, they received, and if they did receive sexual education, whether it met their needs. Data were analyzed using open and axial coding. Key findings were that there is an overarching theme of sexual silence and lack of sex education for people with MD. These findings can help inform efforts to provide more inclusive education for people with MD and individuals with other types of physical disabilities. Study findings contribute to social change by showing the importance of the need for more inclusive sexual education. Providing such education will better meet the basic human needs of an often undeserved and stigmatized population and end the silence that individuals with physical disabilities have regarding sexual health and intimacy.
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vianello, sara. "Molecular modifiers in Duchenne muscular dystrophy." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3426720.
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Duchenne muscular dystrophy (DMD) is an X-linked progressive neuromuscular disease affecting 1:3500 –1/5000 boys at birth. It is caused by the absence of dystrophin, a subsarcolemmal protein that confers membrane stability linking cytoskeletal actin to the extracellular matrix. Dystrophin is part of a multi-protein complex called dystrophin associated protein complex (DAPC), which contains, among the other components, β-dystroglycan and nitric oxide synthase (NOS). The consequences of the absence of dystrophin are: deregulation of calcium homeostasis, tissue necrosis, and progressive accumulation of fat and fibrosis and loss of contractile muscle fibers. The ensuing muscle weakness leads to progressive and severe disability, with loss of independent ambulation around the early teens, and cardiac and respiratory failure leading to patient’s death, usually around the age of 20-30 years.Despite all patients having a complete lack of dystrophin in muscle fibers, a relevant inter-patient variability in disease severity is observed (e.g. loss of ambulation may range from 8 to beyond 15 years of age). Emerging evidence points to genetic modifiers, i.e. polymorphisms in genes different form the disease gene, as one of the causes of this variability, but little is yet known about the underlying molecular mechanisms.My PhD work can be divided into 4 aims: Aim 1: To characterize the molecular mechanism underlying the modifier effect of the rs28357094 T>G SNP in the SPP1gene, encoding osteopontin (OPN) the first identified genetic modifier of DMD. I treated dystrophic and healthy cell line with two different concentrations of deflazacort (DFZ), one of the glucocorticoids mainly used to treat DMD patients, in order to analyze osteopontin expression in relation to genetic background at rs24357094. The results obtained revealed: (I) a developmental regulated expression pattern of OPN; (II) no difference of osteopontin expression are observed related to rs28357094 genotype; (III) an increase in OPN expression only in TG DFZ-treated myotubes, suggesting a possible interaction between glucocorticoid responsive elements (GRs) in the promoter of the SPP1gene and the glucocorticoid.Aim 2: To investigate the possible roles of SPP1splicing isoforms in DMDmuscle biopsies and cells. Three SPP1isoforms, named a, b and c, were analyzed. SPP1mRNA studies revealed that all three isoforms are overexpressed in DMD muscle compared to controls, but not in myogenic cell cultures. Moreover, SPP1isoforms expression was directly correlated withage in DMD patients’ muscle biopsies. Finally, muscle biopsies carrying the rs24357094 TT genotype showed an increased expression of all three SPP1isoforms compared to TG genotype.
Aim 3: To validate the known DMD geneticmodifiers in novel cohorts of DMD patients utilizing different outcome measures. First, we asked if SPP1genotype and LTBP4haplotype (the second identified modifier of DMD) can modulate the cardiac involvement in DMD. LTBP4haplotye and the SPP1rs28357094 were genotyped in 168 DMD patients. LTBP4haplotype is composed of 4 polymorphisms in perfect linkage disequilibrium (LD). The genotype at rs10880 resulted, as expected, to be associated to a delay at age of loss of ambulation (LoA) and, as novel finding, also to a delay in cardiomyopathy onset. The SPP1minor G allele at rs28357094 resulted also associated to a later cardiomyopathy onset.Finally, I participate to the identification of the third genetic modifier in DMD: CD40. CD40was identified through a GWAS approach in a large cohort of DMD patients.The CD40rs1883832 C>T polymorphism is located within the Kozak sequence of the gene and it causes a decrease of transcriptional activity of the promoter resulting in an increase of the CD40 secreted isoform. In order to validate CD40 as a genetic modifier in DMD in an independent cohort from the discovery cohort, rs1883832 was genotyped in 96 DMD patients.DMD patients carrying the minor T allele lost ambulation earlier compared to patients carrying the C allele. Moreover, in order to study the functional role of CD40 in DMD, RT-PCR and immunoblot were performed in a subset of patients’ muscle biopsies stratified according to rs1883832 genotype. Our results reveal that the minor T allele is associated to an increase of the transcript and a decrease of the protein compared to C genotype.Taken together these data contribute to clarify some aspects of the molecular mechanisms underlying the downstream consequences of genetic modifiers in DMD. Further studies are needed to fully translate the knowledge acquired in thefield of genetic modifiers in DMD to the clinic, e.g. to implement patient genotyping for genetic counseling, prognosis, planning of treatments, and stratification in clinical trials
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Laws, Nicola. "Characterisation and strategic treatment of dystrophic muscle." University of Southern Queensland, Faculty of Sciences, 2005. http://eprints.usq.edu.au/archive/00001457/.
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The mdx mouse is widely used as a model for Duchenne Muscular Dystrophy, a fatal X-linked disease caused by a deficiency of the sub-sarcolemmal protein, dystrophin. This dissertation reports characterisation of the features of dystrophy in the mdx mouse, including parameters such as electrophysiological and contractile properties of dystrophic cardiac tissue, quantitative evaluation of kyphosis throughout the mdx lifespan, and contractile properties of respiratory and paraspinal muscles. Following these characterisation studies, the efficacy of antisense oligonucleotides (AOs) to induce alternative mRNA splicing in mdx skeletal muscles (diaphragm and paraspinal muscles) was evaluated. The left atria of younger (<6 weeks) and older (>15 months) mdx mice showed consistently lower basal forces and responsiveness to increased calcium, while action potential duration was significantly shorter in young mice (3 weeks) and older mice (9 and 12 months) (P<0.05). Cardiac fibrosis increased with age in mdx atria and ventricles and was elevated in young (6-8 weeks) and old (15 months) mdx compared to control mice (P<0.01). This study provided insights into DMD cardiomyopathy, and suggested that very young or old mdx mice provide the most useful models. Mdx mice show thoracolumbar kyphosis like boys with Duchenne Muscular Dystrophy. A novel radiographic index, the Kyphotic Index (KI), was developed and showed that mdx mice are significantly more kyphotic from 9 months of age, an effect maintained until 17 months (P<0.05). At 17 months, the paraspinal and respiratory muscles (latissimus dorsi, diaphragm and intercostal muscles) are significantly weaker and more fibrotic (P<0.05). Administration of AOs at four sites within the diaphragm at 4 and 5 months of age significantly increased twitch and tetanic forces compared to sham treated mdx (P<0.05). However, no difference in collagen was evident and dystrophin was not detected, possibly due to the low concentration of AO utilised. This study suggested that AOs can provide functional improvement in treated skeletal muscles. Monthly injections with AOs into the paraspinal muscles from 2 months to 18 months of age alleviated kyphosis, without significantly altering twitch and tetanic forces of latissimus dorsi, diaphragm and intercostal muscles. There was evidence of less fibrosis in diaphragm and latissimus dorsi muscles (P<0.05) and reduced central nucleation of the latissimus dorsi and intercostal muscles (P<0.05). Again, dystrophin was not detected by immunoblot. These studies indicate that very young and old mdx mice display previously uncharacterised dystrophic features, and are useful models for testing new therapies such as AOs. Low doses of AOs were shown to be safe and efficacious for long-term use, however there remains a need for testing higher concentrations and improved delivery strategies.
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Anderson, Jennifer Louise Medical Sciences Faculty of Medicine UNSW. "Cerebellar synaptic plasticity in two animal models of muscular dystrophy." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/43524.
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Duchenne muscular dystrophy (DMD) and congenital muscular dystrophy 1A (MDC1A) are the two most common forms of muscular dystrophy in humans, caused by mutations in dystrophin and laminin α2 genes respectively. Both are severe forms of the disease that lead to premature death due and are both now known to have a significant effect on the central nervous system. This project investigated the role of both proteins involved in each of these diseases in cerebellar Purkinje cells of two murine models of disease: the mdx mouse a dystrophin-deficient model of DMD and the dy2J a laminin α2-deficient murine model of MDC1A. In the case of dystrophin further studies were undertaken in order to determine if increasing age had any effects on cerebellar function. It was found that there is no difference in electrophysiological characteristics (RMP, IR, eEPSP) of the cells when compared to appropriate control groups, nor was there any difference when young and aged dystrophin-deficient mdx groups were compared. Evoked IPSP characteristics were examined in young mdx cerebellar Purkinje cells and again no difference was found when compared to wildtype. There was a significant difference in response to the GABAA antagonist bicuculline, with wildtype increasing eEPSP amplitude by almost double that found in mdx. There was no difference in short term plasticity as measured by paired pulse facilitation in any of these groups. There was no difference in paired pulse depression at the inhibitory interneuron- Purkinje cell synapse of young wildtype and mdx cerebellar Purkinje cells. There a significant blunting of long term depression (LTD, (a form of long term synaptic plasticity) between young wildtype and mdx. When young wildtype animals were compared to aged wildtype animals LTD was found to be similar, when young mdx was compared to aged mdx, there was a recovery of LTD seen in the aged population. There was also significant differences in LTD found when littermate controls were compared to dy2J (laminin α2 mutants). A third of the phenotypic animals (dy2J) potentiated. Finally when rebound potentiation (a GABA-ergic form of long term synaptic plasticity in the cerebellum) was compared in young wildtype and mdx mice, mdx mice displayed depression, rather than the expected potentiation in contrast to potentiation (or no change) as seen in all wildtype cells.
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Abmayr, Simone. "Gene therapy for muscular dystrophy using secondary modifiers of the dystrophic phenotype." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=973452595.
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Judge, Luke Milburn. "Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex in skeletal muscle /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/4989.
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Kim, Jihee. "Evaluating pathogenesis in FKRP related muscular dystrophy." Thesis, Royal Veterinary College (University of London), 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.731277.
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Brais, Bernard. "Oculopharyngeal muscular dystrophy : from phenotype to genotype." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0002/NQ44369.pdf.
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Smith, Philip E. M. "Breathing during sleep in Duchenne muscular dystrophy." Thesis, University of Liverpool, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235539.
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Babaria, Arati. "Molecular Mechanisms that Underlie Duchenne Muscular Dystrophy." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/612573.
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Duchenne muscular dystrophy is an inherited, X-linked recessive skeletal muscle disorder that is characterized by mutations in the dystrophin gene [1]. Therefore, the disease affects primarily males and women are typically carriers. 1 in 3500 males in the United States are affected [1]. Dystrophin is a critical, large scaffolding protein in the dystrophin-glycoprotein complex found at the sarcolemma of skeletal muscle [1]. The complex helps maintain sarcolemma integrity and stability during muscle contractions by coupling the extracellular matrix proteins to the intracellular cytoskeleton in skeletal muscle [1]. Loss-of-function mutations in the dystrophin protein affect all skeletal muscle found throughout the human body. The 427 kD protein is also present in cardiac muscle, the brain, and peripheral nerves, thus affecting these tissues over time, as well [1]. One theory suggests the weakened stability of the dystrophin-glycoprotein complex when dystrophin is not expressed results in transient membrane tears during contraction, which permit pathological calcium influx [1]. Damaged skeletal muscle results in repair and regeneration of the tissue however, continual damage over time (referred to as muscle wasting) results in extensive fibrosis and loss of muscle fibers. The purpose of this thesis is to provide a comprehensive review on several molecular mechanisms that underlie Duchenne muscular dystrophy and to investigate current treatments and propose potential therapeutic targets for future research.
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Skyrme, Sarah Louise. "Research decisions : living with Duchenne muscular dystrophy." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2678.
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Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy that affects males. Muscle deterioration leads to increasing levels of disability during childhood and adolescence, with death commonly occurring in the late teens or early twenties, although changes in care and treatment are leading to increasing numbers of boys with DMD living into adulthood. Parents and parent-led charities are raising funds to find effective treatments and a cure, and much of the medical research they promote requires the participation of those with DMD. This raises questions about children and young people’s involvement in research, including their role and approach to consent and how willing they are to be involved in the medical research their parents and DMD charities advocate. Through qualitative interviews with nine boys and young men with DMD and one young woman with muscular dystrophy, I explored their thoughts on medical research and the broader issue of how they live and cope with their condition. As part of this discussion I examined how they might make a decision to participate in medical research, focusing on the processes, interactions and individuals they consider important in helping them to decide. My approach privileges the participants’ thoughts and opinions, positioning them as able social actors (James & Prout 1997) who can provide insight into their experiences. Currently little is known about the lives of children and young people with a significant, degenerative disability, particularly around their thoughts on medical research participation and decision-making (Dixon-Woods 2006). The views of my participants provide the basis for this research, with work from the sociology of childhood and from disability studies informing and contextualising it. The way in which parents are involved in daily life is discussed to gain an understanding of how the participants work with those they trust. This relationship may provide understandings of how decisions are influenced by family input and how support assists those who are young and have a degenerative condition. It is possible that this model of working with the significant people in their lives promotes agency and independence, aiding the participants towards, rather than away from autonomy.
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Pearce, Marcela. "Genomic structure of the human utrophin gene." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318897.
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Reza, Mojgan. "Engineering and optimisation of mini-dystrophin constructs for Duchenne muscular dystrophy gene therapy." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2827.
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Muscular dystrophies (MDs) are inherited disorders characterised by muscle weakness and atrophy. One of the most severe forms is Duchenne muscular dystrophy (DMD) which together with the milder allelic form Becker muscular dystrophy (BMD) are known as the dystrophinopathies and result from defects in the X-linked gene encoding dystrophin. Dystrophin is a structural protein of the muscle that connects the internal cytoskeleton of muscle fibres to the extracellular matrix. DMD is also amongst the most common forms of muscular dystrophy, affecting ~1 in 4000 live male birth and manifests as rapidly progressive muscle degeneration leading to loss of ambulation and death in the second or third decade from respiratory or cardiac failure. Currently, there is no cure for this devastating disease. Clinical management of symptoms and complications is limited to stabilising the condition, slowing deterioration over time and palliative care. Since discovery of the DMD gene in 1986, researchers have dedicated substantial effort into vector technologies, facilitating the use of gene therapy to reintroduce a functional copy of the dystrophin gene into muscle fibres, a potential approach to treat DMD patients. However, this approach poses additional challenges relative to many gene therapy approaches since the full-length dystrophin cDNA is ~14 kb, exceeding the packaging capacity of most viral vectors. A number of large internal in-frame dystrophin deletions have been identified in patients that produce a relatively mild phenotype with later age of onset and a slower rate of disease progression than classical DMD. This observation has inspired the construction of internally truncated, but largely functional versions of dystrophin suitable for gene transfer using viral vectors. So far the most widely used miniaturised dystrophin transgenes have been tested in AAV-mediated gene delivery which has identified several limitations indicating the use of more favourable transgenes that have smaller deletions, yet carrying more functional parts of dystrophin. In this study human mini-dystrophin constructs of 4.3-7.7 kb in size were designed that retain key functional elements of dystrophin molecule and their relative functionality investigated in mdx mice. The ultimate aim of this study is the characterisation and optimisation of these mini-dystrophin constructs for gene delivery studies via viral vectors as a therapeutic tool for treatment of Duchenne muscular dystrophy.
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Woolf, Peter James. "Cardiac calcium handling in the mouse model of Duchenne Muscular Dystrophy." University of Southern Queensland, Faculty of Sciences, 2003. http://eprints.usq.edu.au/archive/00001525/.
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The dystrophinopathies are a group of disorders characterised by cellular absence of the membrane stabilising protein, dystrophin. Duchenne muscular dystrophy is the most severe disorder clinically. The deficiency of dystrophin, in the muscular dystrophy X-linked (mdx) mouse causes an elevation in intracellular calcium in cardiac myocytes. Potential mechanisms contributing to increased calcium include enhanced influx, sarcoplasmic reticular calcium release and\or reduced sequestration or sarcolemmal efflux. This dissertation examined the potential mechanisms that may contribute to an intracellular calcium overload in a murine model of muscular dystrophy. The general cardiomyopathy of the mdx myocardium was evident, with the left atria from mdx consistently producing less force than control atria. This was associated with delayed relaxation. The role of the L-type calcium channels mediating influx was initially investigated. Dihydropyridines had a lower potency in contracting left atria corresponding to a redued dihydropyridine receptor affinity in radioligand binding studies of mdx ventricular homogenates (P<0.05). This was associated with increased ventricular dihydropyridine receptor protein and mRNA levels (P<0.05). The function of the sarcoplasmic reticulum in terms of release and also sequestration of calcium via the sarco-endoplasmic reticulum ATPase were investigated. A lower force of contraction was evident in mdx left atria in response to a range of stimulation frequencies (P<0.05) and concentrations of extracellular calcium (P<0.05). However, in the presence of 1 nM Ryanodine to block sarcoplasmic reticular calcium release, increased stimulation frequency caused similar forces to those obtained in control mice suggesting enhanced calcium influx via L-type calcium channels in mdx. Rapid cooling contractures showed a reduced contracture in mdx compared to control in response to cooling. This suggests some dysfunction in SR storage, which may be associated with the delayed relaxation time. Concentration-response curves to inhibitors of the sarco-endoplasmic reticulum showed no difference in function of the enzyme responsible for calcium uptake into the sarcoplasmic reticulum. Although sarco-endoplasmic reticulum ATPase mRNA was upregulated, no functional benefit was evident. This study indicates that a deficiency of dystrophin leads to upregulation of L-type calcium channels that contribute to increased calcium influx, with no functional change in sarcoplasmic reticular sequestration. Upregulation of the influx pathway is a potential mechanism for the calcium overload observed in mdx cardiac muscle.
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Cockburn, David James. "Analysis of DMD translocations." Thesis, University of Oxford, 1991. http://ora.ox.ac.uk/objects/uuid:ab53825b-b18e-4f60-954a-4ea9e0435126.
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Duchenne and Becker muscular dystrophies (DMD, BMD) are allelic X-linked diseases which affect approximately one in 3500 male newborns. They are caused by mutations in a gene positioned on the short arm of the X chromosome at Xp21. The first indication of the location of this gene was the description of rare females expressing DMD and who were found to have constitutional X;autosome translocations with an X chromosome breakpoint at this site. There are now 24 such females known worldwide. They express DMD as a consequence of preferential inactivation of the normal X chromosome. In order to contribute to the understanding of the aetiology of mutations causing DMD and the aetiology of constitutional translocations, two types of study have been performed here. Firstly, the detailed mapping of the X chromosome breakpoints of DMD-associated X;autosome translocations has been investigated. The results of this study have been compared with data on the physical distribution of mutations causing DMD in male patients. Secondly, one translocation, an X;l translocation with an autosomal breakpoint at Ip34, has been selected for more detailed investigation and the DNA sequence has been determined at the site of the rearrangement. Translocation breakpoint mapping studies were performed by somatic cell hybrid analysis. Hybrids were karyotyped and this information was used to construct a hybrid panel for the purpose of determining the autosomal localisations of anonymous DNA probes. The mapping of seven probes using this panel is described. The work described in this thesis revealed that the distribution of translocation breakpoints within the DMD gene appears to be random and may differ from the distribution of mutations in male patients. The X;l translocation whose breakpoints are cloned and sequenced was found to involve two expressed loci, one coding for dystrophin on the X chromosome and one for the leukocyte antigen related protein on chromosome 1. Sequence data revealed that a deletion of four to seven nucleotides from the X chromosome and a duplication of two to five nucleotides are associated with the translocation. The possible involvement of trinucleotides adjacent to the breakpoints, and of a LINE, a SINE and a stretch of potential Z-DNA within 1 kb of the X chromosome or the chromosome 1 breakpoint, is discussed.
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Dunant, Patrick. "Strategies for Molecular Therapy of Duchenne Muscular Dystrophy." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-12429.
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Longman, Cheryl Amanda. "Clinical and molecular studies of congenital muscular dystrophy." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423211.
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Weiler, Tracey. "Limb girdle muscular dystrophy in unique Manitoba populations." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ62676.pdf.
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Bia, Britta Lydia. "Cardiomyopathy in mouse models of Duchenne muscular dystrophy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301799.
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Clapp, Jannine. "Investigating the molecular genetics of FSH muscular dystrophy." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435765.
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Bolland, Daniel J. "Comparative mapping of the FSH muscular dystrophy region." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394920.
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Chang, C. F. "Studies of muscle regeneration in avian muscular dystrophy." Thesis, Imperial College London, 1987. http://hdl.handle.net/10044/1/38258.
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Crisp, Edmund Alastair D. "Heart function in mouse models of muscular dystrophy." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:b0dedd86-00d8-4f89-a197-3b78ab989524.
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Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused, in most cases, by the complete absence of the 427 kD cytoskeletal protein, dystrophin. Without dystrophin, the dystrophin-associated protein complex (DAPC) does not form and the plasma membrane is destabilised. There is no effective treatment and affected individuals die from respiratory failure and cardiomyopathy by age 30. This thesis describes experiments in which in vivo cardiac function was measured using non-invasive magnetic resonance imaging in a number of mouse models relevant to muscular dystrophy. As syncoilin forms a link from the DAPC to the cytoskeleton, it was postulated in Chapter 3 that the syncoilin knockout mouse would have cardiac defects similar to those caused by the loss of dystrophin. However, the loss of syncoilin did not alter the protein levels of its binding partners, measured by western blotting, and caused no defect in heart function or structure, measured using histological staining. Similarly, in Chapter 4, a mouse with a mutation in the transient receptor potential channel canonical type 3 (TRPC3), a receptor/stretch-activated cation channel thought to be involved in the pathogenesis of DMD, was found to have no functional or morphological cardiac defect. In the mdx mouse, a mouse model of DMD that lacks dystrophin, cardiomyopathy was prevented by either increasing levels of the dystrophin related protein, utrophin, or of dystrophin, in the diaphragm, which thereby restored diaphragm function. In Chapter 5 it was found that in a transgenic mdx mouse in which utrophin was over-expressed in skeletal muscle and diaphragm, but not in the heart, cardiac function was restored to wild-type levels. However, histologically the transgenic heart showed more fibrosis and immune cell infiltration than that of untreated mdx controls. In Chapter 6 it was found that in mdx mice treated with a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), that resulted in high dystrophin restoration in skeletal muscle and diaphragm only, cardiac function was also restored to wild-type levels. In Chapter 6 it was also found that in dystrophin/utrophin-deficient double-knockout (dKO) mice, a more severely affected animal model of DMD, treatment with a PPMO again produced high levels of dystrophin only in skeletal muscle and diaphragm, and once more restored cardiac function to wild-type levels. In the dKO mouse, there was no difference in heart function between treatment of the diaphragm plus the heart and treatment of the diaphragm alone. Restoration of diaphragm and other respiratory muscle function, irrespective of the method used, was sufficient to prevent cardiomyopathy in dystrophic mice. The novel mechanism of treating respiratory muscles to prevent cardiomyopathy in dystrophic mice has implications for the study of heart function in the current DMD mouse models and suggests a new approach to treatment.
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Winnard, Alissa Vira. "Exception patients in Duchenne and Becker muscular dystrophy /." The Ohio State University, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487847309050842.
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Meredith, Christopher. "Molecular genetic investigation of autosomal dominant muscular dystrophy." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2001. https://ro.ecu.edu.au/theses/1509.
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This thesis contributes to the Human Genome Project by adding detail to the physical and genetic maps of the human genome, and by identifying a strong candidate gene for a form of distal myopathy. Genomic clones for the human skeletal muscle genes slow troponin (TNN/1), alpha actin (ACTA1), and (3-tropomyosin (TPM2) were isolated for use in the fluorescent in situ hybridisation localisation of these genes on the cytogenetic map of the human genome. The localisation of these genes made them potential candidates for inherited skeletal muscle diseases, including the muscular dystrophies investigated here. Microsatellite, VNTR and RFLP markers were used in a search for linkage to a novel form of distal myopathy segregating in a Western Australian family. The decadic logarithm of the likelihood ratio, or 'lod score' method, was used to determine linkage between markers and this distal myopathy gene. A 22.4 cM candidate region was identified at 14q11.2. This was the first localisation of a distal myopathy gene. The Human Genome Organisation Nomenclature Committee reserved MPD1, 'myopathy, distal 1 ', for this form of distal myopathy, now known as Laing myopathy. The MPD1 candidate region was excluded as the disease gene location for two other forms of distal myopathy. Silburn myopathy in 1994, which established the genetic heterogeneity of distal myopathy, and Felice myopathy in 1996. The exclusion of the MPD1 and French-Canadian OPMD candidate regions as disease gene locations for a putative-OPMD segregating in a Western Australian family, proved that this disease gene did not lie at 14q11.2. Testing an MPD1 muscle-specific candidate gene for the Laing myopathy mutation, the myosin heavy polypeptide 7 gene (MYH7), identified seven base changes between the MPD1 proband sequence and the published MYH7 eDNA sequence. All of these base changes were found in eight unrelated, unaffected Western Australians, therefore none of them were the Laing myopathy mutation. Two further differences to the published MYH7 sequence segregated exclusively with the MPD1 proband. One of these, the MYH7 G5073C (cDNA)/G23628C (gDNA) base change, caused a critical change to the MYH7 13-myosin heavy chain polypeptide product (13-MyHC). An A 1663P 13-MyHC substitution. G23628/C 23628 segregated with Laing myopathy in the Western Australian distal myopathy family. This segregation was confirmed by a single-strand conformation polymorphism test, then used to test 256 unaffected chromosomes. None possessed MYH7C23628. Two patients from European distal myopathy families phenotypically similar to Laing myopathy, the Voit and Scoppetta families, were tested for the presence of MYH7 gDNA G23628/C23628 heterozygosity. Both were homozygous MYH7 G23628. One of these patients (Voit) was also tested for MYH7 eDNA G5073/C5073 heterozygosity. She was homozygous MYH7 G5073. An analysis of the effect of the 13-MyHC A 1663P substitution at various levels of protein structure strengthened the candidature of MYH7 G5073C as the Laing myopathy mutation. It demonstrated the extreme rarity of the 13-MyHC A 1663P substitution; it showed that this substitution did have a detrimental effect on coiled-coil formation; and it identified ways in which the 13-MyHC A 1663P substitution could disrupt myofibrillogenesis or contractility. Future research directions are identified and the contribution of this work to evolving concepts in muscular dystrophy is evaluated.
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Fusto, Aurora. "Genetic and clinical modifiers in Duchenne muscular dystrophy." Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3423193.
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La distrofia muscolare di Duchenne (DMD) è una malattia neuromuscolare causata da mutazioni del gene codificante per la distrofina (DMD) che ne impediscono la produzione. Sebbene tutti i pazienti affetti da DMD condividano lo stesso difetto biochimico di distofina, a livello fenotipico è osservabile una grande varietà in termini di progressione della malattia, ad esempio nell'età di perdita della deambulazione o nell'età di insorgenza di complicanze cardiache e respiratorie. Questa variabilità è dovuta a diversi fattori, alcuni di origine ambientale (ad esempio la qualità delle cure a cui hanno accesso i malati) e altri di natura genetica, suddivisibili in cis-acting, ossia l'effetto dei diversi tipi di mutazioni nel gene DMD sul fenotipo, e trans-acting, ovvero l'effetto di SNPs modificatori sul fenotipo. Questi ultimi sono polimorfismi in geni diversi da quello causativo della malattia, che hanno però un effetto sul suo fenotipo. Usando come outcome la perdita della deambulazione sono stati individuati numerosi SNPs modificatori, quali: rs28359074 in SPP1, rs2303729, rs1131620, rs1051303 e rs10880 in LTBP4, rs1883832 e rs6074022 in CD40, rs1815739 in ACTN3, rs2725797 and rs2624259 in THBS1.
L'obiettivo del mio percorso di dottorato è stato lo studio della variabilità genetica e clinica nella distrofia muscolare di Duchenne, conducendo indagini in vitro e studi osservazionali retrospettivi.
Il primo approccio è stato utilizzato per verificare l'interazione dello SNP modificatore rs28357094 nel gene SPP1, codificante la proteina osteopontina (OPN), e il trattamento farmacologico con glucocorticoidi (nello specifico deflazacort) in mioblasti e miotubi primari derivati da controlli sani e da pazienti DMD. Lo studio ha messo in evidenza che l'osteopontina è sovraespressa in miotubi con genotipo TG per lo SNP rs28357094, rispetto a TT. Inoltre, è stato rilevato che il trattamento con Deflazacort induce l'aumento della produzione di OPN solo nei miotubi con genotipo TG. Questi risultati hanno confermato l'interazione tra il modificatore genetico e il trattamento con glucocorticoidi, sottolineando l'importanza del genotipo di rs28357094 nella risposta al trattamento farmacologico nei pazienti DMD.
Successivamente, il nostro interesse si è rivolto allo studio dell'effetto non solo degli SNPs modificatori, ma anche dell'effetto delle diverse mutazioni nel gene della distrofina (DMD) e del trattamento farmacologico sul decorso della malattia nei pazienti DMD, focalizzando la nostra attenzione su diversi aspetti fenotipici, quali: la performance degli arti superiori, la funzione respiratoria e cardiaca. L'obiettivo di questi studi, resi possibili dalla collaborazione di numerosi centri italiani nella raccolta dei dati clinici, è stato quello di evidenziare potenziali nuovi target terapeutici e di fornire importanti informazioni per la stratificazione dei pazienti nel corso dei trial clinici.
Il nostro lavoro ha permesso di confermare l'influenza di alcuni degli SNPs, noti per il loro effetto sulla perdita della deambulazione, anche su altri parametri clinici consentendoci di identificare misure di efficacia clinica nella DMD. E' stato poi possibile documentare l'effetto protettivo del trattamento con glucocorticoidi anche su aspetti della malattia non strettamente correlati alla deambulazione, come la funzionalità respiratoria e cardiaca e dimostrare come alcune mutazioni nel gene DMD abbiano effetti diversi sull'espressione del fenotipo dei pazienti.
Infine, il mio interesse si è rivolto al modelling di malattie neuromuscolari in sistemi di coltura tridimensionali, con lo scopo di far luce sui meccanismi molecolari causativi e fornire piattaforme utili per la ricerca e il test di molecole con azione farmacologica.<br>Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by out-of-frame mutations in the DMD gene resulting in the lack of dystrophin in skeletal muscle fibres. Even though all DMD patients share the same molecular defect, it is possible to observe high variability in the disease's progression, i.e. differences in loss of ambulation age, onset of respiratory and cardiac failure.
This variability is due both to environmental and genetic factors. Genetic factors may be divided in cis-acting, nominally the type of DMD mutation, and trans-acting, or modifier SNPs. These are polymorphisms in genes, different from the causative DMD, that have and effect on the phenotype. There are several modifier SNPs known to alter age at loss of ambulation. These are: rs28359074 in SPP1, rs2303729, rs1131620, rs1051303 e rs10880 in LTBP4, rs1883832 e rs6074022 in CD40, rs1815739 in ACTN3, rs2725797 e rs2624259 in THBS1.
The main goal of my PhD was the study of clinical and genetic variability in DMD, through in vitro and observational retrospective studies.
We carried an in vitro research to verify the interaction of rs28357094 in SPP1, that codifies for osteopontin (OPN), and glucocorticoids treatment (Deflazacort) in primary myoblasts and myotubes derived from healthy individuals and DMD patients. We found that OPN is overexpressed in rs28357094 TG genotype myotubes, compare to TT genotype. Moreover, deflazacort treatment induces an increase in OPN production in TG myotubes. These results confirmed the interaction between rs28357094 and glucocorticoids treatment.
Afterwards, we studied the effect of the known modifiers, on multiple phenotypic aspects: upper limbs performance, respiratory and cardiac function. These analyses had been made possible thanks to the collaboration in the data collection phase of several Italian centres. Our goals were to find new potential therapeutic targets and to provide information useful for patients stratification in clinical trials.
We were able to confirm the effect of some SNPs, known to be modifier of age at loss of ambulation, on diverse outcomes measures as performance of upper limbs, respiratory and cardiac function. Furthermore, we assess the protective effect of glucocorticoids treatments on diseases aspects other than ambulation, and provide new information about the correlation between DMD mutations and phenotype severity.
Finally, I switched my interest to three-dimensional modelling of neuromuscular diseases, aiming to clarify pathological mechanisms and provide a versatile platform for drug screening and test.
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Dutton, Anna Louise. "An investigation into the effects of dystrophin on the lateral mobility of muscle membrane components." Thesis, Durham University, 1999. http://etheses.dur.ac.uk/4576/.
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Dystrophin is the product of the Duchenne Muscular Dystrophy gene locus, whose absence results in progressive skeletal muscle breakdown. Despite considerable work on the localisation of dystrophin and its associated complex, its role in muscle function remains unclear. In the light of the structural and mechanical instability of the dystrophic membrane, the idea was tested that dystrophin might impart membrane integrity and strength by anchoring membrane proteins and/or delineating the surface into specialised subcellular functional domains. Specifically, because dystrophin shows high sequence, structural and spatial similarities to the cytoskeletal protein spectrin; and because spectrin is proven to sterically restrict protein lateral diffusion through a subplasmalemmal network; the capacity of dystrophin to act as a 'molecular fence' to membrane diffusion was studied by comparing lateral mobility of membrane glycoproteins by fluorescence photobleach recovery in mdx and normal tissue. Secondly, as dystrophin has been proven to interact directly with proteins of the dystrophin associated glycoprotein complex in vivo, experiments addressed whether specific binding and immobilisation of the complex by dystrophin at the membrane was essential for function. Finally, given the homology of dystrophin and spectrin, the presence of dystrophin at the neuromuscular junction, and the importance of spectrins in immobilisation of voltage gated sodium channels in the nervous system, the role of dystrophin in regulating voltage gated sodium channel distribution at the neuromuscular junction was investigated. The results show that membrane glycoproteins were immobile in the presence and absence of dystrophin, suggesting dystrophin is not an essential molecular fence component. Alternatively, viability may have been the major influence on protein and lipid diffusion in these fibres and suggestions are made as to how this may be recognised and overcome for subsequent investigation. Three novel exon specific anti-dystrophin peptide antibodies were generated during the work that will be useful for studies into Duchenne muscular dystrophy in general, and dystrophin revertant fibres in particular.
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Lekan, Jaimy Marie. "Exercise-induced mechanisms of muscle adaptation in mdx mice." The Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1095372379.
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Johnson, Eric K. "A new model for the dystrophin associated protein complex in striated muscles." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354554580.
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Kaspar, Rita Wen. "Genotype-Phenotype Association Analysis of Dilated Cardiomyopathy in Becker Muscular Dystrophy." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243469474.
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Messaed, Christiane. "Investigation of molecular mechanisms underlying Oculopharyngeal Muscular Dystrophy (OPMD)." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111879.
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Oculopharyngeal Muscular Dystrophy (OPMD) is a late-onset dominant/recessive myopathy caused by the expansion of a polyalanine repeat in exon 1 of the PABPN1 gene. The expression of expanded PABPN1 (expPABPN1) triggers the formation of insoluble nuclear aggregates within muscle fiber nuclei of OPMD patients. These aggregates are enriched in poly(A)RNA and sequester molecular chaperones, ubiquitin and proteasome subunits. In addition to these cellular components, we first identified two novel PABPN1 interacting partners, hnRNPA1 and hnRNPA/B that also localized to the insoluble expPABPN1 aggregates. However, only hnRNPA1 was observed in inclusions of OPMD patients' muscle fiber nuclei. Following this finding, we next established the involvement of the ubiquitin-proteasome pathway in the clearance of misfolded expPABPN1 and provided more insights into the beneficial role of molecular chaperones in OPMD. The inhibition of proteasome correlated with an increase in the aggregation of expPABPN1, suggesting a possible proteasome impairment in OPMD. Conversely, the overexpression of Hsp70 and Hsp40 coincided with a decrease in nuclear aggregates concomitant with a reduced cellular toxicity, suggesting the therapeutic potential of manipulating molecular chaperones levels. Finally, we demonstrated that soluble forms of expPABPN1 are the primary toxic species in OPMD. In the presence of endogenous HSPs, a decrease in expPABPN1 aggregation correlated with an increased cellular toxicity. A defect in polyadenylation or ubiquitination significantly increased expPABPN1 solubility and cell death. Using live-cell imaging, we observed that nuclear aggregates prolonged the survival of expPABPN1-expressing cells, which led us to speculate that protein aggregates are subnuclear structures that preserve cellular homeostasis by depleting the expPABPN1 from the nuclear soluble pool. We propose that the polyalanine expansion in expPABPN1 could enable aberrant protein-protein interactions that would compromise the cellular function of nuclear factors and the expression of genes essential for muscle integrity and differentiation. For instance, expPABPN1 might compromise the function of hnRNP proteins and lead to altered mRNA processing and nucleocytoplasmic export, which can be detrimental to the cell.
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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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Fair, Jeanette L. "Effects of compensatory hypertrophy on dystrophic (Bio 14.6) hamster muscle : changes in collagen and myofibrillar protein content." Virtual Press, 1987. http://liblink.bsu.edu/uhtbin/catkey/494971.
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Compensatory hypertrophy was induced on the plantaris (PL) and soleus (SOL) muscles of five week old normal and dystrophic (strain 14.6) hamsters. This was done to indicate whether submaximal exercise would be beneficial in reducing the progression of the muscular dystrophy (i.e., by causing muscle hypertrophy, reducing the total collagen content, and increasing the total protein content of the diseased muscle to approximate that of normal tissue).The hamsters were divided into four groups: 1) dystrophic overload (DO), 2) dystrophic control (DC), 3) normal overload (NO), and 4) normal control (NC). Eight weeks of overload of the PL and SOL muscles was induced by surgical ablation of the synergistic gastrocnemius muscle. Muscle wet weight data indicated significant muscle hypertrophy of 125% and 92% in the NO and DO PL respectively, and 60% in the NO SOL. Dry muscle weight data was comparable to the above results. There was no significant difference in the muscle collagen content between the NC and DC groups. Collagen content increased significantly in the NO and DO PL by 81% and 41% respectively, and in the NO and DO SOL by 127% and 57% respectively. The DC muscle was significantly lower in protein content than the NC muscle (180.2mg/g and 210.1 mg/g respectively) when expressed per g of wet muscle weight. This significance disappears when expressed per g dry muscle weight. The overload caused a significant decrease in the protein content of only the NO group when expressed by both wet and dry tissue weights (171.7mg/g and 678.3mg/g rrespectively). The hydration of the DC group was significantly higher than the NC group. The overload resulted in a significant increase in the water content of only the NO muscle.The results of this study indicate that dystrophic muscle will hypertrophy as indicated by muscle weight data. However, the significance of the data from the total collagen and total protein determination of the overload groups was inconclusive due to the formation of scar tissue. This scar tissue resulted in high collagen content. The high glycine content in this collagen in turn resulted in low protein values.
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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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Harris, Sarah Elizabeth. "Expression and functional analysis of the transcription factor DMAHP." Thesis, University of Glasgow, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284736.
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Betts, Corinne A. "Exon skipping peptide-pmos for correction of dystrophin in mouse models of duchenne muscular dystrophy." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:545d586a-ad7b-4089-8537-b2677957b874.
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Duchenne muscular dystrophy (DMD) is a fatal, muscle-wasting disorder due to mutations/deletions in the dystrophin gene. Whilst improvements in palliative care have increased the life expectancy of patients, cardiomyopathy and respiratory complications are still the leading causes of death. A potential therapy for the treatment of DMD is antisense oligonucleotides (AOs), which modulate dystrophin pre-mRNA splicing to restore the dystrophin reading frame and generate a truncated functional protein. Conjugation of AOs to cell penetrating peptides (CPP), such as Pip5e-, significantly improves delivery to skeletal muscles and to the heart, which is imperative given the impact of cardiomyopathy to mortality. However, it should be noted that the contribution of skeletal muscles, such as the core respiratory muscle, the diaphragm, in dystrophic cardiopulmonary function is poorly understood. The specific aims of the work in this thesis were to (i) understand the effect of the diaphragm on cardiac function using magnetic resonance imaging (MRI), (ii) screen a number of derivatives of Pip5e (Pip6) in an effort to discover further promising peptides and define the properties integral to heart penetrating capacity, and (iii) assess whether Pip6-PMOs restore cardiac function (MRI) following a repeat, low dose regimen. In short, the specific restoration of dystrophin in the diaphragm of the dystrophic mouse model, the mdx mouse, did not improve cardiac function, highlighting the importance of a body-wide therapy. The screening of multiple Pip5e-PMO derivatives revealed 3 promising peptides with improved cardiac splicing capacity; however, serial deletions of amino acids from the central core resulted in the diminution of dystrophin restoration, possibly due to a reduction in hydrophobicity. Finally, the Pip6-PMO treatment regimen substantially restored dystrophin protein (28% in heart) and stabilised cardiac function, even with an increased work load. In conclusion, this study illustrates the importance of a body-wide treatment, such as the CPP strategy (Pip-PMO). These Pip-PMO conjugates demonstrate high dystrophin restoration in a number of muscles, including cardiac muscle, and have a beneficial effect on cardiac function.