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.

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 141-160). Also issued on the Internet.

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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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.

Wearable robotics for assistance and rehabilitation are not yet considered commercially mainstream products, and as a result have not yet seen advanced controls systems and interfaces. Consequently, the available technology is mostly adapted from systems used in parallel technologies, rather than custom applications intended for human use. This study concerns itself with the design and development of a custom control system for a 2-degree of freedom powered upper extremity orthosis capable of driving elbow flexion/extension 135º and humeral rotation 95º . The orthosis has been evaluated for use as both a long-term assistive technology device for persons with disabilities, and as a short-term rehabilitative tool for persons recovering injury. The target demographics for such a device vary in age, cognitive ability and physical function, thus requiring several input parameters requiring consideration. This study includes a full evaluation of the potential users of the device, as well as parameter considerations that are required during the design phase. The final control system is capable of driving each DOF independently or simultaneously, for a more realistic and natural coupled-motion, with proportional control by pulse-width modulation. The dual-axis joystick interface wirelessly transmits to the 1.21 pound control pack which houses a custom microcontroller-driven PCB and 1800 milliamp-hour lithium-ion rechargeable battery capable of delivering 4 hours of running time. Upon integration with the 2 DOF orthosis device, a user may complete full range of motion with up to 5 pounds in their hand in less than 7 seconds, providing full functionality to complete acts of daily living, thus improving quality of life.