Information

Molecular analysis of neuromuscular and neurological disorders

Kay E Davies MA DPhil FRCPath FMedSci CBE FRS
Dr Lee's Professor of Anatomy and Co-Director of Department
Honorary Director, MRC Functional Genetics Unit
Co-Director, Oxford Centre for Gene Function
Tel.: 01865 285879/272179
Fax: 01865 285878/272427
Email: kay.davies@anat.ox.ac.uk

Our research is focused on the understanding of muscle disease and movement disorders. We have developed models of these disorders in order to understand the pathogenesis and to devlelop effective treatments.

Duchenne muscular dystrophy (DMD) is the most common genetic form of muscular dystrophy affecting 1 in 3000 boys. Although the disease is known to be caused by the absence of the cytoskeletal protein, dystrophin, no effective treatment is yet available. Our research programme is directed towards an understanding of the role of dystrophin through the analysis of related and associated proteins. These studies in turn are providing insights into the pathogenesis of DMD and of other muscular dystrophies. For example, we have shown recently that the dystrophin associated complex at the sarcolemma is linked to the intermediate filament protein desmin via the novel protein, syncoilin. We are currently investigating the role of syncoilin in both skeletal and cardiac muscle.

Therapy for DMD is a challenge since the protein is large and needs to be delivered to many muscle cells in the body for therapeutic effect. We are taking a novel approach to treatment through the analysis of a protein closely related to dystrophin, called utrophin. We have demonstrated that over expression of utrophin where dystrophin is lacking, prevents the muscle pathology in both skeletal and cardiac muscle. Our data suggest that up-regulation of utrophin might be an effective treatment for the disorder. We are therefore characterising the promoter and setting up high through-put screens for small compounds that could increase thel levels of utrophin in DMD patients.

We are also studying the function of the survival motor neuron (SMN) gene and its role in spinal muscular atrophy (SMA), a motor neuron disease. In collaboration with Dr Sattelle and Dr van den Heuvel in the MRC Unit, we are studying the function of SMN in the worm and the fly using genetic techniques such as siRNA and suppressor screening. We are also using microarray analysis to determine how downregulation affects gene regulation in motor neuron cultures and spinal cord.

We are studying neurological mutants from the ENU mutagenesis programme at the MRC Mammalian Genetics Unit at Harwell. We have a particular interest in mutants which cause movement disorders. For example, we have shown that one of these, known as the robotic mutant, shows a robotic gait and demonstrates early loss of a specific set of Purkinje cells in the cerebellum (see figure below). We are currently inverstigating how the gene involved, AF4, causes this dramatic effect. We are also investigating this gene for mutation in samples from patients with ataxia in collaboration with Dr Talbot, a Clinical Scientist in the Department. Interestingly, AF4 is closely related to FMR2 which we had previously characterized as a cause of mild learning difficulties in X-linked mental retardation. We are therefore also carrying out parallel studies of the function of FMR2 with a focus on its expression in the hippocampus. We are using laser capture microdissection and microarray analysis techniques for these studies.

Current Funding: Association Française Contre les Myopathies (AFM); Families of SMA; Medical Research Council; Muscular Dystrophy Association, USA; Muscular Dystrophy Campaign; Wellcome Trust.

Other Activities: Fellow of Hertford College.

Key Publications:
Squire S, Raymackers JM, Vandebrouck C, Potter A, Tinsley J, Fisher R, Gillis JM, Davies KE (2002) Human Molecular Genetics 11:3333-3344.
Isaacs AM, Jeans A, Oliver PL, Vizor L, Brown SDM, Hunter AJ, Davies KE (2002) Molecular and Cellular Neuroscience 21: 114-125.
Poon E, Howman EV, Newey SE, Davies KE (2002) Journal of Biological Chemistry 277: 3433-3439.
Weir AP, Burton EA, Harrod G, Davies KE (2002) Journal of Biological Chemistry 277: 45285-45290.
Khurana TS, Davies KE (2003) Nature Drug Discovery 2: 379-390.
Isaacs AM, Oliver PL, Jones EL, Jeans A, Potter A, Horvik BH, Nolan PM, Vizor L, Glenister P, Simon AK, Gray IC, Spurr NK, Brown, SDM, Hunter, AJ, Davies KE (2003) Journal of Neuroscience 23: 1631-1637.
Perkins KJ, Davies KE (2003) FEBS Letters 13: 168-172.
Oliver PL, Bitoun E, Clark J, Jones E, and Davies KE. Mediation of Af4 protein function in the cerebellum by Siah proteins. Proc. Nat. Acad. Sci. 101, 41: 14901-14906.

Main Collaborators
Dr Steve Brown MRC Mammalian Genome Unit, Harwell
Dr Arthur Burghes, Ohio State University
Dr Kieran Clarke, Biochemistry, Oxford
Prof Francesco Muntoni, RPMS, London
Dr. Kevin Talbot (GlaxoSmithKline Clinical Scientist Fellow, Department of Human Anatomy and Genetics, Oxford).

Group Members
Postdoctoral Workers
Dr Qing Bai, Dr Kristen Nowak, Dr Karl McCullagh, Dr Peter Oliver, Dr Dilair Baban
Graduate Students
Mr Jeffrey Ehmsen, Dr Alexander Jeans (Clinical Training Fellow) Miss Emma Jones, Mr Graeme Doran, Miss Joanna Clark, Miss Natasha Thomas, Mr Howard Burdett
Research Assistants
Dr Rosie Fisher, Mr Ben Edwards, Mr Steve Phelps, Mrs Allyson Potter, Mr David Powell, Mrs Sarah Squire