Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms |
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| Authors: | FL Mastaglia A Rojana-udomsart I James M Needham TJ Day L Kiers JA Corbett AM Saunders MW Lutz AD Roses |
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| Institution: | 1. Australian Neuro-Muscular Research Institute, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia;2. Institute for Immunology & Infectious Diseases, Murdoch University, Western Australia, Australia;3. Departments of Neurology and Neurophysiology, Royal Melbourne Hospital & Department of Medicine, University of Melbourne, Parkville, Victoria, Australia;4. Department of Neurology, Concord Hospital, Concord, NSW, Australia;5. Duke University, Durham, NC 27705, USA;6. Zinfandel Pharmaceuticals, Durham, NC 27705, USA;1. Department of Paediatric Neurology – Neuromuscular Service, Evelina Children’s Hospital, St Thomas’ Hospital, London, UK;2. Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, London, UK;3. Clinical Neuroscience Division, King’s College, London, UK;4. Department of Medical Genetics, Haartman Institute, University of Helsinki, Biomedicum Helsinki, Finland;5. The Folkhälsan Department of Medical Genetics, Helsinki, Finland;6. Department of Translational Medecine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch F-67404, France;7. Inserm, U964, Illkirch F-67404, France;8. CNRS, UMR7104, Illkirch F-67404, France;9. Université de Strasbourg, Strasbourg F-67404, France;10. Collège de France, Illkirch F-67404, France;1. CHU Saint-Étienne, Hôpital Bellevue, Department of Paediatric Physical Medicine and Rehabilitation, Rhône-Alpes Reference Centre for Neuromuscular Diseases, Saint-Étienne F-42055, France;2. CHU Saint-Étienne, Hôpital Bellevue, Department of Myology, Rhône-Alpes Reference Centre for Neuromuscular Diseases, Saint-Étienne F-42055, France;3. Exercise Physiology Laboratory, Univ Saint-Étienne, EA 4338, Saint-Étienne F-42023, France;4. CHU Saint-Étienne, Hôpital nord, Department of Neurology, Rhône-Alpes Reference Centre for Neuromuscular Diseases, Saint-Étienne F-42055, France;5. AP-HP, Hôpital de la Pitié-Salpêtrière, Paris-Est Reference Centre for Neuromuscular Diseases, Paris F-75651, France;6. AP-HP, Hôpital Antoine Béclère, Laboratory of Molecular Genetics and Metabolic Diseases, Clamart F-92141, France;1. MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK;2. Oxford MDC Muscle and Nerve Centre, West Wing, John Radcliffe Hospital, Oxford, UK;3. Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK;1. Groupe de recherche interdisciplinaire en maladies neuromusculaires (GRIMN), Centre de santé et de services sociaux de Jonquière, Québec, Canada;2. Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada;3. Department of Neurology, University of Milan, IRCCS Policlinico San Donato, Italy;4. Human Genetics Unit, Centre hospitalier de l’Université Laval, Québec, Canada;5. ÉCOBES, Cégep de Jonquière, Québec, Canada;6. Centre hospitalier universitaire de Chicoutimi, Chicoutimi, Québec, Canada;7. Department of Health Sciences, Université du Québec à Chicoutimi, Québec, Canada;8. Faculty of Medicine, Université Laval, Québec, Canada;9. Canadian Forces Health Services HQ, Directorate of Medical Policy, Québec, Canada;1. Department of Obstetrics, Gynecology, and Reproductive Sciences, The University of Texas Medical School at Houston, Houston, TX;2. Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX;3. Shriners Hospital for Children, Houston, TX;1. Department of Genetics, Osmania University, Hyderabad, India;2. Department of Cardiology, Kamineni Hospitals, Hyderabad, India;3. Department of Medicine, Deccan College of Medical Sciences, Hyderabad, India |
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| Abstract: | A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer’s disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer’s disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males; age 69.1 ± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective. Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue. |
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| Keywords: | Sporadic IBM APOE Susceptibility Age of onset |
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