Analysis of the DYSF mutational spectrum in a large cohort of patients |
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Authors: | Martin Krahn Christophe Broud Vronique Labelle Karine Nguyen Rafaëlle Bernard Guillaume Bassez Dominique Figarella‐Branger Carla Fernandez Julien Bouvenot Isabelle Richard Elisabeth Ollagnon‐Roman Jorge A Bevilacqua Eric Salvo Shahram Attarian Franoise Chapon Jean‐Franois Pellissier Jean Pouget El Hadi Hammouda Pascal Laforêt Jon Andoni Urtizberea Bruno Eymard France Leturcq Nicolas Lvy |
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Institution: | 1. Département de Génétique Médicale, H?pital d'Enfants de la Timone, AP‐HM, Marseille, France;2. Inserm UMR910 : “Génétique Médicale et Génomique Fonctionnelle”, Faculté de Médecine Timone, Université de la Méditerranée, Marseille, France;3. CHU de Montpellier, INSERM U827, and Université Montpellier 1, Montpellier, France;4. Service de Neurologie, CHU H?pital Henri Mondor, Créteil, France;5. Laboratoire d'Anatomopathologie, H?pital Timone, AP‐HM, Marseille, France;6. Laboratoire de Santé Publique, Faculté de Médecine Timone, Université de la Méditerranée, Marseille, France;7. Genethon, CNRS FRE 3087, Evry, France;8. Consultation de Génétique, H?pital Croix Rousse, CHU, Lyon, France;9. Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, José Joaquín Aguirre, and Programa de Anatomía y Biología del Desarrollo, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile;10. Service de Neurologie, P?le de Neurosciences Cliniques, Centre de Référence des Maladies Neuromusculaires et de la SLA, H?pital Timone, AP‐HM, Marseille, France;11. Consultation de Pathologies neuromusculaires and Laboratoire de Neuropathologie, CHU C?te de Nacre, Caen, France;12. Association Fran?aise contre les Myopathies, Evry, France;13. Institut de Myologie, Groupe Hospitalier Pitié‐Salpêtrière, Paris, France;14. H?pital Marin, AP‐HP, Hendaye, France;15. Laboratoire de Biochimie Génétique, H?pital Cochin, Paris, France |
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Abstract: | Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc. |
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Keywords: | Dysferlin DYSF Dysferlinopathy Limb Girdle Muscular Dystrophy LGMD2B Miyoshi myopathy Mutation analysis |
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