Missense mutations have unexpected consequences: The McArdle disease paradigm |
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| Authors: | Inés García‐Consuegra Sara Asensio‐Peña Alfonsina Ballester‐Lopez Rosario Francisco‐Velilla Tomás Pinos Guillem Pintos‐Morell Jaume Coll‐Cantí Adrián González‐Quintana Antoni L. Andreu Joaquín Arenas Alejandro Lucia Gisela Nogales‐Gadea Miguel A. Martín |
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| Affiliation: | 1. Grupo de Investigación de Enfermedades Mitocondriales y Neuromusculares, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain;2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain;3. Grup de Recerca en Malalties Neuromusculars i Neuropediatriques, Department of Neurosciences, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain;4. Centro de Biología Molecular Severo Ochoa, CSIC‐UAM, Madrid, Spain;5. Departament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autónoma de Barcelona, Barcelona, Spain;6. Division of Rare Diseases, University Hospital Vall d'Hebron, Barcelona, Spain;7. Servicio de Neurología, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain;8. Universidad Europea, Faculty of Sport Sciences & Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain |
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| Abstract: | McArdle disease is a disorder of muscle glycogen metabolism caused by mutations in the PYGM gene, encoding for the muscle‐specific isoform of glycogen phosphorylase (M‐GP). The activity of this enzyme is completely lost in patients’ muscle biopsies, when measured with a standard biochemical test which, does not allow to determine M‐GP protein levels. We aimed to determine M‐GP protein levels in the muscle of McArdle patients, by studying biopsies of 40 patients harboring a broad spectrum of PYGM mutations and 22 controls. Lack of M‐GP protein was found in muscle in the vast majority (95%) of patients, irrespective of the PYGM genotype, including those carrying missense mutations, with few exceptions. M‐GP protein biosynthesis is not being produced by PYGM mutations inducing premature termination codons (PTC), neither by most PYGM missense mutations. These findings explain the lack of PYGM genotype–phenotype correlation and have important implications for the design of molecular‐based therapeutic approaches. |
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| Keywords: | genotype– phenotype correlation McArdle disease missense mutations muscle glycogen phosphorylase |
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