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Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease

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dc.contributor.author Nogales-Gadea, Gisela spa
dc.contributor.author Pinós, Tomás spa
dc.contributor.author Lucía Mulas, Alejandro spa
dc.contributor.author Arenas, Joaquín spa
dc.contributor.author Cámara, Yolanda spa
dc.contributor.author Brull, Astrid spa
dc.contributor.author Luna, Noemí de spa
dc.contributor.author Martín, Miguel Ángel spa
dc.contributor.author García-Arumi, Elena spa
dc.contributor.author Martí, Ramón spa
dc.contributor.author Andreu, Antoni L. spa
dc.date.accessioned 2013-11-27T17:26:40Z
dc.date.available 2013-11-27T17:26:40Z
dc.date.issued 2012 spa
dc.identifier.citation Nogales-Gadea, G., Pinós, T., Lucía-Mulas, A., Arenas, J., Camara, Y., Brull, A., …, & Andreu, A. L. (2012). Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. Brain, 135(7), 2048-2057. spa
dc.identifier.issn 00068950 spa
dc.identifier.uri http://hdl.handle.net/11268/947
dc.description.abstract McArdle disease (glycogenosis type V), the most common muscle glycogenosis, is a recessive disorder caused by mutations in PYGM, the gene encoding myophosphorylase. Patients with McArdle disease typically experience exercise intolerance manifested as acute crises of early fatigue and contractures, sometimes with rhabdomyolysis and myoblobinuria, triggered by static muscle contractions or dynamic exercises. Currently, there are no therapies to restore myophosphorylase activity in patients. Although two spontaneous animal models for McArdle disease have been identified (cattle and sheep), they have rendered a limited amount of information on the pathophysiology of the disorder; therefore, there have been few opportunities for experimental research in the field. We have developed a knock-in mouse model by replacing the wild-type allele of Pygm with a modified allele carrying the common human mutation, p.R50X, which is the most frequent cause of McArdle disease. Histochemical, biochemical and molecular analyses of the phenotype, as well as exercise tests, were carried out in homozygotes, carriers and wild-type mice. p.R50X/p.R50X mice showed undetectable myophosphorylase protein and activity in skeletal muscle. Histochemical and biochemical analyses revealed massive muscle glycogen accumulation in homozygotes, in contrast to heterozygotes or wild-type mice, which did not show glycogen accumulation in this tissue. Additional characterization confirmed a McArdle disease-like phenotype in p.R50X/p.R50X mice, i.e. they had hyperCKaemia and very poor exercise performance, as assessed in the wire grip and treadmill tests (6% and 5% of the wild-type values, respectively). This model represents a powerful tool for in-depth studies of the pathophysiology of McArdle disease and other neuromuscular disorders, and for exploring new therapeutic approaches for genetic disorders caused by premature stop codon mutations. spa
dc.language.iso eng spa
dc.title Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease spa
dc.type article spa
dc.description.impact 9.915 JCR (2012) Q1, 5/191 Clinical neurology, 10/251 Neurosciences spa
dc.identifier.doi 10.1093/brain/aws141 spa
dc.rights.accessRights openAccess en
dc.subject.unesco Genética humana spa
dc.description.filiation UEM spa
dc.peerreviewed Si spa


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