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

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, s...

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Autores: Nogales-Gadea, G, Pinos, T, Lucia, A, Arenas, J, Camara, Y, Brull, A, De Luna, N, Martin, MA, Garcia-Arumi, E, Marti, R, Andreu, AL
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p11301
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11301
Access Level:acceso abierto
Palabra clave:McArdle disease
knock-in mouse
p
R50X mutation
glycogenosis type V
neuromuscular disorders
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spelling Knock-in mice for the R50X mutation in the PYGM gene present with McArdle diseaseNogales-Gadea, GPinos, TLucia, AArenas, JCamara, YBrull, ADe Luna, NMartin, MAGarcia-Arumi, EMarti, RAndreu, ALMcArdle diseaseknock-in mousepR50X mutationglycogenosis type Vneuromuscular disordersMcArdle 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.OXFORD UNIV PRESS2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11301BRAINISSN: 00068950ISSNe: 14602156reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p113012026-06-14T12:41:47Z
dc.title.none.fl_str_mv Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease
title Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease
spellingShingle Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease
Nogales-Gadea, G
McArdle disease
knock-in mouse
p
R50X mutation
glycogenosis type V
neuromuscular disorders
title_short Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease
title_full Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease
title_fullStr Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease
title_full_unstemmed Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease
title_sort Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease
dc.creator.none.fl_str_mv Nogales-Gadea, G
Pinos, T
Lucia, A
Arenas, J
Camara, Y
Brull, A
De Luna, N
Martin, MA
Garcia-Arumi, E
Marti, R
Andreu, AL
author Nogales-Gadea, G
author_facet Nogales-Gadea, G
Pinos, T
Lucia, A
Arenas, J
Camara, Y
Brull, A
De Luna, N
Martin, MA
Garcia-Arumi, E
Marti, R
Andreu, AL
author_role author
author2 Pinos, T
Lucia, A
Arenas, J
Camara, Y
Brull, A
De Luna, N
Martin, MA
Garcia-Arumi, E
Marti, R
Andreu, AL
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv McArdle disease
knock-in mouse
p
R50X mutation
glycogenosis type V
neuromuscular disorders
topic McArdle disease
knock-in mouse
p
R50X mutation
glycogenosis type V
neuromuscular disorders
description 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.
publishDate 2012
dc.date.none.fl_str_mv 2012
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11301
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=11301
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv OXFORD UNIV PRESS
publisher.none.fl_str_mv OXFORD UNIV PRESS
dc.source.none.fl_str_mv BRAIN
ISSN: 00068950
ISSNe: 14602156
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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