A novel EPM2A mutation yields a slow progression form of Lafora disease

9 páginas, 4 figuras. contiene 2 figuras en material suplementario

Detalles Bibliográficos
Autores: García-Gimeno, María Adelaida, Rodilla-Ramirez, Pilar Natalia, Viana, Rosa, Salas-Puig, Xavier, Brewer, M. Kathryn, Gentry, Matthew S., Sanz, Pascual
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/176831
Acceso en línea:http://hdl.handle.net/10261/176831
Access Level:acceso abierto
Palabra clave:Epilepsy
Gene expression
Genetic modifying factor
Lafora disease
Laforin
Malin
id ES_313d7f89ad4eaaa28f9222d829aaa59d
oai_identifier_str oai:digital.csic.es:10261/176831
network_acronym_str ES
network_name_str España
repository_id_str
spelling A novel EPM2A mutation yields a slow progression form of Lafora diseaseGarcía-Gimeno, María AdelaidaRodilla-Ramirez, Pilar NataliaViana, RosaSalas-Puig, XavierBrewer, M. KathrynGentry, Matthew S.Sanz, PascualEpilepsyGene expressionGenetic modifying factorLafora diseaseLaforinMalin9 páginas, 4 figuras. contiene 2 figuras en material suplementarioLafora disease (LD, OMIM 254780) is a rare disorder characterized by epilepsy and neurodegeneration leading patients to a vegetative state and death, usually within the first decade from the onset of the first symptoms. In the vast majority of cases LD is related to mutations in either the EPM2A gene (encoding the glucan phosphatase laforin) or the EPM2B gene (encoding the E3-ubiquitin ligase malin). In this work, we characterize the mutations present in the EPM2A gene in a patient displaying a slow progression form of the disease. The patient is compound heterozygous with Y112X and N163D mutations in the corresponding alleles. In primary fibroblasts obtained from the patient, we analyzed the expression of the mutated alleles by quantitative real time PCR and found slightly lower levels of expression of the EPM2A gene respect to control cells. However, by Western blotting we were unable to detect endogenous levels of the protein in crude extracts from patient fibroblasts. The Y112X mutation would render a truncated protein lacking the phosphatase domain and likely degraded. Since minute amounts of laforin-N163D might still play a role in cell physiology, we analyzed the biochemical characteristics of the N163D mutation. We found that recombinant laforin N163D protein was as stable as wild type and exhibited near wild type phosphatase activity towards biologically relevant substrates. On the contrary, it showed a severe impairment in the interaction profile with previously identified laforin binding partners. These results lead us to conclude that the slow progression of the disease present in this patient could be either due to the specific biochemical properties of laforin N163D or to the presence of alternative genetic modifying factors separate from pathogenicity.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness SAF2014-54604-C3-1-R and a grant from Generalitat Valenciana (PrometeoII/2014/029); and National Institute of Health grants R01NS070899 and P01NS097197, which established the Lafora Epilepsy Cure Initiative (LECI).Peer reviewedElsevierMinisterio de Economía y Competitividad (España)Generalitat ValencianaNational Institutes of Health (US)Sanz, Pascual [0000-0002-2399-4103]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/176831reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-54604-C3-1-Rhttp://dx.doi.org/10.1016/j.eplepsyres.2018.07.003Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1768312026-05-22T06:33:51Z
dc.title.none.fl_str_mv A novel EPM2A mutation yields a slow progression form of Lafora disease
title A novel EPM2A mutation yields a slow progression form of Lafora disease
spellingShingle A novel EPM2A mutation yields a slow progression form of Lafora disease
García-Gimeno, María Adelaida
Epilepsy
Gene expression
Genetic modifying factor
Lafora disease
Laforin
Malin
title_short A novel EPM2A mutation yields a slow progression form of Lafora disease
title_full A novel EPM2A mutation yields a slow progression form of Lafora disease
title_fullStr A novel EPM2A mutation yields a slow progression form of Lafora disease
title_full_unstemmed A novel EPM2A mutation yields a slow progression form of Lafora disease
title_sort A novel EPM2A mutation yields a slow progression form of Lafora disease
dc.creator.none.fl_str_mv García-Gimeno, María Adelaida
Rodilla-Ramirez, Pilar Natalia
Viana, Rosa
Salas-Puig, Xavier
Brewer, M. Kathryn
Gentry, Matthew S.
Sanz, Pascual
author García-Gimeno, María Adelaida
author_facet García-Gimeno, María Adelaida
Rodilla-Ramirez, Pilar Natalia
Viana, Rosa
Salas-Puig, Xavier
Brewer, M. Kathryn
Gentry, Matthew S.
Sanz, Pascual
author_role author
author2 Rodilla-Ramirez, Pilar Natalia
Viana, Rosa
Salas-Puig, Xavier
Brewer, M. Kathryn
Gentry, Matthew S.
Sanz, Pascual
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Generalitat Valenciana
National Institutes of Health (US)
Sanz, Pascual [0000-0002-2399-4103]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Epilepsy
Gene expression
Genetic modifying factor
Lafora disease
Laforin
Malin
topic Epilepsy
Gene expression
Genetic modifying factor
Lafora disease
Laforin
Malin
description 9 páginas, 4 figuras. contiene 2 figuras en material suplementario
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/176831
url http://hdl.handle.net/10261/176831
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-54604-C3-1-R
http://dx.doi.org/10.1016/j.eplepsyres.2018.07.003
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405597974134784
score 15.811543

Similares en LA Referencia