New and potential strategies for the treatment of PMM2-CDG

Background: Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5′-diphospho-D-m...

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Autores: Gámez Abascal, María Alejandra, Pérez González, María Belén, Serrano, Mercedes, Gallego Martínez, Diana, Vilas Lagoa, Alicia
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/709748
Acceso en línea:http://hdl.handle.net/10486/709748
https://dx.doi.org/10.1016/j.bbagen.2020.129686
Access Level:acceso abierto
Palabra clave:Congenital disorders of glycosylation
Mannose
Pharmacological chaperones
Phosphomannomutase
PMM2-CDG
Proteostasis regulators
Biología y Biomedicina / Biología
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spelling New and potential strategies for the treatment of PMM2-CDGGámez Abascal, María AlejandraPérez González, María BelénSerrano, MercedesGallego Martínez, DianaVilas Lagoa, AliciaCongenital disorders of glycosylationMannosePharmacological chaperonesPhosphomannomutasePMM2-CDGProteostasis regulatorsBiología y Biomedicina / BiologíaBackground: Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5′-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic. Scope of review: This review covers the latest advances in the search for a treatment for PMM2-CDG. Major conclusions: Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins. General significance: The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussedThe authors are grateful to the Spanish families affected by PMM2- CDG who actively participated in this work. Financial support was provided by grant PI19/01155, PI17/00101, B2017/BMD-3721, the Fundación Isabel Gemio/Fundación La Caixa (LCF/PR/PR16/11110018), and the European Regional Development Fund. MS research is supported by the Generalitat de Catalunya (PERIS SLT008/18/00194ElsevierDepartamento de Biología MolecularFacultad de Ciencias20202020-07-23research articlehttp://purl.org/coar/resource_type/c_2df8fbb1AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/709748https://dx.doi.org/10.1016/j.bbagen.2020.129686reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7097482026-06-23T12:46:27Z
dc.title.none.fl_str_mv New and potential strategies for the treatment of PMM2-CDG
title New and potential strategies for the treatment of PMM2-CDG
spellingShingle New and potential strategies for the treatment of PMM2-CDG
Gámez Abascal, María Alejandra
Congenital disorders of glycosylation
Mannose
Pharmacological chaperones
Phosphomannomutase
PMM2-CDG
Proteostasis regulators
Biología y Biomedicina / Biología
title_short New and potential strategies for the treatment of PMM2-CDG
title_full New and potential strategies for the treatment of PMM2-CDG
title_fullStr New and potential strategies for the treatment of PMM2-CDG
title_full_unstemmed New and potential strategies for the treatment of PMM2-CDG
title_sort New and potential strategies for the treatment of PMM2-CDG
dc.creator.none.fl_str_mv Gámez Abascal, María Alejandra
Pérez González, María Belén
Serrano, Mercedes
Gallego Martínez, Diana
Vilas Lagoa, Alicia
author Gámez Abascal, María Alejandra
author_facet Gámez Abascal, María Alejandra
Pérez González, María Belén
Serrano, Mercedes
Gallego Martínez, Diana
Vilas Lagoa, Alicia
author_role author
author2 Pérez González, María Belén
Serrano, Mercedes
Gallego Martínez, Diana
Vilas Lagoa, Alicia
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Biología Molecular
Facultad de Ciencias
dc.subject.none.fl_str_mv Congenital disorders of glycosylation
Mannose
Pharmacological chaperones
Phosphomannomutase
PMM2-CDG
Proteostasis regulators
Biología y Biomedicina / Biología
topic Congenital disorders of glycosylation
Mannose
Pharmacological chaperones
Phosphomannomutase
PMM2-CDG
Proteostasis regulators
Biología y Biomedicina / Biología
description Background: Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5′-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic. Scope of review: This review covers the latest advances in the search for a treatment for PMM2-CDG. Major conclusions: Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins. General significance: The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussed
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-07-23
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/709748
https://dx.doi.org/10.1016/j.bbagen.2020.129686
url http://hdl.handle.net/10486/709748
https://dx.doi.org/10.1016/j.bbagen.2020.129686
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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