Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis

Rubio-Moscardo, Fanny; Setó-Salvia, Núria|||0000-0002-3753-0027; Pera, Marta|||0000-0003-4317-6623; Bosch-Morató, Mònica; Plata, Cristina; Belbin, Olivia|||0000-0002-6109-6371; Gené, Gemma G.; Dols Icardo, Oriol|||0000-0003-2656-8748; Ingelsson, Martin|||0000-0001-5466-8370; Helisalmi, Seppo; Soininen, Hilkka|||0000-0002-2785-9937; Hiltunen, Mikko|||0000-0003-3566-4096; Giedraitis, Vilmantas|||0000-0003-3423-2021; Lannfelt, Lars; Frank, Ana; Bullido, MªJesús; Combarros, Onofre; Sánchez-Juan, Pascual|||0000-0002-6081-8037; Boada, Mercè|||0000-0003-2617-3009; Tárraga, Lluís|||0000-0002-8423-946X; Pastor, Pau|||0000-0002-7493-8777; Pérez-Tur, Jordi|||0000-0002-9111-1712; Baquero, Miquel|||0000-0002-6861-1831; Molinuevo, José Luis|||0000-0003-0485-6001; Sanchez-Valle, Raquel|||0000-0001-7750-896X; Fuentes-Prior, Pablo|||0000-0002-6618-3204; Fortea, Juan|||0000-0002-1340-638X; Blesa, Rafael|||0000-0003-4026-2884; Muñoz, Francisco J.; Lleó, Alberto|||0000-0002-2568-5478; Valverde, Miguel A.; Clarimón, Jordi|||0000-0002-6824-6942

Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis

Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD). Recently, the calcium hypothesis of AD has received support with the identificatio...

Descripción completa

Detalles Bibliográficos
Autores:	Rubio-Moscardo, Fanny, Setó-Salvia, Núria\|\|\|0000-0002-3753-0027, Pera, Marta\|\|\|0000-0003-4317-6623, Bosch-Morató, Mònica, Plata, Cristina, Belbin, Olivia\|\|\|0000-0002-6109-6371, Gené, Gemma G., Dols Icardo, Oriol\|\|\|0000-0003-2656-8748, Ingelsson, Martin\|\|\|0000-0001-5466-8370, Helisalmi, Seppo, Soininen, Hilkka\|\|\|0000-0002-2785-9937, Hiltunen, Mikko\|\|\|0000-0003-3566-4096, Giedraitis, Vilmantas\|\|\|0000-0003-3423-2021, Lannfelt, Lars, Frank, Ana, Bullido, MªJesús, Combarros, Onofre, Sánchez-Juan, Pascual\|\|\|0000-0002-6081-8037, Boada, Mercè\|\|\|0000-0003-2617-3009, Tárraga, Lluís\|\|\|0000-0002-8423-946X, Pastor, Pau\|\|\|0000-0002-7493-8777, Pérez-Tur, Jordi\|\|\|0000-0002-9111-1712, Baquero, Miquel\|\|\|0000-0002-6861-1831, Molinuevo, José Luis\|\|\|0000-0003-0485-6001, Sanchez-Valle, Raquel\|\|\|0000-0001-7750-896X, Fuentes-Prior, Pablo\|\|\|0000-0002-6618-3204, Fortea, Juan\|\|\|0000-0002-1340-638X, Blesa, Rafael\|\|\|0000-0003-4026-2884, Muñoz, Francisco J., Lleó, Alberto\|\|\|0000-0002-2568-5478, Valverde, Miguel A., Clarimón, Jordi\|\|\|0000-0002-6824-6942
Tipo de recurso:	artículo
Fecha de publicación:	2013
País:	España
Institución:	Universitat Autònoma de Barcelona
Repositorio:	Dipòsit Digital de Documents de la UAB
Idioma:	inglés
OAI Identifier:	oai:ddd.uab.cat:303805
Acceso en línea:	https://ddd.uab.cat/record/303805 https://dx.doi.org/urn:doi:10.1371/journal.pone.0074203
Access Level:	acceso abierto

id	ES_fffcefa7cea82db4135bb21b1b60bed4
oai_identifier_str	oai:ddd.uab.cat:303805
network_acronym_str	ES
network_name_str	España
repository_id_str
spelling	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium HomeostasisRubio-Moscardo, FannySetó-Salvia, Núria\|\|\|0000-0002-3753-0027Pera, Marta\|\|\|0000-0003-4317-6623Bosch-Morató, MònicaPlata, CristinaBelbin, Olivia\|\|\|0000-0002-6109-6371Gené, Gemma G.Dols Icardo, Oriol\|\|\|0000-0003-2656-8748Ingelsson, Martin\|\|\|0000-0001-5466-8370Helisalmi, SeppoSoininen, Hilkka\|\|\|0000-0002-2785-9937Hiltunen, Mikko\|\|\|0000-0003-3566-4096Giedraitis, Vilmantas\|\|\|0000-0003-3423-2021Lannfelt, LarsFrank, AnaBullido, MªJesúsCombarros, OnofreSánchez-Juan, Pascual\|\|\|0000-0002-6081-8037Boada, Mercè\|\|\|0000-0003-2617-3009Tárraga, Lluís\|\|\|0000-0002-8423-946XPastor, Pau\|\|\|0000-0002-7493-8777Pérez-Tur, Jordi\|\|\|0000-0002-9111-1712Baquero, Miquel\|\|\|0000-0002-6861-1831Molinuevo, José Luis\|\|\|0000-0003-0485-6001Sanchez-Valle, Raquel\|\|\|0000-0001-7750-896XFuentes-Prior, Pablo\|\|\|0000-0002-6618-3204Fortea, Juan\|\|\|0000-0002-1340-638XBlesa, Rafael\|\|\|0000-0003-4026-2884Muñoz, Francisco J.Lleó, Alberto\|\|\|0000-0002-2568-5478Valverde, Miguel A.Clarimón, Jordi\|\|\|0000-0002-6824-6942Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade. © 2013 Rubio-Moscardo et al.Universitat Autònoma de Barcelona 22013-01-0120132013-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/303805https://dx.doi.org/urn:doi:10.1371/journal.pone.0074203reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 PI12/01311open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3038052026-06-06T12:50:31Z
dc.title.none.fl_str_mv	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis
title	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis
spellingShingle	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis Rubio-Moscardo, Fanny
title_short	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis
title_full	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis
title_fullStr	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis
title_full_unstemmed	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis
title_sort	Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis
dc.creator.none.fl_str_mv	Rubio-Moscardo, Fanny Setó-Salvia, Núria\|\|\|0000-0002-3753-0027 Pera, Marta\|\|\|0000-0003-4317-6623 Bosch-Morató, Mònica Plata, Cristina Belbin, Olivia\|\|\|0000-0002-6109-6371 Gené, Gemma G. Dols Icardo, Oriol\|\|\|0000-0003-2656-8748 Ingelsson, Martin\|\|\|0000-0001-5466-8370 Helisalmi, Seppo Soininen, Hilkka\|\|\|0000-0002-2785-9937 Hiltunen, Mikko\|\|\|0000-0003-3566-4096 Giedraitis, Vilmantas\|\|\|0000-0003-3423-2021 Lannfelt, Lars Frank, Ana Bullido, MªJesús Combarros, Onofre Sánchez-Juan, Pascual\|\|\|0000-0002-6081-8037 Boada, Mercè\|\|\|0000-0003-2617-3009 Tárraga, Lluís\|\|\|0000-0002-8423-946X Pastor, Pau\|\|\|0000-0002-7493-8777 Pérez-Tur, Jordi\|\|\|0000-0002-9111-1712 Baquero, Miquel\|\|\|0000-0002-6861-1831 Molinuevo, José Luis\|\|\|0000-0003-0485-6001 Sanchez-Valle, Raquel\|\|\|0000-0001-7750-896X Fuentes-Prior, Pablo\|\|\|0000-0002-6618-3204 Fortea, Juan\|\|\|0000-0002-1340-638X Blesa, Rafael\|\|\|0000-0003-4026-2884 Muñoz, Francisco J. Lleó, Alberto\|\|\|0000-0002-2568-5478 Valverde, Miguel A. Clarimón, Jordi\|\|\|0000-0002-6824-6942
author	Rubio-Moscardo, Fanny
author_facet	Rubio-Moscardo, Fanny Setó-Salvia, Núria\|\|\|0000-0002-3753-0027 Pera, Marta\|\|\|0000-0003-4317-6623 Bosch-Morató, Mònica Plata, Cristina Belbin, Olivia\|\|\|0000-0002-6109-6371 Gené, Gemma G. Dols Icardo, Oriol\|\|\|0000-0003-2656-8748 Ingelsson, Martin\|\|\|0000-0001-5466-8370 Helisalmi, Seppo Soininen, Hilkka\|\|\|0000-0002-2785-9937 Hiltunen, Mikko\|\|\|0000-0003-3566-4096 Giedraitis, Vilmantas\|\|\|0000-0003-3423-2021 Lannfelt, Lars Frank, Ana Bullido, MªJesús Combarros, Onofre Sánchez-Juan, Pascual\|\|\|0000-0002-6081-8037 Boada, Mercè\|\|\|0000-0003-2617-3009 Tárraga, Lluís\|\|\|0000-0002-8423-946X Pastor, Pau\|\|\|0000-0002-7493-8777 Pérez-Tur, Jordi\|\|\|0000-0002-9111-1712 Baquero, Miquel\|\|\|0000-0002-6861-1831 Molinuevo, José Luis\|\|\|0000-0003-0485-6001 Sanchez-Valle, Raquel\|\|\|0000-0001-7750-896X Fuentes-Prior, Pablo\|\|\|0000-0002-6618-3204 Fortea, Juan\|\|\|0000-0002-1340-638X Blesa, Rafael\|\|\|0000-0003-4026-2884 Muñoz, Francisco J. Lleó, Alberto\|\|\|0000-0002-2568-5478 Valverde, Miguel A. Clarimón, Jordi\|\|\|0000-0002-6824-6942
author_role	author
author2	Setó-Salvia, Núria\|\|\|0000-0002-3753-0027 Pera, Marta\|\|\|0000-0003-4317-6623 Bosch-Morató, Mònica Plata, Cristina Belbin, Olivia\|\|\|0000-0002-6109-6371 Gené, Gemma G. Dols Icardo, Oriol\|\|\|0000-0003-2656-8748 Ingelsson, Martin\|\|\|0000-0001-5466-8370 Helisalmi, Seppo Soininen, Hilkka\|\|\|0000-0002-2785-9937 Hiltunen, Mikko\|\|\|0000-0003-3566-4096 Giedraitis, Vilmantas\|\|\|0000-0003-3423-2021 Lannfelt, Lars Frank, Ana Bullido, MªJesús Combarros, Onofre Sánchez-Juan, Pascual\|\|\|0000-0002-6081-8037 Boada, Mercè\|\|\|0000-0003-2617-3009 Tárraga, Lluís\|\|\|0000-0002-8423-946X Pastor, Pau\|\|\|0000-0002-7493-8777 Pérez-Tur, Jordi\|\|\|0000-0002-9111-1712 Baquero, Miquel\|\|\|0000-0002-6861-1831 Molinuevo, José Luis\|\|\|0000-0003-0485-6001 Sanchez-Valle, Raquel\|\|\|0000-0001-7750-896X Fuentes-Prior, Pablo\|\|\|0000-0002-6618-3204 Fortea, Juan\|\|\|0000-0002-1340-638X Blesa, Rafael\|\|\|0000-0003-4026-2884 Muñoz, Francisco J. Lleó, Alberto\|\|\|0000-0002-2568-5478 Valverde, Miguel A. Clarimón, Jordi\|\|\|0000-0002-6824-6942
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Universitat Autònoma de Barcelona
description	Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer's disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade. © 2013 Rubio-Moscardo et al.
publishDate	2013
dc.date.none.fl_str_mv	2 2013-01-01 2013 2013-01-01
dc.type.none.fl_str_mv	Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://ddd.uab.cat/record/303805 https://dx.doi.org/urn:doi:10.1371/journal.pone.0074203
url	https://ddd.uab.cat/record/303805 https://dx.doi.org/urn:doi:10.1371/journal.pone.0074203
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 PI12/01311
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/
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 https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.source.none.fl_str_mv	reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona
instname_str	Universitat Autònoma de Barcelona
reponame_str	Dipòsit Digital de Documents de la UAB
collection	Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_	1869425824145342464
score	15,811543

Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis

Similares en LA Referencia