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...
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oai:doaj.org-article:2c1409358f4347c499ddc120e20587a62021-11-18T08:54:56ZRare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimer's disease patients alter calcium homeostasis.1932-620310.1371/journal.pone.0074203https://doaj.org/article/2c1409358f4347c499ddc120e20587a62013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24069280/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Calcium 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(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) 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(2+) 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(2+) 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(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.Fanny Rubio-MoscardoNúria Setó-SalviaMarta PeraMònica Bosch-MoratóCristina PlataOlivia BelbinOlivia BelbinGemma GenéOriol Dols-IcardoMartin IngelssonSeppo HelisalmiHilkka SoininenMikko HiltunenVilmantas GiedraitisLars LannfeltAna FrankMa Jesús BullidoOnofre CombarrosPascual Sánchez-JuanMercè BoadaLluís TárragaPau PastorJordi Pérez-TurMiquel BaqueroJosé L MolinuevoRaquel Sánchez-VallePablo Fuentes-PriorJuan ForteaRafael BlesaFrancisco J MuñozAlberto LleóMiguel A ValverdeJordi ClarimónPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e74203 (2013) |
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Medicine R Science Q Fanny Rubio-Moscardo Núria Setó-Salvia Marta Pera Mònica Bosch-Morató Cristina Plata Olivia Belbin Olivia Belbin Gemma Gené Oriol Dols-Icardo Martin Ingelsson Seppo Helisalmi Hilkka Soininen Mikko Hiltunen Vilmantas Giedraitis Lars Lannfelt Ana Frank Ma Jesús Bullido Onofre Combarros Pascual Sánchez-Juan Mercè Boada Lluís Tárraga Pau Pastor Jordi Pérez-Tur Miquel Baquero José L Molinuevo Raquel Sánchez-Valle Pablo Fuentes-Prior Juan Fortea Rafael Blesa Francisco J Muñoz Alberto Lleó Miguel A Valverde Jordi Clarimón Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimer's disease patients alter calcium homeostasis. |
| 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(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) 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(2+) 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(2+) 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(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade. |
| format |
article |
| author |
Fanny Rubio-Moscardo Núria Setó-Salvia Marta Pera Mònica Bosch-Morató Cristina Plata Olivia Belbin Olivia Belbin Gemma Gené Oriol Dols-Icardo Martin Ingelsson Seppo Helisalmi Hilkka Soininen Mikko Hiltunen Vilmantas Giedraitis Lars Lannfelt Ana Frank Ma Jesús Bullido Onofre Combarros Pascual Sánchez-Juan Mercè Boada Lluís Tárraga Pau Pastor Jordi Pérez-Tur Miquel Baquero José L Molinuevo Raquel Sánchez-Valle Pablo Fuentes-Prior Juan Fortea Rafael Blesa Francisco J Muñoz Alberto Lleó Miguel A Valverde Jordi Clarimón |
| author_facet |
Fanny Rubio-Moscardo Núria Setó-Salvia Marta Pera Mònica Bosch-Morató Cristina Plata Olivia Belbin Olivia Belbin Gemma Gené Oriol Dols-Icardo Martin Ingelsson Seppo Helisalmi Hilkka Soininen Mikko Hiltunen Vilmantas Giedraitis Lars Lannfelt Ana Frank Ma Jesús Bullido Onofre Combarros Pascual Sánchez-Juan Mercè Boada Lluís Tárraga Pau Pastor Jordi Pérez-Tur Miquel Baquero José L Molinuevo Raquel Sánchez-Valle Pablo Fuentes-Prior Juan Fortea Rafael Blesa Francisco J Muñoz Alberto Lleó Miguel A Valverde Jordi Clarimón |
| author_sort |
Fanny Rubio-Moscardo |
| title |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimer's disease patients alter calcium homeostasis. |
| 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. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/2c1409358f4347c499ddc120e20587a6 |
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