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

Content Provider	PubMed Central
Author	Fanny, Rubio-moscardo Setó-salvia, Núria Pera, Marta Bosch-morató, Mònica Plata, Cristina Belbin, Olivia Gené, Gemma Oriol, Dols-icardo Ingelsson, Martin Seppo, Helisalmi Soininen, Hilkka Hiltunen, Mikko Giedraitis, Vilmantas Lars, Lannfelt Frank, Ana Combarros, Onofre Pascual, Sánchez-juan Boada, Mercè Tárraga, Lluís Pastor, Pau Jordi, Pérez-tur Baquero, Miquel Molinuevo, José L. Raquel, Sánchez-valle Pablo, Fuentes-prior Fortea, Juan Blesa, Rafael Muñoz, Francisco J. Alberto, Lleó Valverde, Miguel A. Jordi, Clarimón Bullido, Mjesús
Editor	Singh, Brij
Copyright Year	2013
Abstract	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 Ca2+-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.
Related Links	http://dx.doi.org/10.1371/journal.pone.0074203
Starting Page	74203
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	9
Volume Number	8
Language	English
Publisher	Public Library of Science
Publisher Date	2013-09-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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