1. Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer's Disease Patients Alter Calcium Homeostasis
- Author
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Fanny Rubio-Moscardo, Núria Setó-Salvia, Marta Pera, Mònica Bosch-Morató, Cristina Plata, 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, and Universitat de Barcelona
- Subjects
Male ,Medicin och hälsovetenskap ,DNA Mutational Analysis ,Homeòstasi ,medicine.disease_cause ,Medical and Health Sciences ,Missense mutation ,Homeostasis ,Early-onset Alzheimer's disease ,Age of Onset ,Genetics ,Mutation ,Membrane Glycoproteins ,Multidisciplinary ,Voltage-dependent calcium channel ,Middle Aged ,Alzheimer's disease ,Medicine ,Female ,Research Article ,Adult ,medicine.medical_specialty ,Science ,Biology ,Presenilin ,Calcium imaging ,Alzheimer Disease ,Calci -- Metabolisme ,Internal medicine ,medicine ,Humans ,Amino Acid Sequence ,Calcium Signaling ,Aged ,Amyloid beta-Peptides ,Polymorphism, Genetic ,Calci ,medicine.disease ,Alzheimer, Malaltia d' ,Endocrinology ,Malaltia d'Alzheimer ,Case-Control Studies ,CALHM1 ,Calcium ,Calcium Channels ,Sequence Alignment - Abstract
8 páginas, 3 figuras, 1 tabla., 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, This study was supported by grants from Instituto de Salud Carlos III (PI12/01311, PI10/000587, Red HERACLES RD12/0042/0014), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain), Spanish Ministry of Economy and Competiveness (SAF2012-38140), FEDER Funds, and Generalitat de Catalunya (SGR05-266). Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, the Strategic Funding of the University on Eastern Finland (UEF-Brain) (to M.H and H.S). M.A.V. is the recipient of an ICREA Academia Award.
- Published
- 2013