A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk

Ute Dreses-Werringloer, Jean Charles Lambert, Valérie Vingtdeux, Haitian Zhao, Horia Vais, Adam Siebert, Ankit Jain, Jeremy Koppel, Anne Rovelet-Lecrux, Didier Hannequin, Florence Pasquier, Daniela Galimberti, Elio Scarpini, David Mann, Corinne Lendon, Dominique Campion, Philippe Amouyel, Peter Davies, J. Kevin Foskett, Fabien CampagnePhilippe Marambaud

    Research output: Contribution to journalArticlepeer-review


    Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-β (Aβ) peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca2+ concentrations and Aβ levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca2+ conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3404 participants (allele-specific OR = 1.44, p = 2 × 10-10). We further found that the P86L polymorphism increases Aβ levels by interfering with CALHM1-mediated Ca2+ permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca2+ channel that controls Aβ levels and susceptibility to late-onset AD. © 2008 Elsevier Inc. All rights reserved.
    Original languageEnglish
    Pages (from-to)1149-1161
    Number of pages12
    Issue number7
    Publication statusPublished - 27 Jun 2008




    Dive into the research topics of 'A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk'. Together they form a unique fingerprint.

    Cite this