A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk by Dreses-Werringloer Ute, Lambert Jean-Charles, Vingtdeux Valérie, Zhao Haitian, Vais Horia, Siebert Adam, Jain Ankit, Koppel Jeremy, Rovelet-Lecrux Anne, Hannequin Didier, Pasquier Florence, Galimberti Daniela, Scarpini Elio, Mann David, Lendon Corinne, Campion Dominique, Amouyel Philippe, Davies Peter, Foskett J Kevin, Campagne Fabien, Marambaud Philippe in Cell (2008).

[PMID: 18585350] PubMed


Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (Abeta) 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 Ca(2+) concentrations and Abeta levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca(2+) 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 x 10(-10)). We further found that the P86L polymorphism increases Abeta levels by interfering with CALHM1-mediated Ca(2+) permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca(2+) channel that controls Abeta levels and susceptibility to late-onset AD.

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