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A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk.
Dreses-Werringloer, U, Lambert, J, Vingtdeux, V, Zhao, H, Vais, H, Siebert, A, Jain, A, Koppel, J, Rovelet-Lecrux, A, Hannequin, D, Pasquier, F, Galimberti, D, Scarpini, E, Mann, DMA, Lendon, C, Campion, D, Amouyel, P, Davies, P, Foskett, J, Campagne, F, Marambaud, P
Cell. 2008;133( 7).
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Abstract
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.
Keyword(s)
Aged; Aged, 80 and over; Amino Acid Sequence; Chromosomes, Human, Pair 10; Female; Genetic Predisposition to Disease; Genome, Human; Humans; Male; Middle Aged; Molecular Sequence Data; Phylogeny; Polymorphism, Genetic; Sequence Alignment; chemistry: Membrane Glycoproteins; genetics: Alzheimer Disease; metabolism: Amyloid beta-Protein; metabolism: Calcium; metabolism: Cell Membrane; metabolism: Cytosol