title: A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk.
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.
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA.
authors.forename: Ute
authors.initials: U
authors.lastname: Dreses-Werringloer
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.forename: Haitian
authors.initials: H
authors.lastname: Zhao
authors.forename: Horia
authors.initials: H
authors.lastname: Vais
authors.forename: Adam
authors.initials: A
authors.lastname: Siebert
authors.forename: Ankit
authors.initials: A
authors.lastname: Jain
authors.forename: Jeremy
authors.initials: J
authors.lastname: Koppel
authors.forename: Anne
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.forename: Corinne
authors.initials: C
authors.lastname: Lendon
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
authors.forename: Fabien
authors.initials: F
authors.lastname: Campagne
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D002462:Cell Membrane / Q000378:metabolism; D002879:Chromosomes, Human, Pair 10; D003600:Cytosol / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D011110:Polymorphism, Genetic; D016415:Sequence Alignment
chemical_list: D016229:Amyloid beta-Peptides; C530077:CALHM1 protein, human; D015220:Calcium Channels; D008562:Membrane Glycoproteins; D002118:Calcium