A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk.
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.
Dreses-Werringloer
Ute
U
Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA.
Lambert
Jean-Charles
JC
Vingtdeux
Valérie
V
Zhao
Haitian
H
Vais
Horia
H
Siebert
Adam
A
Jain
Ankit
A
Koppel
Jeremy
J
Rovelet-Lecrux
Anne
A
Hannequin
Didier
D
Pasquier
Florence
F
Galimberti
Daniela
D
Scarpini
Elio
E
Mann
David
D
Lendon
Corinne
C
Campion
Dominique
D
Amouyel
Philippe
P
Davies
Peter
P
Foskett
J Kevin
JK
Campagne
Fabien
F
Marambaud
Philippe
P
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
D016229:Amyloid beta-Peptides; C530077:CALHM1 protein, human; D015220:Calcium Channels; D008562:Membrane Glycoproteins; D002118:Calcium