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 Campagne; Philippe Marambaud

doi:10.1016/j.cell.2008.05.048

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 Campagne

Philippe Marambaud

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English
Pages (from-to)	1149-1161
Number of pages	12
Journal	Cell
Volume	133
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2008.05.048
Publication status	Published - 27 Jun 2008

Keywords

HUMDISEASE
PROTEINS
SIGNALING

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10.1016/j.cell.2008.05.048

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Dreses-Werringloer, U., Lambert, J. C., Vingtdeux, V., Zhao, H., Vais, H., Siebert, A., Jain, A., Koppel, J., Rovelet-Lecrux, A., Hannequin, D., Pasquier, F., Galimberti, D., Scarpini, E., Mann, D., Lendon, C., Campion, D., Amouyel, P., Davies, P., Foskett, J. K., ... Marambaud, P. (2008). A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk. Cell, 133(7), 1149-1161. https://doi.org/10.1016/j.cell.2008.05.048

@article{3ef163b70d7f4a85a7fbe9a842f445cb,

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

abstract = "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. {\textcopyright} 2008 Elsevier Inc. All rights reserved.",

keywords = "HUMDISEASE, PROTEINS, SIGNALING",

author = "Ute Dreses-Werringloer and Lambert, \{Jean Charles\} and Val{\'e}rie Vingtdeux and Haitian Zhao and Horia Vais and Adam Siebert and Ankit Jain and Jeremy Koppel and Anne Rovelet-Lecrux and Didier Hannequin and Florence Pasquier and Daniela Galimberti and Elio Scarpini and David Mann and Corinne Lendon and Dominique Campion and Philippe Amouyel and Peter Davies and Foskett, \{J. Kevin\} and Fabien Campagne and Philippe Marambaud",

year = "2008",

month = jun,

day = "27",

doi = "10.1016/j.cell.2008.05.048",

language = "English",

volume = "133",

pages = "1149--1161",

journal = "Cell",

issn = "1097-4172",

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Dreses-Werringloer, U, Lambert, JC, Vingtdeux, V, Zhao, H, Vais, H, Siebert, A, Jain, A, Koppel, J, Rovelet-Lecrux, A, Hannequin, D, Pasquier, F, Galimberti, D, Scarpini, E, Mann, D, Lendon, C, Campion, D, Amouyel, P, Davies, P, Foskett, JK, Campagne, F & Marambaud, P 2008, 'A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk', Cell, vol. 133, no. 7, pp. 1149-1161. https://doi.org/10.1016/j.cell.2008.05.048

TY - JOUR

T1 - A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk

AU - Dreses-Werringloer, Ute

AU - Lambert, Jean Charles

AU - Vingtdeux, Valérie

AU - Zhao, Haitian

AU - Vais, Horia

AU - Siebert, Adam

AU - Jain, Ankit

AU - Koppel, Jeremy

AU - Rovelet-Lecrux, Anne

AU - Hannequin, Didier

AU - Pasquier, Florence

AU - Galimberti, Daniela

AU - Scarpini, Elio

AU - Mann, David

AU - Lendon, Corinne

AU - Campion, Dominique

AU - Amouyel, Philippe

AU - Davies, Peter

AU - Foskett, J. Kevin

AU - Campagne, Fabien

AU - Marambaud, Philippe

PY - 2008/6/27

Y1 - 2008/6/27

N2 - 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.

AB - 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.

KW - HUMDISEASE

KW - PROTEINS

KW - SIGNALING

U2 - 10.1016/j.cell.2008.05.048

DO - 10.1016/j.cell.2008.05.048

M3 - Article

SN - 1097-4172

VL - 133

SP - 1149

EP - 1161

JO - Cell

JF - Cell

IS - 7

ER -

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

Abstract

Keywords

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