AustralieFrV1, Main, Exploration, bibRecord, 008633

A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβlevels, and Alzheimer’s disease risk

Identifieur interne : 008633 ( Main/Exploration ); précédent : 008632; suivant : 008634

A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβlevels, and Alzheimer’s disease risk

Auteurs : Ute Dreses-Werringloer [États-Unis] ; Jean-Charles Lambert [France] ; Valérie Vingtdeux [États-Unis] ; Haitian Zhao [États-Unis] ; Horia Vais [États-Unis] ; Adam Siebert [États-Unis] ; Ankit Jain [États-Unis] ; Jeremy Koppel [États-Unis] ; Anne Rovelet-Lecrux [France] ; Didier Hannequin [France] ; Florence Pasquier [France] ; Daniela Galimberti [Italie] ; Elio Scarpini [Italie] ; David Mann [Royaume-Uni] ; Corinne Lendon [Australie] ; Dominique Campion [France] ; Philippe Amouyel [France] ; Peter Davies [États-Unis] ; J. Kevin Foskett [États-Unis] ; Fabien Campagne [États-Unis] ; Philippe Marambaud [États-Unis]

Source :

Cell [ 0092-8674 ] ; 2008.

RBID : PMC:2577842

Abstract

SUMMARY

Alzheimer’s disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral Aβ peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a novel 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 3,404 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 novel cerebral Ca²⁺ channel that controls Aβ levels and susceptibility to AD.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577842

DOI: 10.1016/j.cell.2008.05.048
PubMed: 18585350
PubMed Central: 2577842

Affiliations:

Le document en format XML

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<author><name sortKey="Jain, Ankit" sort="Jain, Ankit" uniqKey="Jain A" first="Ankit" last="Jain">Ankit Jain</name>
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<author><name sortKey="Koppel, Jeremy" sort="Koppel, Jeremy" uniqKey="Koppel J" first="Jeremy" last="Koppel">Jeremy Koppel</name>
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<author><name sortKey="Lendon, Corinne" sort="Lendon, Corinne" uniqKey="Lendon C" first="Corinne" last="Lendon">Corinne Lendon</name>
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<author><name sortKey="Campion, Dominique" sort="Campion, Dominique" uniqKey="Campion D" first="Dominique" last="Campion">Dominique Campion</name>
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<author><name sortKey="Foskett, J Kevin" sort="Foskett, J Kevin" uniqKey="Foskett J" first="J. Kevin" last="Foskett">J. Kevin Foskett</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Department of Physiology and Biophysics, and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
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<author><name sortKey="Marambaud, Philippe" sort="Marambaud, Philippe" uniqKey="Marambaud P" first="Philippe" last="Marambaud">Philippe Marambaud</name>
<affiliation wicri:level="2"><nlm:aff id="A1"> Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
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<affiliation wicri:level="2"><nlm:aff id="A9"> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
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 homeostasis, Aβlevels, and Alzheimer’s disease risk</title>
<author><name sortKey="Dreses Werringloer, Ute" sort="Dreses Werringloer, Ute" uniqKey="Dreses Werringloer U" first="Ute" last="Dreses-Werringloer">Ute Dreses-Werringloer</name>
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<author><name sortKey="Zhao, Haitian" sort="Zhao, Haitian" uniqKey="Zhao H" first="Haitian" last="Zhao">Haitian Zhao</name>
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<author><name sortKey="Vais, Horia" sort="Vais, Horia" uniqKey="Vais H" first="Horia" last="Vais">Horia Vais</name>
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</placeName>
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<author><name sortKey="Siebert, Adam" sort="Siebert, Adam" uniqKey="Siebert A" first="Adam" last="Siebert">Adam Siebert</name>
<affiliation wicri:level="2"><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
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<author><name sortKey="Jain, Ankit" sort="Jain, Ankit" uniqKey="Jain A" first="Ankit" last="Jain">Ankit Jain</name>
<affiliation wicri:level="2"><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Koppel, Jeremy" sort="Koppel, Jeremy" uniqKey="Koppel J" first="Jeremy" last="Koppel">Jeremy Koppel</name>
<affiliation wicri:level="2"><nlm:aff id="A1"> Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rovelet Lecrux, Anne" sort="Rovelet Lecrux, Anne" uniqKey="Rovelet Lecrux A" first="Anne" last="Rovelet-Lecrux">Anne Rovelet-Lecrux</name>
<affiliation wicri:level="3"><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> INSERM, U614, Faculté de médecine, Rouen</wicri:regionArea>
<placeName><region type="region">Région Normandie</region>
<region type="old region">Haute-Normandie</region>
<settlement type="city">Rouen</settlement>
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</author>
<author><name sortKey="Hannequin, Didier" sort="Hannequin, Didier" uniqKey="Hannequin D" first="Didier" last="Hannequin">Didier Hannequin</name>
<affiliation wicri:level="3"><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> INSERM, U614, Faculté de médecine, Rouen</wicri:regionArea>
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<settlement type="city">Rouen</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pasquier, Florence" sort="Pasquier, Florence" uniqKey="Pasquier F" first="Florence" last="Pasquier">Florence Pasquier</name>
<affiliation wicri:level="3"><nlm:aff id="A5"> Department of Neurology, University Hospital, Lille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> Department of Neurology, University Hospital, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Galimberti, Daniela" sort="Galimberti, Daniela" uniqKey="Galimberti D" first="Daniela" last="Galimberti">Daniela Galimberti</name>
<affiliation wicri:level="3"><nlm:aff id="A6"> Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea> Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Scarpini, Elio" sort="Scarpini, Elio" uniqKey="Scarpini E" first="Elio" last="Scarpini">Elio Scarpini</name>
<affiliation wicri:level="3"><nlm:aff id="A6"> Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea> Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mann, David" sort="Mann, David" uniqKey="Mann D" first="David" last="Mann">David Mann</name>
<affiliation wicri:level="4"><nlm:aff id="A7"> Greater Manchester Neurosciences Centre, University of Manchester, Manchester, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea> Greater Manchester Neurosciences Centre, University of Manchester, Manchester</wicri:regionArea>
<placeName><settlement type="city">Manchester</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Manchester</region>
<settlement type="city">Manchester</settlement>
</placeName>
<orgName type="university">Université de Manchester</orgName>
</affiliation>
</author>
<author><name sortKey="Lendon, Corinne" sort="Lendon, Corinne" uniqKey="Lendon C" first="Corinne" last="Lendon">Corinne Lendon</name>
<affiliation wicri:level="1"><nlm:aff id="A8"> Molecular Psychiatry Group, Queensland Institute of Medical Research, Brisbane, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea> Molecular Psychiatry Group, Queensland Institute of Medical Research, Brisbane</wicri:regionArea>
<wicri:noRegion>Brisbane</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Campion, Dominique" sort="Campion, Dominique" uniqKey="Campion D" first="Dominique" last="Campion">Dominique Campion</name>
<affiliation wicri:level="3"><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> INSERM, U614, Faculté de médecine, Rouen</wicri:regionArea>
<placeName><region type="region">Région Normandie</region>
<region type="old region">Haute-Normandie</region>
<settlement type="city">Rouen</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name>
<affiliation wicri:level="3"><nlm:aff id="A2"> INSERM, U744, Institut Pasteur de Lille, Université de Lille II, Lille, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> INSERM, U744, Institut Pasteur de Lille, Université de Lille II, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Davies, Peter" sort="Davies, Peter" uniqKey="Davies P" first="Peter" last="Davies">Peter Davies</name>
<affiliation wicri:level="2"><nlm:aff id="A1"> Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A9"> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Foskett, J Kevin" sort="Foskett, J Kevin" uniqKey="Foskett J" first="J. Kevin" last="Foskett">J. Kevin Foskett</name>
<affiliation wicri:level="2"><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Campagne, Fabien" sort="Campagne, Fabien" uniqKey="Campagne F" first="Fabien" last="Campagne">Fabien Campagne</name>
<affiliation wicri:level="2"><nlm:aff id="A10"> Department of Physiology and Biophysics, and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Department of Physiology and Biophysics, and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Marambaud, Philippe" sort="Marambaud, Philippe" uniqKey="Marambaud P" first="Philippe" last="Marambaud">Philippe Marambaud</name>
<affiliation wicri:level="2"><nlm:aff id="A1"> Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="A9"> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell</title>
<idno type="ISSN">0092-8674</idno>
<idno type="eISSN">1097-4172</idno>
<imprint><date when="2008">2008</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>SUMMARY</title>
<p id="P3">Alzheimer’s disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral Aβ peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a novel gene on 10q24.33 that we call <italic>CALHM1</italic>
. We show that <italic>CALHM1</italic>
 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca<sup>2+</sup>
 concentrations and Aβ levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca<sup>2+</sup>
 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 3,404 participants (allele-specific OR=1.44, <italic>P</italic>
=2×10<sup>−10</sup>
). We further found that the P86L polymorphism increases Aβ levels by interfering with CALHM1-mediated Ca<sup>2+</sup>
 permeability. We propose that <italic>CALHM1</italic>
 encodes an essential component of a novel cerebral Ca<sup>2+</sup>
 channel that controls Aβ levels and susceptibility to AD.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Italie</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
<region><li>Angleterre</li>
<li>Grand Manchester</li>
<li>Haute-Normandie</li>
<li>Hauts-de-France</li>
<li>Lombardie</li>
<li>Nord-Pas-de-Calais</li>
<li>Pennsylvanie</li>
<li>Région Normandie</li>
<li>État de New York</li>
</region>
<settlement><li>Lille</li>
<li>Manchester</li>
<li>Milan</li>
<li>Rouen</li>
</settlement>
<orgName><li>Université de Manchester</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="État de New York"><name sortKey="Dreses Werringloer, Ute" sort="Dreses Werringloer, Ute" uniqKey="Dreses Werringloer U" first="Ute" last="Dreses-Werringloer">Ute Dreses-Werringloer</name>
</region>
<name sortKey="Campagne, Fabien" sort="Campagne, Fabien" uniqKey="Campagne F" first="Fabien" last="Campagne">Fabien Campagne</name>
<name sortKey="Davies, Peter" sort="Davies, Peter" uniqKey="Davies P" first="Peter" last="Davies">Peter Davies</name>
<name sortKey="Davies, Peter" sort="Davies, Peter" uniqKey="Davies P" first="Peter" last="Davies">Peter Davies</name>
<name sortKey="Foskett, J Kevin" sort="Foskett, J Kevin" uniqKey="Foskett J" first="J. Kevin" last="Foskett">J. Kevin Foskett</name>
<name sortKey="Jain, Ankit" sort="Jain, Ankit" uniqKey="Jain A" first="Ankit" last="Jain">Ankit Jain</name>
<name sortKey="Koppel, Jeremy" sort="Koppel, Jeremy" uniqKey="Koppel J" first="Jeremy" last="Koppel">Jeremy Koppel</name>
<name sortKey="Marambaud, Philippe" sort="Marambaud, Philippe" uniqKey="Marambaud P" first="Philippe" last="Marambaud">Philippe Marambaud</name>
<name sortKey="Marambaud, Philippe" sort="Marambaud, Philippe" uniqKey="Marambaud P" first="Philippe" last="Marambaud">Philippe Marambaud</name>
<name sortKey="Siebert, Adam" sort="Siebert, Adam" uniqKey="Siebert A" first="Adam" last="Siebert">Adam Siebert</name>
<name sortKey="Vais, Horia" sort="Vais, Horia" uniqKey="Vais H" first="Horia" last="Vais">Horia Vais</name>
<name sortKey="Vingtdeux, Valerie" sort="Vingtdeux, Valerie" uniqKey="Vingtdeux V" first="Valérie" last="Vingtdeux">Valérie Vingtdeux</name>
<name sortKey="Zhao, Haitian" sort="Zhao, Haitian" uniqKey="Zhao H" first="Haitian" last="Zhao">Haitian Zhao</name>
</country>
<country name="France"><region name="Hauts-de-France"><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name>
</region>
<name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name>
<name sortKey="Campion, Dominique" sort="Campion, Dominique" uniqKey="Campion D" first="Dominique" last="Campion">Dominique Campion</name>
<name sortKey="Hannequin, Didier" sort="Hannequin, Didier" uniqKey="Hannequin D" first="Didier" last="Hannequin">Didier Hannequin</name>
<name sortKey="Pasquier, Florence" sort="Pasquier, Florence" uniqKey="Pasquier F" first="Florence" last="Pasquier">Florence Pasquier</name>
<name sortKey="Rovelet Lecrux, Anne" sort="Rovelet Lecrux, Anne" uniqKey="Rovelet Lecrux A" first="Anne" last="Rovelet-Lecrux">Anne Rovelet-Lecrux</name>
</country>
<country name="Italie"><region name="Lombardie"><name sortKey="Galimberti, Daniela" sort="Galimberti, Daniela" uniqKey="Galimberti D" first="Daniela" last="Galimberti">Daniela Galimberti</name>
</region>
<name sortKey="Scarpini, Elio" sort="Scarpini, Elio" uniqKey="Scarpini E" first="Elio" last="Scarpini">Elio Scarpini</name>
</country>
<country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Mann, David" sort="Mann, David" uniqKey="Mann D" first="David" last="Mann">David Mann</name>
</region>
</country>
<country name="Australie"><noRegion><name sortKey="Lendon, Corinne" sort="Lendon, Corinne" uniqKey="Lendon C" first="Corinne" last="Lendon">Corinne Lendon</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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Serveur d'exploration sur les relations entre la France et l'Australie

A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβlevels, and Alzheimer’s disease risk

A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβlevels, and Alzheimer’s disease risk

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