A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβlevels, and Alzheimer’s disease risk
Identifieur interne : 001416 ( Pmc/Corpus ); précédent : 001415; suivant : 001417A polymorphism in CALHM1 influences Ca2+ homeostasis, Aβlevels, and Alzheimer’s disease risk
Auteurs : 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 MarambaudSource :
- Cell [ 0092-8674 ] ; 2008.
Abstract
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
Url:
DOI: 10.1016/j.cell.2008.05.048
PubMed: 18585350
PubMed Central: 2577842
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PMC:2577842Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A polymorphism in CALHM1 influences Ca<sup>2+</sup>
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>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name>
<affiliation><nlm:aff id="A2"> INSERM, U744, Institut Pasteur de Lille, Université de Lille II, Lille, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vingtdeux, Valerie" sort="Vingtdeux, Valerie" uniqKey="Vingtdeux V" first="Valérie" last="Vingtdeux">Valérie Vingtdeux</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Zhao, Haitian" sort="Zhao, Haitian" uniqKey="Zhao H" first="Haitian" last="Zhao">Haitian Zhao</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Vais, Horia" sort="Vais, Horia" uniqKey="Vais H" first="Horia" last="Vais">Horia Vais</name>
<affiliation><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Siebert, Adam" sort="Siebert, Adam" uniqKey="Siebert A" first="Adam" last="Siebert">Adam Siebert</name>
<affiliation><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jain, Ankit" sort="Jain, Ankit" uniqKey="Jain A" first="Ankit" last="Jain">Ankit Jain</name>
<affiliation><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Koppel, Jeremy" sort="Koppel, Jeremy" uniqKey="Koppel J" first="Jeremy" last="Koppel">Jeremy Koppel</name>
<affiliation><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>
</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><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hannequin, Didier" sort="Hannequin, Didier" uniqKey="Hannequin D" first="Didier" last="Hannequin">Didier Hannequin</name>
<affiliation><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pasquier, Florence" sort="Pasquier, Florence" uniqKey="Pasquier F" first="Florence" last="Pasquier">Florence Pasquier</name>
<affiliation><nlm:aff id="A5"> Department of Neurology, University Hospital, Lille, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Galimberti, Daniela" sort="Galimberti, Daniela" uniqKey="Galimberti D" first="Daniela" last="Galimberti">Daniela Galimberti</name>
<affiliation><nlm:aff id="A6"> Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Scarpini, Elio" sort="Scarpini, Elio" uniqKey="Scarpini E" first="Elio" last="Scarpini">Elio Scarpini</name>
<affiliation><nlm:aff id="A6"> Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mann, David" sort="Mann, David" uniqKey="Mann D" first="David" last="Mann">David Mann</name>
<affiliation><nlm:aff id="A7"> Greater Manchester Neurosciences Centre, University of Manchester, Manchester, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lendon, Corinne" sort="Lendon, Corinne" uniqKey="Lendon C" first="Corinne" last="Lendon">Corinne Lendon</name>
<affiliation><nlm:aff id="A8"> Molecular Psychiatry Group, Queensland Institute of Medical Research, Brisbane, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Campion, Dominique" sort="Campion, Dominique" uniqKey="Campion D" first="Dominique" last="Campion">Dominique Campion</name>
<affiliation><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name>
<affiliation><nlm:aff id="A2"> INSERM, U744, Institut Pasteur de Lille, Université de Lille II, Lille, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Davies, Peter" sort="Davies, Peter" uniqKey="Davies P" first="Peter" last="Davies">Peter Davies</name>
<affiliation><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>
</affiliation>
<affiliation><nlm:aff id="A9"> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA</nlm:aff>
</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><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Campagne, Fabien" sort="Campagne, Fabien" uniqKey="Campagne F" first="Fabien" last="Campagne">Fabien Campagne</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Marambaud, Philippe" sort="Marambaud, Philippe" uniqKey="Marambaud P" first="Philippe" last="Marambaud">Philippe Marambaud</name>
<affiliation><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>
</affiliation>
<affiliation><nlm:aff id="A9"> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA</nlm:aff>
</affiliation>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A polymorphism in CALHM1 influences Ca<sup>2+</sup>
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>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Lambert, Jean Charles" sort="Lambert, Jean Charles" uniqKey="Lambert J" first="Jean-Charles" last="Lambert">Jean-Charles Lambert</name>
<affiliation><nlm:aff id="A2"> INSERM, U744, Institut Pasteur de Lille, Université de Lille II, Lille, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vingtdeux, Valerie" sort="Vingtdeux, Valerie" uniqKey="Vingtdeux V" first="Valérie" last="Vingtdeux">Valérie Vingtdeux</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Zhao, Haitian" sort="Zhao, Haitian" uniqKey="Zhao H" first="Haitian" last="Zhao">Haitian Zhao</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Vais, Horia" sort="Vais, Horia" uniqKey="Vais H" first="Horia" last="Vais">Horia Vais</name>
<affiliation><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Siebert, Adam" sort="Siebert, Adam" uniqKey="Siebert A" first="Adam" last="Siebert">Adam Siebert</name>
<affiliation><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jain, Ankit" sort="Jain, Ankit" uniqKey="Jain A" first="Ankit" last="Jain">Ankit Jain</name>
<affiliation><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Koppel, Jeremy" sort="Koppel, Jeremy" uniqKey="Koppel J" first="Jeremy" last="Koppel">Jeremy Koppel</name>
<affiliation><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>
</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><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hannequin, Didier" sort="Hannequin, Didier" uniqKey="Hannequin D" first="Didier" last="Hannequin">Didier Hannequin</name>
<affiliation><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pasquier, Florence" sort="Pasquier, Florence" uniqKey="Pasquier F" first="Florence" last="Pasquier">Florence Pasquier</name>
<affiliation><nlm:aff id="A5"> Department of Neurology, University Hospital, Lille, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Galimberti, Daniela" sort="Galimberti, Daniela" uniqKey="Galimberti D" first="Daniela" last="Galimberti">Daniela Galimberti</name>
<affiliation><nlm:aff id="A6"> Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Scarpini, Elio" sort="Scarpini, Elio" uniqKey="Scarpini E" first="Elio" last="Scarpini">Elio Scarpini</name>
<affiliation><nlm:aff id="A6"> Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mann, David" sort="Mann, David" uniqKey="Mann D" first="David" last="Mann">David Mann</name>
<affiliation><nlm:aff id="A7"> Greater Manchester Neurosciences Centre, University of Manchester, Manchester, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lendon, Corinne" sort="Lendon, Corinne" uniqKey="Lendon C" first="Corinne" last="Lendon">Corinne Lendon</name>
<affiliation><nlm:aff id="A8"> Molecular Psychiatry Group, Queensland Institute of Medical Research, Brisbane, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Campion, Dominique" sort="Campion, Dominique" uniqKey="Campion D" first="Dominique" last="Campion">Dominique Campion</name>
<affiliation><nlm:aff id="A4"> INSERM, U614, Faculté de médecine, Rouen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name>
<affiliation><nlm:aff id="A2"> INSERM, U744, Institut Pasteur de Lille, Université de Lille II, Lille, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Davies, Peter" sort="Davies, Peter" uniqKey="Davies P" first="Peter" last="Davies">Peter Davies</name>
<affiliation><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>
</affiliation>
<affiliation><nlm:aff id="A9"> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA</nlm:aff>
</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><nlm:aff id="A3"> Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Campagne, Fabien" sort="Campagne, Fabien" uniqKey="Campagne F" first="Fabien" last="Campagne">Fabien Campagne</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Marambaud, Philippe" sort="Marambaud, Philippe" uniqKey="Marambaud P" first="Philippe" last="Marambaud">Philippe Marambaud</name>
<affiliation><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>
</affiliation>
<affiliation><nlm:aff id="A9"> Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA</nlm:aff>
</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>
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<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>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0413066</journal-id>
<journal-id journal-id-type="pubmed-jr-id">2830</journal-id>
<journal-id journal-id-type="nlm-ta">Cell</journal-id>
<journal-title>Cell</journal-title>
<issn pub-type="ppub">0092-8674</issn>
<issn pub-type="epub">1097-4172</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">18585350</article-id>
<article-id pub-id-type="pmc">2577842</article-id>
<article-id pub-id-type="doi">10.1016/j.cell.2008.05.048</article-id>
<article-id pub-id-type="manuscript">NIHMS56596</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>A polymorphism in CALHM1 influences Ca<sup>2+</sup>
homeostasis, Aβlevels, and Alzheimer’s disease risk</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Dreses-Werringloer</surname>
<given-names>Ute</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lambert</surname>
<given-names>Jean-Charles</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vingtdeux</surname>
<given-names>Valérie</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhao</surname>
<given-names>Haitian</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vais</surname>
<given-names>Horia</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Siebert</surname>
<given-names>Adam</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jain</surname>
<given-names>Ankit</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Koppel</surname>
<given-names>Jeremy</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rovelet-Lecrux</surname>
<given-names>Anne</given-names>
</name>
<xref rid="A4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hannequin</surname>
<given-names>Didier</given-names>
</name>
<xref rid="A4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pasquier</surname>
<given-names>Florence</given-names>
</name>
<xref rid="A5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Galimberti</surname>
<given-names>Daniela</given-names>
</name>
<xref rid="A6" ref-type="aff">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Scarpini</surname>
<given-names>Elio</given-names>
</name>
<xref rid="A6" ref-type="aff">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mann</surname>
<given-names>David</given-names>
</name>
<xref rid="A7" ref-type="aff">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lendon</surname>
<given-names>Corinne</given-names>
</name>
<xref rid="A8" ref-type="aff">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Campion</surname>
<given-names>Dominique</given-names>
</name>
<xref rid="A4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Amouyel</surname>
<given-names>Philippe</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Davies</surname>
<given-names>Peter</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
<xref rid="A9" ref-type="aff">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Foskett</surname>
<given-names>J. Kevin</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Campagne</surname>
<given-names>Fabien</given-names>
</name>
<xref rid="A10" ref-type="aff">10</xref>
<xref rid="FN1" ref-type="author-notes">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marambaud</surname>
<given-names>Philippe</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
<xref rid="A9" ref-type="aff">9</xref>
<xref rid="FN1" ref-type="author-notes">*</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, USA</aff>
<aff id="A2"><label>2</label>
INSERM, U744, Institut Pasteur de Lille, Université de Lille II, Lille, France</aff>
<aff id="A3"><label>3</label>
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA</aff>
<aff id="A4"><label>4</label>
INSERM, U614, Faculté de médecine, Rouen, France</aff>
<aff id="A5"><label>5</label>
Department of Neurology, University Hospital, Lille, France</aff>
<aff id="A6"><label>6</label>
Department of Neurological Sciences, Dino Ferrari Center, IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy</aff>
<aff id="A7"><label>7</label>
Greater Manchester Neurosciences Centre, University of Manchester, Manchester, UK</aff>
<aff id="A8"><label>8</label>
Molecular Psychiatry Group, Queensland Institute of Medical Research, Brisbane, Australia</aff>
<aff id="A9"><label>9</label>
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA</aff>
<aff id="A10"><label>10</label>
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</aff>
<author-notes><corresp id="FN1">*Correspondence: <email>pmaramba@aecom.yu.edu</email>
(P.M.), <email>fac2003@med.cornell.edu</email>
(F.C.)</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>15</day>
<month>7</month>
<year>2008</year>
</pub-date>
<pub-date pub-type="ppub"><day>27</day>
<month>6</month>
<year>2008</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>27</day>
<month>6</month>
<year>2009</year>
</pub-date>
<volume>133</volume>
<issue>7</issue>
<fpage>1149</fpage>
<lpage>1161</lpage>
<abstract><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>
</abstract>
<contract-num rid="MH1">R01 MH059937-09</contract-num>
<contract-sponsor id="MH1">National Institute of Mental Health : NIMH</contract-sponsor>
</article-meta>
</front>
</pmc>
</record>
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