Coding mutations in SORL1 and Alzheimer’s disease
Identifieur interne : 000799 ( Pmc/Corpus ); précédent : 000798; suivant : 000800Coding mutations in SORL1 and Alzheimer’s disease
Auteurs : Badri N. Vardarajan ; Yalun Zhang ; Joseph H. Lee ; Rong Cheng ; Christopher Bohm ; Mahdi Ghani ; Christiane Reitz ; Dolly Reyes-Dumeyer ; Yufeng Shen ; Ekaterina Rogaeva ; Peter St George-Hyslop ; Richard MayeuxSource :
- Annals of neurology [ 0364-5134 ] ; 2015.
Abstract
Common single nucleotide polymorphisms in the
To identify functional
This was a family- and cohort-based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin recruited from Canada.
Prioritized coding variants in
17 coding exonic variants were significantly associated with disease. Two rare variants (rs117260922-E270K and rs143571823-T947M) with MAF<1% and one common variant (rs2298813-A528T) with MAF=14.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased Aβ40 and Aβ42 secretion for the rare variants (E270K and T947M) and increased Aβ42 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, though in slightly different ways, thereby failing to direct full-length APP into the retromer-recycling endosome pathway.
Common and rare variants in
Url:
DOI: 10.1002/ana.24305
PubMed: 25382023
PubMed Central: 4367199
Links to Exploration step
PMC:4367199Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Coding mutations in <italic>SORL1</italic>
and Alzheimer’s disease</title>
<author><name sortKey="Vardarajan, Badri N" sort="Vardarajan, Badri N" uniqKey="Vardarajan B" first="Badri N." last="Vardarajan">Badri N. Vardarajan</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zhang, Yalun" sort="Zhang, Yalun" uniqKey="Zhang Y" first="Yalun" last="Zhang">Yalun Zhang</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Joseph H" sort="Lee, Joseph H" uniqKey="Lee J" first="Joseph H." last="Lee">Joseph H. Lee</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A8">Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, CB2 0XY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cheng, Rong" sort="Cheng, Rong" uniqKey="Cheng R" first="Rong" last="Cheng">Rong Cheng</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bohm, Christopher" sort="Bohm, Christopher" uniqKey="Bohm C" first="Christopher" last="Bohm">Christopher Bohm</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Reyes Dumeyer, Dolly" sort="Reyes Dumeyer, Dolly" uniqKey="Reyes Dumeyer D" first="Dolly" last="Reyes-Dumeyer">Dolly Reyes-Dumeyer</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shen, Yufeng" sort="Shen, Yufeng" uniqKey="Shen Y" first="Yufeng" last="Shen">Yufeng Shen</name>
<affiliation><nlm:aff id="A5">The Department Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
</author>
<author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A8">Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, CB2 0XY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">The Department Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A6">The Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">25382023</idno>
<idno type="pmc">4367199</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367199</idno>
<idno type="RBID">PMC:4367199</idno>
<idno type="doi">10.1002/ana.24305</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">000799</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000799</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Coding mutations in <italic>SORL1</italic>
and Alzheimer’s disease</title>
<author><name sortKey="Vardarajan, Badri N" sort="Vardarajan, Badri N" uniqKey="Vardarajan B" first="Badri N." last="Vardarajan">Badri N. Vardarajan</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zhang, Yalun" sort="Zhang, Yalun" uniqKey="Zhang Y" first="Yalun" last="Zhang">Yalun Zhang</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Joseph H" sort="Lee, Joseph H" uniqKey="Lee J" first="Joseph H." last="Lee">Joseph H. Lee</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A8">Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, CB2 0XY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cheng, Rong" sort="Cheng, Rong" uniqKey="Cheng R" first="Rong" last="Cheng">Rong Cheng</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bohm, Christopher" sort="Bohm, Christopher" uniqKey="Bohm C" first="Christopher" last="Bohm">Christopher Bohm</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Reyes Dumeyer, Dolly" sort="Reyes Dumeyer, Dolly" uniqKey="Reyes Dumeyer D" first="Dolly" last="Reyes-Dumeyer">Dolly Reyes-Dumeyer</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shen, Yufeng" sort="Shen, Yufeng" uniqKey="Shen Y" first="Yufeng" last="Shen">Yufeng Shen</name>
<affiliation><nlm:aff id="A5">The Department Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
</author>
<author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name>
<affiliation><nlm:aff id="A7">Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A8">Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, CB2 0XY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name>
<affiliation><nlm:aff id="A1">The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A2">The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">The Department Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A6">The Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Annals of neurology</title>
<idno type="ISSN">0364-5134</idno>
<idno type="eISSN">1531-8249</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Importance</title>
<p id="P2">Common single nucleotide polymorphisms in the <italic>SORL1</italic>
gene have been associated with late onset Alzheimer’s disease (LOAD) but causal variants have not been fully characterized nor has the mechanism been established.</p>
</sec>
<sec id="S2"><title>Objective</title>
<p id="P3">To identify functional <italic>SORL1</italic>
mutations in patients with LOAD.</p>
</sec>
<sec id="S3"><title>Design and Participants</title>
<p id="P4">This was a family- and cohort-based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin recruited from Canada.</p>
</sec>
<sec id="S4"><title>Main Outcome Measure(s)</title>
<p id="P5">Prioritized coding variants in <italic>SORL1</italic>
detected by targeted re-sequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 (HEK) cell lines were tested for Aβ40 and Aβ42 secretion and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined.</p>
</sec>
<sec id="S5"><title>Results</title>
<p id="P6">17 coding exonic variants were significantly associated with disease. Two rare variants (rs117260922-E270K and rs143571823-T947M) with MAF<1% and one common variant (rs2298813-A528T) with MAF=14.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased Aβ40 and Aβ42 secretion for the rare variants (E270K and T947M) and increased Aβ42 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, though in slightly different ways, thereby failing to direct full-length APP into the retromer-recycling endosome pathway.</p>
</sec>
<sec id="S6"><title>Conclusions and Relevance</title>
<p id="P7">Common and rare variants in <italic>SORL1</italic>
elevate the risk of LOAD by directly affecting APP processing which, in turn can result in increased Aβ40 and Aβ42 secretion.</p>
</sec>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">7707449</journal-id>
<journal-id journal-id-type="pubmed-jr-id">656</journal-id>
<journal-id journal-id-type="nlm-ta">Ann Neurol</journal-id>
<journal-id journal-id-type="iso-abbrev">Ann. Neurol.</journal-id>
<journal-title-group><journal-title>Annals of neurology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0364-5134</issn>
<issn pub-type="epub">1531-8249</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25382023</article-id>
<article-id pub-id-type="pmc">4367199</article-id>
<article-id pub-id-type="doi">10.1002/ana.24305</article-id>
<article-id pub-id-type="manuscript">NIHMS641446</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Coding mutations in <italic>SORL1</italic>
and Alzheimer’s disease</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Vardarajan</surname>
<given-names>Badri N.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="author-notes" rid="FN1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Yalun</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
<xref ref-type="author-notes" rid="FN1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Joseph H.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A8">8</xref>
<xref ref-type="author-notes" rid="FN1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cheng</surname>
<given-names>Rong</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bohm</surname>
<given-names>Christopher</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ghani</surname>
<given-names>Mahdi</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Reitz</surname>
<given-names>Christiane</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Reyes-Dumeyer</surname>
<given-names>Dolly</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shen</surname>
<given-names>Yufeng</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rogaeva</surname>
<given-names>Ekaterina</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>St George-Hyslop</surname>
<given-names>Peter</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
<xref ref-type="aff" rid="A8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mayeux</surname>
<given-names>Richard</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A4">4</xref>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain</aff>
<aff id="A2"><label>2</label>
The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA</aff>
<aff id="A3"><label>3</label>
The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA</aff>
<aff id="A4"><label>4</label>
The Department Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA</aff>
<aff id="A5"><label>5</label>
The Department Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA</aff>
<aff id="A6"><label>6</label>
The Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA</aff>
<aff id="A7"><label>7</label>
Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto, Ontario, Canada, M5T 2S8</aff>
<aff id="A8"><label>8</label>
Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK, CB2 0XY</aff>
<author-notes><corresp id="cor1"><bold>Correspondence:</bold>
Richard Mayeux, MD, MSc., Sergievsky Center, 630 West 168<sup>th</sup>
Street, Columbia University, New York, NY 10032, Phone: 212-305-2391, <email>rpm2@columbia.edu</email>
, or, Peter St George Hyslop, MD, Tanz Center for Research, in Neurodegenerative Disease, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, Toronto M5T 2S8, Canada, Phone: 416-507-6861, <email>p.hyslop@utoronto.ca</email>
</corresp>
<fn id="FN1" fn-type="equal"><label>*</label>
<p id="P1">These authors contributed equally to the manuscript</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>23</day>
<month>2</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="ppub"><month>2</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>2</month>
<year>2016</year>
</pub-date>
<volume>77</volume>
<issue>2</issue>
<fpage>215</fpage>
<lpage>227</lpage>
<pmc-comment>elocation-id from pubmed: 10.1002/ana.24305</pmc-comment>
<abstract><sec id="S1"><title>Importance</title>
<p id="P2">Common single nucleotide polymorphisms in the <italic>SORL1</italic>
gene have been associated with late onset Alzheimer’s disease (LOAD) but causal variants have not been fully characterized nor has the mechanism been established.</p>
</sec>
<sec id="S2"><title>Objective</title>
<p id="P3">To identify functional <italic>SORL1</italic>
mutations in patients with LOAD.</p>
</sec>
<sec id="S3"><title>Design and Participants</title>
<p id="P4">This was a family- and cohort-based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin recruited from Canada.</p>
</sec>
<sec id="S4"><title>Main Outcome Measure(s)</title>
<p id="P5">Prioritized coding variants in <italic>SORL1</italic>
detected by targeted re-sequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 (HEK) cell lines were tested for Aβ40 and Aβ42 secretion and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined.</p>
</sec>
<sec id="S5"><title>Results</title>
<p id="P6">17 coding exonic variants were significantly associated with disease. Two rare variants (rs117260922-E270K and rs143571823-T947M) with MAF<1% and one common variant (rs2298813-A528T) with MAF=14.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased Aβ40 and Aβ42 secretion for the rare variants (E270K and T947M) and increased Aβ42 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, though in slightly different ways, thereby failing to direct full-length APP into the retromer-recycling endosome pathway.</p>
</sec>
<sec id="S6"><title>Conclusions and Relevance</title>
<p id="P7">Common and rare variants in <italic>SORL1</italic>
elevate the risk of LOAD by directly affecting APP processing which, in turn can result in increased Aβ40 and Aβ42 secretion.</p>
</sec>
</abstract>
<kwd-group><kwd>SORL1</kwd>
<kwd>common and rare variants</kwd>
<kwd>amyloid β</kwd>
<kwd>Alzheimer’s disease</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Canada/explor/ParkinsonCanadaV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000799 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000799 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Canada |area= ParkinsonCanadaV1 |flux= Pmc |étape= Corpus |type= RBID |clé= PMC:4367199 |texte= Coding mutations in SORL1 and Alzheimer’s disease }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:25382023" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \ | NlmPubMed2Wicri -a ParkinsonCanadaV1
This area was generated with Dilib version V0.6.29. |