SORL1 mutations in early- and late-onset Alzheimer disease
Identifieur interne : 000460 ( Main/Exploration ); précédent : 000459; suivant : 000461SORL1 mutations in early- and late-onset Alzheimer disease
Auteurs : Michael L. Cuccaro ; Regina M. Carney ; Yalun Zhang ; Christopher Bohm ; Brian W. Kunkle ; Badri N. Vardarajan ; Patrice L. Whitehead ; Holly N. Cukier ; Richard Mayeux ; Peter St. George-Hyslop ; Margaret A. Pericak-VanceSource :
- Neurology: Genetics [ 2376-7839 ] ; 2016.
Abstract
To characterize the clinical and molecular effect of mutations in the sortilin-related receptor (
We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with
The findings from this study support an important role for
Url:
DOI: 10.1212/NXG.0000000000000116
PubMed: 27822510
PubMed Central: 5082932
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>SORL1</italic> mutations in early- and late-onset Alzheimer disease</title><author><name sortKey="Cuccaro, Michael L" sort="Cuccaro, Michael L" uniqKey="Cuccaro M" first="Michael L." last="Cuccaro">Michael L. Cuccaro</name></author><author><name sortKey="Carney, Regina M" sort="Carney, Regina M" uniqKey="Carney R" first="Regina M." last="Carney">Regina M. Carney</name></author><author><name sortKey="Zhang, Yalun" sort="Zhang, Yalun" uniqKey="Zhang Y" first="Yalun" last="Zhang">Yalun Zhang</name></author><author><name sortKey="Bohm, Christopher" sort="Bohm, Christopher" uniqKey="Bohm C" first="Christopher" last="Bohm">Christopher Bohm</name></author><author><name sortKey="Kunkle, Brian W" sort="Kunkle, Brian W" uniqKey="Kunkle B" first="Brian W." last="Kunkle">Brian W. Kunkle</name></author><author><name sortKey="Vardarajan, Badri N" sort="Vardarajan, Badri N" uniqKey="Vardarajan B" first="Badri N." last="Vardarajan">Badri N. Vardarajan</name></author><author><name sortKey="Whitehead, Patrice L" sort="Whitehead, Patrice L" uniqKey="Whitehead P" first="Patrice L." last="Whitehead">Patrice L. Whitehead</name></author><author><name sortKey="Cukier, Holly N" sort="Cukier, Holly N" uniqKey="Cukier H" first="Holly N." last="Cukier">Holly N. Cukier</name></author><author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name></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></author><author><name sortKey="Pericak Vance, Margaret A" sort="Pericak Vance, Margaret A" uniqKey="Pericak Vance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27822510</idno><idno type="pmc">5082932</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082932</idno><idno type="RBID">PMC:5082932</idno><idno type="doi">10.1212/NXG.0000000000000116</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000A50</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A50</idno><idno type="wicri:Area/Pmc/Curation">000A50</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A50</idno><idno type="wicri:Area/Pmc/Checkpoint">000169</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000169</idno><idno type="wicri:Area/Ncbi/Merge">002139</idno><idno type="wicri:Area/Ncbi/Curation">002139</idno><idno type="wicri:Area/Ncbi/Checkpoint">002139</idno><idno type="wicri:Area/Main/Merge">000461</idno><idno type="wicri:Area/Main/Curation">000460</idno><idno type="wicri:Area/Main/Exploration">000460</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>SORL1</italic> mutations in early- and late-onset Alzheimer disease</title><author><name sortKey="Cuccaro, Michael L" sort="Cuccaro, Michael L" uniqKey="Cuccaro M" first="Michael L." last="Cuccaro">Michael L. Cuccaro</name></author><author><name sortKey="Carney, Regina M" sort="Carney, Regina M" uniqKey="Carney R" first="Regina M." last="Carney">Regina M. Carney</name></author><author><name sortKey="Zhang, Yalun" sort="Zhang, Yalun" uniqKey="Zhang Y" first="Yalun" last="Zhang">Yalun Zhang</name></author><author><name sortKey="Bohm, Christopher" sort="Bohm, Christopher" uniqKey="Bohm C" first="Christopher" last="Bohm">Christopher Bohm</name></author><author><name sortKey="Kunkle, Brian W" sort="Kunkle, Brian W" uniqKey="Kunkle B" first="Brian W." last="Kunkle">Brian W. Kunkle</name></author><author><name sortKey="Vardarajan, Badri N" sort="Vardarajan, Badri N" uniqKey="Vardarajan B" first="Badri N." last="Vardarajan">Badri N. Vardarajan</name></author><author><name sortKey="Whitehead, Patrice L" sort="Whitehead, Patrice L" uniqKey="Whitehead P" first="Patrice L." last="Whitehead">Patrice L. Whitehead</name></author><author><name sortKey="Cukier, Holly N" sort="Cukier, Holly N" uniqKey="Cukier H" first="Holly N." last="Cukier">Holly N. Cukier</name></author><author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name></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></author><author><name sortKey="Pericak Vance, Margaret A" sort="Pericak Vance, Margaret A" uniqKey="Pericak Vance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name></author></analytic><series><title level="j">Neurology: Genetics</title><idno type="eISSN">2376-7839</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective:</title><p>To characterize the clinical and molecular effect of mutations in the sortilin-related receptor (<italic>SORL1</italic>) gene.</p></sec><sec><title>Methods:</title><p>We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with <italic>SORL1</italic> mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with <italic>SORL1</italic> mutations.</p></sec><sec><title>Results:</title><p><italic>SORL1</italic> alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking.</p></sec><sec><title>Conclusions:</title><p>The findings from this study support an important role for <italic>SORL1</italic> mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and <italic>SORL1</italic> mutations merits further investigation.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Karch, Cm" uniqKey="Karch C">CM Karch</name></author><author><name sortKey="Goate, Am" uniqKey="Goate A">AM Goate</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Rogaeva, E" uniqKey="Rogaeva E">E Rogaeva</name></author><author><name sortKey="Meng, Y" uniqKey="Meng Y">Y Meng</name></author><author><name sortKey="Lee, Jh" uniqKey="Lee J">JH Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Offe, K" uniqKey="Offe K">K Offe</name></author><author><name sortKey="Dodson, Se" uniqKey="Dodson S">SE Dodson</name></author><author><name sortKey="Shoemaker, Jt" uniqKey="Shoemaker J">JT 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Attie</name></author><author><name sortKey="Gandy, S" uniqKey="Gandy S">S Gandy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schmidt, V" uniqKey="Schmidt V">V Schmidt</name></author><author><name sortKey="Sporbert, A" uniqKey="Sporbert A">A Sporbert</name></author><author><name sortKey="Rohe, M" uniqKey="Rohe M">M Rohe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mehmedbasic, A" uniqKey="Mehmedbasic A">A Mehmedbasic</name></author><author><name sortKey="Christensen, Sk" uniqKey="Christensen S">SK Christensen</name></author><author><name sortKey="Nilsson, J" uniqKey="Nilsson J">J Nilsson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gustafsen, C" uniqKey="Gustafsen C">C Gustafsen</name></author><author><name sortKey="Glerup, S" uniqKey="Glerup S">S Glerup</name></author><author><name sortKey="Pallesen, Lt" uniqKey="Pallesen L">LT Pallesen</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list></list><tree><noCountry><name sortKey="Bohm, Christopher" sort="Bohm, Christopher" uniqKey="Bohm C" first="Christopher" last="Bohm">Christopher Bohm</name><name sortKey="Carney, Regina M" sort="Carney, Regina M" uniqKey="Carney R" first="Regina M." last="Carney">Regina M. Carney</name><name sortKey="Cuccaro, Michael L" sort="Cuccaro, Michael L" uniqKey="Cuccaro M" first="Michael L." last="Cuccaro">Michael L. Cuccaro</name><name sortKey="Cukier, Holly N" sort="Cukier, Holly N" uniqKey="Cukier H" first="Holly N." last="Cukier">Holly N. Cukier</name><name sortKey="Kunkle, Brian W" sort="Kunkle, Brian W" uniqKey="Kunkle B" first="Brian W." last="Kunkle">Brian W. Kunkle</name><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><name sortKey="Pericak Vance, Margaret A" sort="Pericak Vance, Margaret A" uniqKey="Pericak Vance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name><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><name sortKey="Vardarajan, Badri N" sort="Vardarajan, Badri N" uniqKey="Vardarajan B" first="Badri N." last="Vardarajan">Badri N. Vardarajan</name><name sortKey="Whitehead, Patrice L" sort="Whitehead, Patrice L" uniqKey="Whitehead P" first="Patrice L." last="Whitehead">Patrice L. Whitehead</name><name sortKey="Zhang, Yalun" sort="Zhang, Yalun" uniqKey="Zhang Y" first="Yalun" last="Zhang">Yalun Zhang</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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