Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease
Identifieur interne : 001A50 ( Main/Corpus ); précédent : 001A49; suivant : 001A51Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease
Auteurs : Frank P. Marx ; Carsten Holzmann ; Karsten M. Strauss ; Lei Li ; Olaf Eberhardt ; Ellen Gerhardt ; Mark R. Cookson ; Dena Hernandez ; Matt J. Farrer ; Jennifer Kachergus ; Simone Engelender ; Christopher A. Ross ; Klaus Berger ; Ludger Scho Ls ; Jo Rg B. Schulz ; Olaf Riess ; Rejko Kru GerSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2003-06-01.
Abstract
Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an α-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.
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DOI: 10.1093/hmg/ddg134
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Farrer</name><affiliation><mods:affiliation>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</mods:affiliation></affiliation></author><author><name sortKey="Kachergus, Jennifer" sort="Kachergus, Jennifer" uniqKey="Kachergus J" first="Jennifer" last="Kachergus">Jennifer Kachergus</name><affiliation><mods:affiliation>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</mods:affiliation></affiliation></author><author><name sortKey="Engelender, Simone" sort="Engelender, Simone" uniqKey="Engelender S" first="Simone" last="Engelender">Simone Engelender</name><affiliation><mods:affiliation>Department of Pharmacology, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,</mods:affiliation></affiliation></author><author><name sortKey="Ross, Christopher A" sort="Ross, Christopher A" uniqKey="Ross C" first="Christopher A." last="Ross">Christopher A. Ross</name><affiliation><mods:affiliation>Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA,</mods:affiliation></affiliation></author><author><name sortKey="Berger, Klaus" sort="Berger, Klaus" uniqKey="Berger K" first="Klaus" last="Berger">Klaus Berger</name><affiliation><mods:affiliation>Department of Epidemiology and Social Medicine, University of Münster, Germany,</mods:affiliation></affiliation></author><author><name sortKey="Scho Ls, Ludger" sort="Scho Ls, Ludger" uniqKey="Scho Ls L" first="Ludger" last="Scho Ls">Ludger Scho Ls</name><affiliation><mods:affiliation>Neurology, University of Bochum, Bochum, Germany and</mods:affiliation></affiliation></author><author><name sortKey="Schulz, Jo Rg B" sort="Schulz, Jo Rg B" uniqKey="Schulz J" first="Jo Rg B." last="Schulz">Jo Rg B. Schulz</name><affiliation><mods:affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</mods:affiliation></affiliation></author><author><name sortKey="Riess, Olaf" sort="Riess, Olaf" uniqKey="Riess O" first="Olaf" last="Riess">Olaf Riess</name><affiliation><mods:affiliation>Department of Medical Genetics, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Kru Ger, Rejko" sort="Kru Ger, Rejko" uniqKey="Kru Ger R" first="Rejko" last="Kru Ger">Rejko Kru Ger</name><affiliation><mods:affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Hum. Mol. Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2003-06-01">2003-06-01</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1223">1223</biblScope><biblScope unit="page" to="1231">1231</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">A26BAACBE6D61CBA3B0772B2E62FB05A9A9A8118</idno><idno type="DOI">10.1093/hmg/ddg134</idno><idno type="local">ddg134</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an α-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Frank P. Marx</name><affiliations><json:string>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</json:string></affiliations></json:item><json:item><name>Carsten Holzmann</name><affiliations><json:string>Department of Medical Genetics, University of Rostock, Rostock, Germany,</json:string></affiliations></json:item><json:item><name>Karsten M. Strauss</name><affiliations><json:string>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</json:string></affiliations></json:item><json:item><name>Lei Li</name><affiliations><json:string>Department of Medical Genetics, University of Rostock, Rostock, Germany,</json:string><json:string>Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical University, Wuhan, People's Republic of China,</json:string></affiliations></json:item><json:item><name>Olaf Eberhardt</name><affiliations><json:string>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</json:string></affiliations></json:item><json:item><name>Ellen Gerhardt</name><affiliations><json:string>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</json:string></affiliations></json:item><json:item><name>Mark R. Cookson</name><affiliations><json:string>Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA,</json:string></affiliations></json:item><json:item><name>Dena Hernandez</name><affiliations><json:string>Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA,</json:string></affiliations></json:item><json:item><name>Matt J. Farrer</name><affiliations><json:string>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</json:string></affiliations></json:item><json:item><name>Jennifer Kachergus</name><affiliations><json:string>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</json:string></affiliations></json:item><json:item><name>Simone Engelender</name><affiliations><json:string>Department of Pharmacology, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,</json:string></affiliations></json:item><json:item><name>Christopher A. Ross</name><affiliations><json:string>Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA,</json:string></affiliations></json:item><json:item><name>Klaus Berger</name><affiliations><json:string>Department of Epidemiology and Social Medicine, University of Münster, Germany,</json:string></affiliations></json:item><json:item><name>Ludger Schöls</name><affiliations><json:string>Neurology, University of Bochum, Bochum, Germany and</json:string></affiliations></json:item><json:item><name>Jörg B. Schulz</name><affiliations><json:string>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</json:string></affiliations></json:item><json:item><name>Olaf Riess</name><affiliations><json:string>Department of Medical Genetics, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Rejko Krüger</name><affiliations><json:string>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Article</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an α-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.</abstract><qualityIndicators><score>7.592</score><pdfVersion>1.2</pdfVersion><pdfPageSize>610 x 795 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1509</abstractCharCount><pdfWordCount>4868</pdfWordCount><pdfCharCount>32877</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>227</abstractWordCount></qualityIndicators><title>Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's 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M.</forename><surname>Strauss</surname></persName><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation></author><author><persName><forename type="first">Lei</forename><surname>Li</surname></persName><affiliation>Department of Medical Genetics, University of Rostock, Rostock, Germany,</affiliation><affiliation>Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical University, Wuhan, People's Republic of China,</affiliation></author><author><persName><forename type="first">Olaf</forename><surname>Eberhardt</surname></persName><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation></author><author><persName><forename type="first">Ellen</forename><surname>Gerhardt</surname></persName><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation></author><author><persName><forename type="first">Mark R.</forename><surname>Cookson</surname></persName><affiliation>Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA,</affiliation></author><author><persName><forename type="first">Dena</forename><surname>Hernandez</surname></persName><affiliation>Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA,</affiliation></author><author><persName><forename type="first">Matt J.</forename><surname>Farrer</surname></persName><affiliation>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</affiliation></author><author><persName><forename type="first">Jennifer</forename><surname>Kachergus</surname></persName><affiliation>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</affiliation></author><author><persName><forename type="first">Simone</forename><surname>Engelender</surname></persName><affiliation>Department of Pharmacology, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,</affiliation></author><author><persName><forename type="first">Christopher A.</forename><surname>Ross</surname></persName><affiliation>Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA,</affiliation></author><author><persName><forename type="first">Klaus</forename><surname>Berger</surname></persName><affiliation>Department of Epidemiology and Social Medicine, University of Münster, Germany,</affiliation></author><author><persName><forename type="first">Ludger</forename><surname>Schöls</surname></persName><affiliation>Neurology, University of Bochum, Bochum, Germany and</affiliation></author><author><persName><forename type="first">Jörg B.</forename><surname>Schulz</surname></persName><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation></author><author><persName><forename type="first">Olaf</forename><surname>Riess</surname></persName><affiliation>Department of Medical Genetics, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Rejko</forename><surname>Krüger</surname></persName><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Hum. Mol. Genet.</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2003-06-01"></date><biblScope unit="volume">12</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1223">1223</biblScope><biblScope unit="page" to="1231">1231</biblScope></imprint></monogr><idno type="istex">A26BAACBE6D61CBA3B0772B2E62FB05A9A9A8118</idno><idno type="DOI">10.1093/hmg/ddg134</idno><idno type="local">ddg134</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2003</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an α-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.</p></abstract></profileDesc><revisionDesc><change when="2003-06-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/A26BAACBE6D61CBA3B0772B2E62FB05A9A9A8118/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">hmg</journal-id><journal-id journal-id-type="nlm-ta">Hum Mol Genet</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">Hum. Mol. Genet.</abbrev-journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">ddg134</article-id><article-id pub-id-type="doi">10.1093/hmg/ddg134</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Marx</surname><given-names>Frank P.</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Holzmann</surname><given-names>Carsten</given-names></name><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Strauss</surname><given-names>Karsten M.</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Lei</given-names></name><xref rid="AF2">2</xref><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Eberhardt</surname><given-names>Olaf</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gerhardt</surname><given-names>Ellen</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Cookson</surname><given-names>Mark R.</given-names></name><xref rid="AF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Hernandez</surname><given-names>Dena</given-names></name><xref rid="AF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Farrer</surname><given-names>Matt J.</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Kachergus</surname><given-names>Jennifer</given-names></name><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Engelender</surname><given-names>Simone</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Ross</surname><given-names>Christopher A.</given-names></name><xref rid="AF7">7</xref></contrib><contrib contrib-type="author"><name><surname>Berger</surname><given-names>Klaus</given-names></name><xref rid="AF8">8</xref></contrib><contrib contrib-type="author"><name><surname>Schöls</surname><given-names>Ludger</given-names></name><xref rid="AF9">9</xref></contrib><contrib contrib-type="author"><name><surname>Schulz</surname><given-names>Jörg B.</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Riess</surname><given-names>Olaf</given-names></name><xref rid="AF10">10</xref></contrib><contrib contrib-type="author"><name><surname>Krüger</surname><given-names>Rejko</given-names></name><xref rid="AF1">1</xref><xref rid="FN1">*</xref></contrib><aff id="AF1"><sup>1</sup>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</aff><aff id="AF2"><sup>2</sup>Department of Medical Genetics, University of Rostock, Rostock, Germany,</aff><aff id="AF3"><sup>3</sup>Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical University, Wuhan, People's Republic of China,</aff><aff id="AF4"><sup>4</sup>Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA,</aff><aff id="AF5"><sup>5</sup>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</aff><aff id="AF6"><sup>6</sup>Department of Pharmacology, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,</aff><aff id="AF7"><sup>7</sup>Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA,</aff><aff id="AF8"><sup>8</sup>Department of Epidemiology and Social Medicine, University of Münster, Germany,</aff><aff id="AF9"><sup>9</sup>Neurology, University of Bochum, Bochum, Germany and</aff><aff id="AF10"><sup>10</sup>Department of Medical Genetics, University of Tübingen, Tübingen, Germany</aff></contrib-group><pub-date pub-type="ppub"><day>1</day><month>06</month><year>2003</year></pub-date><volume>12</volume><issue>11</issue><fpage>1223</fpage><lpage>1231</lpage><history><date date-type="accepted"><day>21</day><month>03</month><year>2003</year></date><date date-type="received"><day>4</day><month>02</month><year>2003</year></date></history><permissions><copyright-year>2003</copyright-year></permissions><abstract xml:lang="en"><p>Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an α-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>1223</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Frank P.</namePart><namePart type="family">Marx</namePart><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carsten</namePart><namePart type="family">Holzmann</namePart><affiliation>Department of Medical Genetics, University of Rostock, Rostock, Germany,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Karsten M.</namePart><namePart type="family">Strauss</namePart><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lei</namePart><namePart type="family">Li</namePart><affiliation>Department of Medical Genetics, University of Rostock, Rostock, Germany,</affiliation><affiliation>Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical University, Wuhan, People's Republic of China,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Olaf</namePart><namePart type="family">Eberhardt</namePart><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ellen</namePart><namePart type="family">Gerhardt</namePart><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark R.</namePart><namePart type="family">Cookson</namePart><affiliation>Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dena</namePart><namePart type="family">Hernandez</namePart><affiliation>Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Matt J.</namePart><namePart type="family">Farrer</namePart><affiliation>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jennifer</namePart><namePart type="family">Kachergus</namePart><affiliation>Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Simone</namePart><namePart type="family">Engelender</namePart><affiliation>Department of Pharmacology, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher A.</namePart><namePart type="family">Ross</namePart><affiliation>Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Klaus</namePart><namePart type="family">Berger</namePart><affiliation>Department of Epidemiology and Social Medicine, University of Münster, Germany,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ludger</namePart><namePart type="family">Schöls</namePart><affiliation>Neurology, University of Bochum, Bochum, Germany and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jörg B.</namePart><namePart type="family">Schulz</namePart><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Olaf</namePart><namePart type="family">Riess</namePart><affiliation>Department of Medical Genetics, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rejko</namePart><namePart type="family">Krüger</namePart><affiliation>Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2003-06-01</dateIssued><copyrightDate encoding="w3cdtf">2003</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an α-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><titleInfo type="abbreviated"><title>Hum. Mol. 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