Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease
Identifieur interne : 002076 ( Main/Corpus ); précédent : 002075; suivant : 002077Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease
Auteurs : Jan O. Aasly ; Carles Vilari O-Güell ; Justus C. Dachsel ; Philip J. Webber ; Andrew B. West ; Kristoffer Haugarvoll ; Krisztina K. Johansen ; Mathias Toft ; John G. Nutt ; Haydeh Payami ; Jennifer M. Kachergus ; Sarah J. Lincoln ; Amela Felic ; Christian Wider ; Alexandra I. Soto-Ortolaza ; Stephanie A. Cobb ; Linda R. White ; Owen A. Ross ; Matthew J. FarrerSource :
- Movement Disorders [ 0885-3185 ] ; 2010-10-15.
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Abstract
Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism. © 2010 Movement Disorder Society
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DOI: 10.1002/mds.23265
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Aasly</name><affiliation><mods:affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</mods:affiliation></affiliation></author><author><name sortKey="Vilari O Ell, Carles" sort="Vilari O Ell, Carles" uniqKey="Vilari O Ell C" first="Carles" last="Vilari O-Güell">Carles Vilari O-Güell</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Dachsel, Justus C" sort="Dachsel, Justus C" uniqKey="Dachsel J" first="Justus C." last="Dachsel">Justus C. 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Soto-Ortolaza</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Cobb, Stephanie A" sort="Cobb, Stephanie A" uniqKey="Cobb S" first="Stephanie A." last="Cobb">Stephanie A. Cobb</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="White, Linda R" sort="White, Linda R" uniqKey="White L" first="Linda R." last="White">Linda R. White</name><affiliation><mods:affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</mods:affiliation></affiliation></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:E5FE65FB9782A041639FE9E054D4FF21331F0E9F</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1002/mds.23265</idno><idno type="url">https://api.istex.fr/document/E5FE65FB9782A041639FE9E054D4FF21331F0E9F/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">002076</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease</title><author><name sortKey="Aasly, Jan O" sort="Aasly, Jan O" uniqKey="Aasly J" first="Jan O." last="Aasly">Jan O. Aasly</name><affiliation><mods:affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</mods:affiliation></affiliation></author><author><name sortKey="Vilari O Ell, Carles" sort="Vilari O Ell, Carles" uniqKey="Vilari O Ell C" first="Carles" last="Vilari O-Güell">Carles Vilari O-Güell</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Dachsel, Justus C" sort="Dachsel, Justus C" uniqKey="Dachsel J" first="Justus C." last="Dachsel">Justus C. Dachsel</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Webber, Philip J" sort="Webber, Philip J" uniqKey="Webber P" first="Philip J." last="Webber">Philip J. Webber</name><affiliation><mods:affiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</mods:affiliation></affiliation></author><author><name sortKey="West, Andrew B" sort="West, Andrew B" uniqKey="West A" first="Andrew B." last="West">Andrew B. West</name><affiliation><mods:affiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</mods:affiliation></affiliation></author><author><name sortKey="Haugarvoll, Kristoffer" sort="Haugarvoll, Kristoffer" uniqKey="Haugarvoll K" first="Kristoffer" last="Haugarvoll">Kristoffer Haugarvoll</name><affiliation><mods:affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Johansen, Krisztina K" sort="Johansen, Krisztina K" uniqKey="Johansen K" first="Krisztina K." last="Johansen">Krisztina K. Johansen</name><affiliation><mods:affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</mods:affiliation></affiliation></author><author><name sortKey="Toft, Mathias" sort="Toft, Mathias" uniqKey="Toft M" first="Mathias" last="Toft">Mathias Toft</name><affiliation><mods:affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Nutt, John G" sort="Nutt, John G" uniqKey="Nutt J" first="John G." last="Nutt">John G. Nutt</name><affiliation><mods:affiliation>Department of Neurology, Oregon Health and Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon, USA</mods:affiliation></affiliation></author><author><name sortKey="Payami, Haydeh" sort="Payami, Haydeh" uniqKey="Payami H" first="Haydeh" last="Payami">Haydeh Payami</name><affiliation><mods:affiliation>Division of Genetic Disorders, New York State Department of Health, Wadsworth Center, Albany, New York, USA</mods:affiliation></affiliation></author><author><name sortKey="Kachergus, Jennifer M" sort="Kachergus, Jennifer M" uniqKey="Kachergus J" first="Jennifer M." last="Kachergus">Jennifer M. Kachergus</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Lincoln, Sarah J" sort="Lincoln, Sarah J" uniqKey="Lincoln S" first="Sarah J." last="Lincoln">Sarah J. Lincoln</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Felic, Amela" sort="Felic, Amela" uniqKey="Felic A" first="Amela" last="Felic">Amela Felic</name><affiliation><mods:affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Wider, Christian" sort="Wider, Christian" uniqKey="Wider C" first="Christian" last="Wider">Christian Wider</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Soto Rtolaza, Alexandra I" sort="Soto Rtolaza, Alexandra I" uniqKey="Soto Rtolaza A" first="Alexandra I." last="Soto-Ortolaza">Alexandra I. Soto-Ortolaza</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Cobb, Stephanie A" sort="Cobb, Stephanie A" uniqKey="Cobb S" first="Stephanie A." last="Cobb">Stephanie A. Cobb</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="White, Linda R" sort="White, Linda R" uniqKey="White L" first="Linda R." last="White">Linda R. White</name><affiliation><mods:affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</mods:affiliation></affiliation></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><affiliation><mods:affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-10-15">2010-10-15</date><biblScope unit="volume">25</biblScope><biblScope unit="issue">13</biblScope><biblScope unit="page" from="2156">2156</biblScope><biblScope unit="page" to="2163">2163</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">E5FE65FB9782A041639FE9E054D4FF21331F0E9F</idno><idno type="DOI">10.1002/mds.23265</idno><idno type="ArticleID">MDS23265</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>LRRK2</term><term>Parkinson's disease</term><term>genetic</term><term>kinase</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism. © 2010 Movement Disorder Society</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Jan O. Aasly MD, PhD</name><affiliations><json:string>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</json:string><json:string>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</json:string></affiliations></json:item><json:item><name>Carles Vilariño‐Güell PhD</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Justus C. Dachsel PhD</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Philip J. Webber PhD</name><affiliations><json:string>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</json:string></affiliations></json:item><json:item><name>Andrew B. West PhD</name><affiliations><json:string>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</json:string></affiliations></json:item><json:item><name>Kristoffer Haugarvoll MD, PhD</name><affiliations><json:string>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</json:string><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Krisztina K. Johansen MD</name><affiliations><json:string>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</json:string></affiliations></json:item><json:item><name>Mathias Toft MD, PhD</name><affiliations><json:string>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</json:string><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>John G. Nutt MD</name><affiliations><json:string>Department of Neurology, Oregon Health and Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon, USA</json:string></affiliations></json:item><json:item><name>Haydeh Payami PhD</name><affiliations><json:string>Division of Genetic Disorders, New York State Department of Health, Wadsworth Center, Albany, New York, USA</json:string></affiliations></json:item><json:item><name>Jennifer M. Kachergus BS</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Sarah J. Lincoln MSc</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Amela Felic MSc</name><affiliations><json:string>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</json:string><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Christian Wider MD</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Alexandra I. Soto‐Ortolaza BS</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Stephanie A. Cobb BA</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Linda R. White PhD</name><affiliations><json:string>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</json:string><json:string>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</json:string></affiliations></json:item><json:item><name>Owen A. Ross PhD</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Matthew J. Farrer PhD</name><affiliations><json:string>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>LRRK2</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>genetic</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>kinase</value></json:item></subject><articleId><json:string>MDS23265</json:string></articleId><language><json:string>eng</json:string></language><abstract>Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism. © 2010 Movement Disorder Society</abstract><qualityIndicators><score>5.829</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 810 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>4</keywordCount><abstractCharCount>900</abstractCharCount><pdfWordCount>4269</pdfWordCount><pdfCharCount>28369</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>130</abstractWordCount></qualityIndicators><title>Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease</title><genre><json:string>article</json:string></genre><host><volume>25</volume><publisherId><json:string>MDS</json:string></publisherId><pages><total>8</total><last>2163</last><first>2156</first></pages><issn><json:string>0885-3185</json:string></issn><issue>13</issue><subject><json:item><value>Research Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8257</json:string></eissn><title>Movement Disorders</title><doi><json:string>10.1002/(ISSN)1531-8257</json:string></doi></host><publicationDate>2010</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1002/mds.23265</json:string></doi><id>E5FE65FB9782A041639FE9E054D4FF21331F0E9F</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/E5FE65FB9782A041639FE9E054D4FF21331F0E9F/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/E5FE65FB9782A041639FE9E054D4FF21331F0E9F/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/E5FE65FB9782A041639FE9E054D4FF21331F0E9F/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2010</date></publicationStmt><notesStmt><note type="content">*Potential conflict of interest: Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 NS40256). MJF and OAR are supported by the Michael J. Fox Foundation. JOA is supported by the Research Council of Norway. Additional support for ABW was from an NIH R00NS058111 award, for HP from an NIH R01NS36960, and for PJW an American Parkinson's Disease Association fellowship. CVG, JCD, KH, KKJ, MT, JGN, JMK, SJL, AF, CW, AIS, SAC, LRW have no financial disclosures to make.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease</title><author><persName><forename type="first">Jan O.</forename><surname>Aasly</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation></author><author><persName><forename type="first">Carles</forename><surname>Vilariño‐Güell</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Justus C.</forename><surname>Dachsel</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Philip J.</forename><surname>Webber</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</affiliation></author><author><persName><forename type="first">Andrew B.</forename><surname>West</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</affiliation></author><author><persName><forename type="first">Kristoffer</forename><surname>Haugarvoll</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Krisztina K.</forename><surname>Johansen</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation></author><author><persName><forename type="first">Mathias</forename><surname>Toft</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">John G.</forename><surname>Nutt</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Oregon Health and Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon, USA</affiliation></author><author><persName><forename type="first">Haydeh</forename><surname>Payami</surname></persName><roleName type="degree">PhD</roleName><affiliation>Division of Genetic Disorders, New York State Department of Health, Wadsworth Center, Albany, New York, USA</affiliation></author><author><persName><forename type="first">Jennifer M.</forename><surname>Kachergus</surname></persName><roleName type="degree">BS</roleName><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Sarah J.</forename><surname>Lincoln</surname></persName><roleName type="degree">MSc</roleName><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Amela</forename><surname>Felic</surname></persName><roleName type="degree">MSc</roleName><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Christian</forename><surname>Wider</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Alexandra I.</forename><surname>Soto‐Ortolaza</surname></persName><roleName type="degree">BS</roleName><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Stephanie A.</forename><surname>Cobb</surname></persName><roleName type="degree">BA</roleName><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Linda R.</forename><surname>White</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation></author><author><persName><forename type="first">Owen A.</forename><surname>Ross</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Matthew J.</forename><surname>Farrer</surname></persName><roleName type="degree">PhD</roleName><note type="correspondence"><p>Correspondence: Department of Neuroscience, Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224</p></note><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation></author></analytic><monogr><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="pISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><idno type="DOI">10.1002/(ISSN)1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-10-15"></date><biblScope unit="volume">25</biblScope><biblScope unit="issue">13</biblScope><biblScope unit="page" from="2156">2156</biblScope><biblScope unit="page" to="2163">2163</biblScope></imprint></monogr><idno type="istex">E5FE65FB9782A041639FE9E054D4FF21331F0E9F</idno><idno type="DOI">10.1002/mds.23265</idno><idno type="ArticleID">MDS23265</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism. © 2010 Movement Disorder Society</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>LRRK2</term></item><item><term>Parkinson's disease</term></item><item><term>genetic</term></item><item><term>kinase</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-11-13">Received</change><change when="2010-04-27">Registration</change><change when="2010-10-15">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/E5FE65FB9782A041639FE9E054D4FF21331F0E9F/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1531-8257</doi><issn type="print">0885-3185</issn><issn type="electronic">1531-8257</issn><idGroup><id type="product" value="MDS"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="short">Mov. Disord.</title></titleGroup></publicationMeta><publicationMeta level="part" position="130"><doi origin="wiley" registered="yes">10.1002/mds.v25:13</doi><numberingGroup><numbering type="journalVolume" number="25">25</numbering><numbering type="journalIssue">13</numbering></numberingGroup><coverDate startDate="2010-10-15">15 October 2010</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="210" status="forIssue"><doi origin="wiley" registered="yes">10.1002/mds.23265</doi><idGroup><id type="unit" value="MDS23265"></id></idGroup><countGroup><count type="pageTotal" number="8"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2010 Movement Disorder Society</copyright><eventGroup><event type="manuscriptReceived" date="2009-11-13"></event><event type="manuscriptRevised" date="2010-02-28"></event><event type="manuscriptAccepted" date="2010-04-27"></event><event type="firstOnline" date="2010-07-28"></event><event type="publishedOnlineAcceptedOrEarlyUnpaginated" date="2010-07-28"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.5.2 mode:FullText source:FullText result:FullText" date="2011-07-06"></event><event type="publishedOnlineFinalForm" date="2010-07-28"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-02-02"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-31"></event></eventGroup><numberingGroup><numbering type="pageFirst">2156</numbering><numbering type="pageLast">2163</numbering></numberingGroup><correspondenceTo>Department of Neuroscience, Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:MDS.MDS23265.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="0"></count><count type="referenceTotal" number="22"></count><count type="wordTotal" number="4581"></count></countGroup><titleGroup><title type="main" xml:lang="en">Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease<link href="#fn1"></link></title><title type="short" xml:lang="en">LRRK2 P.Asn1437His and Parkinson's Disease</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Jan O.</givenNames><familyName>Aasly</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Carles</givenNames><familyName>Vilariño‐Güell</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Justus C.</givenNames><familyName>Dachsel</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Philip J.</givenNames><familyName>Webber</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Andrew B.</givenNames><familyName>West</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1 #af3"><personName><givenNames>Kristoffer</givenNames><familyName>Haugarvoll</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Krisztina K.</givenNames><familyName>Johansen</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af2 #af3"><personName><givenNames>Mathias</givenNames><familyName>Toft</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af5"><personName><givenNames>John G.</givenNames><familyName>Nutt</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Haydeh</givenNames><familyName>Payami</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Jennifer M.</givenNames><familyName>Kachergus</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Sarah J.</givenNames><familyName>Lincoln</familyName><degrees>MSc</degrees></personName></creator><creator xml:id="au13" creatorRole="author" affiliationRef="#af2 #af3"><personName><givenNames>Amela</givenNames><familyName>Felic</familyName><degrees>MSc</degrees></personName></creator><creator xml:id="au14" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Christian</givenNames><familyName>Wider</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au15" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Alexandra I.</givenNames><familyName>Soto‐Ortolaza</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au16" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Stephanie A.</givenNames><familyName>Cobb</familyName><degrees>BA</degrees></personName></creator><creator xml:id="au17" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Linda R.</givenNames><familyName>White</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au18" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Owen A.</givenNames><familyName>Ross</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au19" creatorRole="author" affiliationRef="#af3" corresponding="yes"><personName><givenNames>Matthew J.</givenNames><familyName>Farrer</familyName><degrees>PhD</degrees></personName><contactDetails><email>farrer.matthew@mayo.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="NO" type="organization"><unparsedAffiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="NO" type="organization"><unparsedAffiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Oregon Health and Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon, USA</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="US" type="organization"><unparsedAffiliation>Division of Genetic Disorders, New York State Department of Health, Wadsworth Center, Albany, New York, USA</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1"><i>LRRK2</i></keyword><keyword xml:id="kwd2">Parkinson's disease</keyword><keyword xml:id="kwd3">genetic</keyword><keyword xml:id="kwd4">kinase</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic <i>LRRK2</i> mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie <i>LRRK2</i>‐linked parkinsonism. © 2010 Movement Disorder Society</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Potential conflict of interest: Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 NS40256). MJF and OAR are supported by the Michael J. Fox Foundation. JOA is supported by the Research Council of Norway. Additional support for ABW was from an NIH R00NS058111 award, for HP from an NIH R01NS36960, and for PJW an American Parkinson's Disease Association fellowship. CVG, JCD, KH, KKJ, MT, JGN, JMK, SJL, AF, CW, AIS, SAC, LRW have no financial disclosures to make.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>LRRK2 P.Asn1437His and Parkinson's Disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Jan O.</namePart><namePart type="family">Aasly</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carles</namePart><namePart type="family">Vilariño‐Güell</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Justus C.</namePart><namePart type="family">Dachsel</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philip J.</namePart><namePart type="family">Webber</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andrew B.</namePart><namePart type="family">West</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kristoffer</namePart><namePart type="family">Haugarvoll</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Krisztina K.</namePart><namePart type="family">Johansen</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mathias</namePart><namePart type="family">Toft</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John G.</namePart><namePart type="family">Nutt</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Oregon Health and Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Haydeh</namePart><namePart type="family">Payami</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Division of Genetic Disorders, New York State Department of Health, Wadsworth Center, Albany, New York, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jennifer M.</namePart><namePart type="family">Kachergus</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sarah J.</namePart><namePart type="family">Lincoln</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Amela</namePart><namePart type="family">Felic</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian</namePart><namePart type="family">Wider</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexandra I.</namePart><namePart type="family">Soto‐Ortolaza</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stephanie A.</namePart><namePart type="family">Cobb</namePart><namePart type="termsOfAddress">BA</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Linda R.</namePart><namePart type="family">White</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurology, St. Olav's Hospital, Trondheim, Norway</affiliation><affiliation>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Owen A.</namePart><namePart type="family">Ross</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Matthew J.</namePart><namePart type="family">Farrer</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA</affiliation><description>Correspondence: Department of Neuroscience, Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2010-10-15</dateIssued><dateCaptured encoding="w3cdtf">2009-11-13</dateCaptured><dateValid encoding="w3cdtf">2010-04-27</dateValid><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">3</extent><extent unit="references">22</extent><extent unit="words">4581</extent></physicalDescription><abstract lang="en">Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism. © 2010 Movement Disorder Society</abstract><note type="content">*Potential conflict of interest: Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 NS40256). MJF and OAR are supported by the Michael J. Fox Foundation. JOA is supported by the Research Council of Norway. Additional support for ABW was from an NIH R00NS058111 award, for HP from an NIH R01NS36960, and for PJW an American Parkinson's Disease Association fellowship. CVG, JCD, KH, KKJ, MT, JGN, JMK, SJL, AF, CW, AIS, SAC, LRW have no financial disclosures to make.</note><subject lang="en"><genre>Keywords</genre><topic>LRRK2</topic><topic>Parkinson's disease</topic><topic>genetic</topic><topic>kinase</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title></titleInfo><titleInfo type="abbreviated"><title>Mov. Disord.</title></titleInfo><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0885-3185</identifier><identifier type="eISSN">1531-8257</identifier><identifier type="DOI">10.1002/(ISSN)1531-8257</identifier><identifier type="PublisherID">MDS</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>25</number></detail><detail type="issue"><caption>no.</caption><number>13</number></detail><extent unit="pages"><start>2156</start><end>2163</end><total>8</total></extent></part></relatedItem><identifier type="istex">E5FE65FB9782A041639FE9E054D4FF21331F0E9F</identifier><identifier type="DOI">10.1002/mds.23265</identifier><identifier type="ArticleID">MDS23265</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2010 Movement Disorder Society</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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