Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease
Identifieur interne : 000621 ( Main/Exploration ); précédent : 000620; suivant : 000622Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease
Auteurs : Jan O. Aasly [Norvège] ; Carles Vilari O-Güell [États-Unis] ; Justus C. Dachsel [États-Unis] ; Philip J. Webber [États-Unis] ; Andrew B. West [États-Unis] ; Kristoffer Haugarvoll [Norvège, États-Unis] ; Krisztina K. Johansen [Norvège] ; Mathias Toft [Norvège, États-Unis] ; John G. Nutt [États-Unis] ; Haydeh Payami [États-Unis] ; Jennifer M. Kachergus [États-Unis] ; Sarah J. Lincoln [États-Unis] ; Amela Felic [Norvège, États-Unis] ; Christian Wider [États-Unis] ; Alexandra I. Soto-Ortolaza [États-Unis] ; Stephanie A. Cobb [États-Unis] ; Linda R. White [Norvège] ; Owen A. Ross [États-Unis] ; Matthew J. Farrer [États-Unis]Source :
- 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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Dachsel</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Haugarvoll, Kristoffer" sort="Haugarvoll, Kristoffer" uniqKey="Haugarvoll K" first="Kristoffer" last="Haugarvoll">Kristoffer Haugarvoll</name><affiliation wicri:level="3"><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Neurology, St. Olav's Hospital, Trondheim</wicri:regionArea><placeName><settlement type="city">Trondheim</settlement><region type="région" nuts="2">Trøndelag</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></affiliation></author><author><name sortKey="Johansen, Krisztina K" sort="Johansen, Krisztina K" uniqKey="Johansen K" first="Krisztina K." last="Johansen">Krisztina K. 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Nutt</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Oregon Health and Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon</wicri:regionArea><placeName><region type="state">Oregon</region></placeName></affiliation></author><author><name sortKey="Payami, Haydeh" sort="Payami, Haydeh" uniqKey="Payami H" first="Haydeh" last="Payami">Haydeh Payami</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Genetic Disorders, New York State Department of Health, Wadsworth Center, Albany, New York</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></affiliation></author><author><name sortKey="Felic, Amela" sort="Felic, Amela" uniqKey="Felic A" first="Amela" last="Felic">Amela Felic</name><affiliation wicri:level="3"><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim</wicri:regionArea><placeName><settlement type="city">Trondheim</settlement><region type="région" nuts="2">Trøndelag</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></affiliation></author><author><name sortKey="Wider, Christian" sort="Wider, Christian" uniqKey="Wider C" first="Christian" last="Wider">Christian Wider</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></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 wicri:level="3"><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Neurology, St. Olav's Hospital, Trondheim</wicri:regionArea><placeName><settlement type="city">Trondheim</settlement><region type="région" nuts="2">Trøndelag</region></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Neuroscience, Norwegian University of Science and Technology, Trondheim</wicri:regionArea><placeName><settlement type="city">Trondheim</settlement><region type="région" nuts="2">Trøndelag</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida</wicri:regionArea><placeName><region type="state">Floride</region></placeName></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><affiliations><list><country><li>Norvège</li><li>États-Unis</li></country><region><li>Alabama</li><li>Floride</li><li>Oregon</li><li>Trøndelag</li><li>État de New York</li></region><settlement><li>Trondheim</li></settlement></list><tree><country name="Norvège"><region name="Trøndelag"><name sortKey="Aasly, Jan O" sort="Aasly, Jan O" uniqKey="Aasly J" first="Jan O." last="Aasly">Jan O. Aasly</name></region><name sortKey="Aasly, Jan O" sort="Aasly, Jan O" uniqKey="Aasly J" first="Jan O." last="Aasly">Jan O. Aasly</name><name sortKey="Felic, Amela" sort="Felic, Amela" uniqKey="Felic A" first="Amela" last="Felic">Amela Felic</name><name sortKey="Haugarvoll, Kristoffer" sort="Haugarvoll, Kristoffer" uniqKey="Haugarvoll K" first="Kristoffer" last="Haugarvoll">Kristoffer Haugarvoll</name><name sortKey="Johansen, Krisztina K" sort="Johansen, Krisztina K" uniqKey="Johansen K" first="Krisztina K." last="Johansen">Krisztina K. Johansen</name><name sortKey="Toft, Mathias" sort="Toft, Mathias" uniqKey="Toft M" first="Mathias" last="Toft">Mathias Toft</name><name sortKey="White, Linda R" sort="White, Linda R" uniqKey="White L" first="Linda R." last="White">Linda R. White</name><name sortKey="White, Linda R" sort="White, Linda R" uniqKey="White L" first="Linda R." last="White">Linda R. White</name></country><country name="États-Unis"><region name="Floride"><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></region><name sortKey="Cobb, Stephanie A" sort="Cobb, Stephanie A" uniqKey="Cobb S" first="Stephanie A." last="Cobb">Stephanie A. Cobb</name><name sortKey="Dachsel, Justus C" sort="Dachsel, Justus C" uniqKey="Dachsel J" first="Justus C." last="Dachsel">Justus C. Dachsel</name><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J." last="Farrer">Matthew J. Farrer</name><name sortKey="Felic, Amela" sort="Felic, Amela" uniqKey="Felic A" first="Amela" last="Felic">Amela Felic</name><name sortKey="Haugarvoll, Kristoffer" sort="Haugarvoll, Kristoffer" uniqKey="Haugarvoll K" first="Kristoffer" last="Haugarvoll">Kristoffer Haugarvoll</name><name sortKey="Kachergus, Jennifer M" sort="Kachergus, Jennifer M" uniqKey="Kachergus J" first="Jennifer M." last="Kachergus">Jennifer M. Kachergus</name><name sortKey="Lincoln, Sarah J" sort="Lincoln, Sarah J" uniqKey="Lincoln S" first="Sarah J." last="Lincoln">Sarah J. Lincoln</name><name sortKey="Nutt, John G" sort="Nutt, John G" uniqKey="Nutt J" first="John G." last="Nutt">John G. Nutt</name><name sortKey="Payami, Haydeh" sort="Payami, Haydeh" uniqKey="Payami H" first="Haydeh" last="Payami">Haydeh Payami</name><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><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><name sortKey="Toft, Mathias" sort="Toft, Mathias" uniqKey="Toft M" first="Mathias" last="Toft">Mathias Toft</name><name sortKey="Webber, Philip J" sort="Webber, Philip J" uniqKey="Webber P" first="Philip J." last="Webber">Philip J. Webber</name><name sortKey="West, Andrew B" sort="West, Andrew B" uniqKey="West A" first="Andrew B." last="West">Andrew B. West</name><name sortKey="Wider, Christian" sort="Wider, Christian" uniqKey="Wider C" first="Christian" last="Wider">Christian Wider</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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