A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease
Identifieur interne : 000720 ( Main/Exploration ); précédent : 000719; suivant : 000721A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease
Auteurs : Celia Kun-Rodrigues [Royaume-Uni] ; Christos Ganos [Allemagne, Royaume-Uni] ; Rita Guerreiro [Royaume-Uni] ; Susanne A. Schneider [Allemagne] ; Claudia Schulte [Allemagne] ; Suzanne Lesage [France] ; Lee Darwent [Royaume-Uni] ; Peter Holmans [Royaume-Uni] ; Andrew Singleton [États-Unis] ; Kailash Bhatia [Royaume-Uni] ; Jose Bras [Royaume-Uni]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2015.
English descriptors
- KwdEn :
- Adult, Arsenite Transporting ATPases (genetics), DNA Mutational Analysis, Exome, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, PTEN Phosphohydrolase (genetics), Parkinson Disease (genetics), Parkinson Disease (metabolism), Pedigree, Protein Interaction Maps, Vesicular Transport Proteins (genetics), Young Adult.
- MESH :
- chemical , genetics : Arsenite Transporting ATPases, PTEN Phosphohydrolase, Vesicular Transport Proteins.
- genetics : Parkinson Disease.
- metabolism : Parkinson Disease.
- Adult, DNA Mutational Analysis, Exome, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Pedigree, Protein Interaction Maps, Young Adult.
Abstract
Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that
Url:
DOI: 10.1093/hmg/ddv376
PubMed: 26362251
PubMed Central: 4634375
Affiliations:
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type="wicri:Area/Main/Exploration">000720</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A systematic screening to identify <italic>de novo</italic> mutations causing sporadic early-onset Parkinson's disease</title><author><name sortKey="Kun Rodrigues, Celia" sort="Kun Rodrigues, Celia" uniqKey="Kun Rodrigues C" first="Celia" last="Kun-Rodrigues">Celia Kun-Rodrigues</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Molecular Neuroscience</addr-line>,<institution>UCL Institute of Neurology</institution>,<addr-line>London WC1N 3AR</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ganos, Christos" sort="Ganos, Christos" uniqKey="Ganos C" first="Christos" last="Ganos">Christos Ganos</name><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Department of Neurology</addr-line>,<institution>University Medical Center Hamburg-Eppendorf (UKE)</institution>,<addr-line>Hamburg 20246</addr-line>,<country>Germany</country>,</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3"><addr-line>Sobell Department of Motor Neuroscience and Movement Disorders</addr-line>,<institution>UCL Institute of Neurology, University College London</institution>,<addr-line>London WC1N 3BG</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Guerreiro, Rita" sort="Guerreiro, Rita" uniqKey="Guerreiro R" first="Rita" last="Guerreiro">Rita Guerreiro</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Molecular Neuroscience</addr-line>,<institution>UCL Institute of Neurology</institution>,<addr-line>London WC1N 3AR</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Schneider, Susanne A" sort="Schneider, Susanne A" uniqKey="Schneider S" first="Susanne A." last="Schneider">Susanne A. Schneider</name><affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Neurology</addr-line>,<institution>University Hospital Schleswig Holstein</institution>,<addr-line>Campus Kiel 24105</addr-line>,<country>Germany</country>,</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Schulte, Claudia" sort="Schulte, Claudia" uniqKey="Schulte C" first="Claudia" last="Schulte">Claudia Schulte</name><affiliation wicri:level="1"><nlm:aff id="af5"><institution>German Center for Neurodegenerative Diseases</institution>,<addr-line>Tübingen</addr-line>,<country>Germany</country>,</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af6"><addr-line>Department of Neurodegenerative Diseases</addr-line>,<institution>Hertie Institute for Clinical Brain Research, University of Tübingen</institution>,<addr-line>Tübingen 72076</addr-line>,<country>Germany</country>,</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lesage, Suzanne" sort="Lesage, Suzanne" uniqKey="Lesage S" first="Suzanne" last="Lesage">Suzanne Lesage</name><affiliation wicri:level="1"><nlm:aff id="af7"><addr-line>INSERM U M27</addr-line>,<institution>Pitié-Salpêtrière Hospital, Brain and Spinal Cord Institute (ICM)</institution>,<addr-line>Paris 75013</addr-line>,<country>France</country>,</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Darwent, Lee" sort="Darwent, Lee" uniqKey="Darwent L" first="Lee" last="Darwent">Lee Darwent</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Molecular Neuroscience</addr-line>,<institution>UCL Institute of Neurology</institution>,<addr-line>London WC1N 3AR</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Holmans, Peter" sort="Holmans, Peter" uniqKey="Holmans P" first="Peter" last="Holmans">Peter Holmans</name><affiliation wicri:level="1"><nlm:aff wicri:cut=" and" id="af8"><addr-line>Medical Research Council Centre for Neuropsychiatric Genetics and Genomics</addr-line>,<institution>Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University</institution>,<addr-line>Cardiff CF24 4HQ</addr-line>,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation wicri:level="1"><nlm:aff id="af9"><addr-line>Laboratory of Neurogenetics</addr-line>,<institution>National Institutes on Aging, National Institutes of Health</institution>,<addr-line>Bethesda, MD 20892</addr-line>,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bhatia, Kailash" sort="Bhatia, Kailash" uniqKey="Bhatia K" first="Kailash" last="Bhatia">Kailash Bhatia</name><affiliation wicri:level="1"><nlm:aff id="af3"><addr-line>Sobell Department of Motor Neuroscience and Movement Disorders</addr-line>,<institution>UCL Institute of Neurology, University College London</institution>,<addr-line>London WC1N 3BG</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bras, Jose" sort="Bras, Jose" uniqKey="Bras J" first="Jose" last="Bras">Jose Bras</name><affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Department of Molecular Neuroscience</addr-line>,<institution>UCL Institute of Neurology</institution>,<addr-line>London WC1N 3AR</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Arsenite Transporting ATPases (genetics)</term><term>DNA Mutational Analysis</term><term>Exome</term><term>Genetic Predisposition to Disease</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Mutation</term><term>PTEN Phosphohydrolase (genetics)</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (metabolism)</term><term>Pedigree</term><term>Protein Interaction Maps</term><term>Vesicular Transport Proteins (genetics)</term><term>Young Adult</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Arsenite Transporting ATPases</term><term>PTEN Phosphohydrolase</term><term>Vesicular Transport Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>DNA Mutational Analysis</term><term>Exome</term><term>Genetic Predisposition to Disease</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Mutation</term><term>Pedigree</term><term>Protein Interaction Maps</term><term>Young Adult</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that <italic>de novo</italic> mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent–child trios where the proband presents with typical PD to unequivocally identify <italic>de novo</italic> mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding <italic>de novo</italic> mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry <italic>de novo</italic> mutations, <italic>PTEN</italic>, <italic>VAPB</italic> and <italic>ASNA1</italic> are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein–protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for <italic>de novo</italic> mutations in sporadic disease may aid in the identification of novel disease-causing genes.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lill, C M" uniqKey="Lill C">C.M. Lill</name></author><author><name sortKey="Bertram, L" uniqKey="Bertram L">L. Bertram</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bras, J" uniqKey="Bras J">J. 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Hardy</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Allemagne</li><li>France</li><li>Royaume-Uni</li><li>États-Unis</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Kun Rodrigues, Celia" sort="Kun Rodrigues, Celia" uniqKey="Kun Rodrigues C" first="Celia" last="Kun-Rodrigues">Celia Kun-Rodrigues</name></noRegion><name sortKey="Bhatia, Kailash" sort="Bhatia, Kailash" uniqKey="Bhatia K" first="Kailash" last="Bhatia">Kailash Bhatia</name><name sortKey="Bras, Jose" sort="Bras, Jose" uniqKey="Bras J" first="Jose" last="Bras">Jose Bras</name><name sortKey="Darwent, Lee" sort="Darwent, Lee" uniqKey="Darwent L" first="Lee" last="Darwent">Lee Darwent</name><name sortKey="Ganos, Christos" sort="Ganos, Christos" uniqKey="Ganos C" first="Christos" last="Ganos">Christos Ganos</name><name sortKey="Guerreiro, Rita" sort="Guerreiro, Rita" uniqKey="Guerreiro R" first="Rita" last="Guerreiro">Rita Guerreiro</name><name sortKey="Holmans, Peter" sort="Holmans, Peter" uniqKey="Holmans P" first="Peter" last="Holmans">Peter Holmans</name></country><country name="Allemagne"><noRegion><name sortKey="Ganos, Christos" sort="Ganos, Christos" uniqKey="Ganos C" first="Christos" last="Ganos">Christos Ganos</name></noRegion><name sortKey="Schneider, Susanne A" sort="Schneider, Susanne A" uniqKey="Schneider S" first="Susanne A." last="Schneider">Susanne A. Schneider</name><name sortKey="Schulte, Claudia" sort="Schulte, Claudia" uniqKey="Schulte C" first="Claudia" last="Schulte">Claudia Schulte</name><name sortKey="Schulte, Claudia" sort="Schulte, Claudia" uniqKey="Schulte C" first="Claudia" last="Schulte">Claudia Schulte</name></country><country name="France"><noRegion><name sortKey="Lesage, Suzanne" sort="Lesage, Suzanne" uniqKey="Lesage S" first="Suzanne" last="Lesage">Suzanne Lesage</name></noRegion></country><country name="États-Unis"><noRegion><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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