The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor
Identifieur interne : 000D50 ( Main/Corpus ); précédent : 000D49; suivant : 000D51The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor
Auteurs : S. Goldwurm ; A Di Fonzo ; E J Simons ; C F Rohé ; M. Zini ; M. Canesi ; S. Tesei ; A. Zecchinelli ; A. Antonini ; C. Mariani ; N. Meucci ; G. Sacilotto ; F. Sironi ; G. Salani ; J. Ferreira ; H F Chien ; E. Fabrizio ; N. Vanacore ; A Dalla Libera ; F. Stocchi ; C. Diroma ; P. Lamberti ; C. Sampaio ; G. Meco ; E. Barbosa ; A M Bertoli-Avella ; G J Breedveld ; B A Oostra ; G. Pezzoli ; V. BonifatiSource :
- Journal of Medical Genetics [ 0022-2593 ] ; 2005-11.
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Abstract
Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.
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DOI: 10.1136/jmg.2005.035568
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Goldwurm</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Fonzo, A Di" sort="Fonzo, A Di" uniqKey="Fonzo A" first="A Di" last="Fonzo">A Di Fonzo</name><affiliation><mods:affiliation>Centro Dino Ferrari, Department of Neurological Sciences, University of Milan, and Foundation “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena”, Milan</mods:affiliation></affiliation></author><author><name sortKey="Simons, E J" sort="Simons, E J" uniqKey="Simons E" first="E J" last="Simons">E J Simons</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Rohe, C F" sort="Rohe, C F" uniqKey="Rohe C" first="C F" last="Rohé">C F Rohé</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Zini, M" sort="Zini, M" uniqKey="Zini M" first="M" last="Zini">M. Zini</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Canesi, M" sort="Canesi, M" uniqKey="Canesi M" first="M" last="Canesi">M. Canesi</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Tesei, S" sort="Tesei, S" uniqKey="Tesei S" first="S" last="Tesei">S. Tesei</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Zecchinelli, A" sort="Zecchinelli, A" uniqKey="Zecchinelli A" first="A" last="Zecchinelli">A. Zecchinelli</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Antonini, A" sort="Antonini, A" uniqKey="Antonini A" first="A" last="Antonini">A. Antonini</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Mariani, C" sort="Mariani, C" uniqKey="Mariani C" first="C" last="Mariani">C. Mariani</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Meucci, N" sort="Meucci, N" uniqKey="Meucci N" first="N" last="Meucci">N. Meucci</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Sacilotto, G" sort="Sacilotto, G" uniqKey="Sacilotto G" first="G" last="Sacilotto">G. Sacilotto</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Sironi, F" sort="Sironi, F" uniqKey="Sironi F" first="F" last="Sironi">F. Sironi</name><affiliation><mods:affiliation>Molecular Genetics Laboratory, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan</mods:affiliation></affiliation></author><author><name sortKey="Salani, G" sort="Salani, G" uniqKey="Salani G" first="G" last="Salani">G. Salani</name><affiliation><mods:affiliation>Neuroimmunology Unit, San Raffaele Scientific Institute, Milan</mods:affiliation></affiliation></author><author><name sortKey="Ferreira, J" sort="Ferreira, J" uniqKey="Ferreira J" first="J" last="Ferreira">J. Ferreira</name><affiliation><mods:affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</mods:affiliation></affiliation></author><author><name sortKey="Chien, H F" sort="Chien, H F" uniqKey="Chien H" first="H F" last="Chien">H F Chien</name><affiliation><mods:affiliation>Department of Neurology, University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Fabrizio, E" sort="Fabrizio, E" uniqKey="Fabrizio E" first="E" last="Fabrizio">E. Fabrizio</name><affiliation><mods:affiliation>Department of Neurological Sciences, La Sapienza University, Rome, Italy</mods:affiliation></affiliation></author><author><name sortKey="Vanacore, N" sort="Vanacore, N" uniqKey="Vanacore N" first="N" last="Vanacore">N. Vanacore</name><affiliation><mods:affiliation>National Centre of Epidemiology, National Institute for Health, Rome</mods:affiliation></affiliation></author><author><name sortKey="Libera, A Dalla" sort="Libera, A Dalla" uniqKey="Libera A" first="A Dalla" last="Libera">A Dalla Libera</name><affiliation><mods:affiliation>Neurology Division, “Boldrini” Hospital, Thiene, Italy</mods:affiliation></affiliation></author><author><name sortKey="Stocchi, F" sort="Stocchi, F" uniqKey="Stocchi F" first="F" last="Stocchi">F. Stocchi</name><affiliation><mods:affiliation>IRCSS Neuromed, Pozzilli, Italy</mods:affiliation></affiliation></author><author><name sortKey="Diroma, C" sort="Diroma, C" uniqKey="Diroma C" first="C" last="Diroma">C. Diroma</name><affiliation><mods:affiliation>Department of Neurology, University of Bari, Italy</mods:affiliation></affiliation></author><author><name sortKey="Lamberti, P" sort="Lamberti, P" uniqKey="Lamberti P" first="P" last="Lamberti">P. Lamberti</name><affiliation><mods:affiliation>Department of Neurology, University of Bari, Italy</mods:affiliation></affiliation></author><author><name sortKey="Sampaio, C" sort="Sampaio, C" uniqKey="Sampaio C" first="C" last="Sampaio">C. Sampaio</name><affiliation><mods:affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</mods:affiliation></affiliation></author><author><name sortKey="Meco, G" sort="Meco, G" uniqKey="Meco G" first="G" last="Meco">G. Meco</name><affiliation><mods:affiliation>Department of Neurological Sciences, La Sapienza University, Rome, Italy</mods:affiliation></affiliation></author><author><name sortKey="Barbosa, E" sort="Barbosa, E" uniqKey="Barbosa E" first="E" last="Barbosa">E. Barbosa</name><affiliation><mods:affiliation>Department of Neurology, University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Bertoli Avella, A M" sort="Bertoli Avella, A M" uniqKey="Bertoli Avella A" first="A M" last="Bertoli-Avella">A M Bertoli-Avella</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Breedveld, G J" sort="Breedveld, G J" uniqKey="Breedveld G" first="G J" last="Breedveld">G J Breedveld</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Oostra, B A" sort="Oostra, B A" uniqKey="Oostra B" first="B A" last="Oostra">B A Oostra</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Pezzoli, G" sort="Pezzoli, G" uniqKey="Pezzoli G" first="G" last="Pezzoli">G. Pezzoli</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Bonifati, V" sort="Bonifati, V" uniqKey="Bonifati V" first="V" last="Bonifati">V. Bonifati</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:F93943A446D88EA8C4635BDE09A1CFC04C5ACD54</idno><date when="2005" year="2005">2005</date><idno type="doi">10.1136/jmg.2005.035568</idno><idno type="url">https://api.istex.fr/document/F93943A446D88EA8C4635BDE09A1CFC04C5ACD54/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000D50</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor</title><author><name sortKey="Goldwurm, S" sort="Goldwurm, S" uniqKey="Goldwurm S" first="S" last="Goldwurm">S. Goldwurm</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Fonzo, A Di" sort="Fonzo, A Di" uniqKey="Fonzo A" first="A Di" last="Fonzo">A Di Fonzo</name><affiliation><mods:affiliation>Centro Dino Ferrari, Department of Neurological Sciences, University of Milan, and Foundation “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena”, Milan</mods:affiliation></affiliation></author><author><name sortKey="Simons, E J" sort="Simons, E J" uniqKey="Simons E" first="E J" last="Simons">E J Simons</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Rohe, C F" sort="Rohe, C F" uniqKey="Rohe C" first="C F" last="Rohé">C F Rohé</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Zini, M" sort="Zini, M" uniqKey="Zini M" first="M" last="Zini">M. Zini</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Canesi, M" sort="Canesi, M" uniqKey="Canesi M" first="M" last="Canesi">M. Canesi</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Tesei, S" sort="Tesei, S" uniqKey="Tesei S" first="S" last="Tesei">S. Tesei</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Zecchinelli, A" sort="Zecchinelli, A" uniqKey="Zecchinelli A" first="A" last="Zecchinelli">A. Zecchinelli</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Antonini, A" sort="Antonini, A" uniqKey="Antonini A" first="A" last="Antonini">A. Antonini</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Mariani, C" sort="Mariani, C" uniqKey="Mariani C" first="C" last="Mariani">C. Mariani</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Meucci, N" sort="Meucci, N" uniqKey="Meucci N" first="N" last="Meucci">N. Meucci</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Sacilotto, G" sort="Sacilotto, G" uniqKey="Sacilotto G" first="G" last="Sacilotto">G. Sacilotto</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Sironi, F" sort="Sironi, F" uniqKey="Sironi F" first="F" last="Sironi">F. Sironi</name><affiliation><mods:affiliation>Molecular Genetics Laboratory, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan</mods:affiliation></affiliation></author><author><name sortKey="Salani, G" sort="Salani, G" uniqKey="Salani G" first="G" last="Salani">G. Salani</name><affiliation><mods:affiliation>Neuroimmunology Unit, San Raffaele Scientific Institute, Milan</mods:affiliation></affiliation></author><author><name sortKey="Ferreira, J" sort="Ferreira, J" uniqKey="Ferreira J" first="J" last="Ferreira">J. Ferreira</name><affiliation><mods:affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</mods:affiliation></affiliation></author><author><name sortKey="Chien, H F" sort="Chien, H F" uniqKey="Chien H" first="H F" last="Chien">H F Chien</name><affiliation><mods:affiliation>Department of Neurology, University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Fabrizio, E" sort="Fabrizio, E" uniqKey="Fabrizio E" first="E" last="Fabrizio">E. Fabrizio</name><affiliation><mods:affiliation>Department of Neurological Sciences, La Sapienza University, Rome, Italy</mods:affiliation></affiliation></author><author><name sortKey="Vanacore, N" sort="Vanacore, N" uniqKey="Vanacore N" first="N" last="Vanacore">N. Vanacore</name><affiliation><mods:affiliation>National Centre of Epidemiology, National Institute for Health, Rome</mods:affiliation></affiliation></author><author><name sortKey="Libera, A Dalla" sort="Libera, A Dalla" uniqKey="Libera A" first="A Dalla" last="Libera">A Dalla Libera</name><affiliation><mods:affiliation>Neurology Division, “Boldrini” Hospital, Thiene, Italy</mods:affiliation></affiliation></author><author><name sortKey="Stocchi, F" sort="Stocchi, F" uniqKey="Stocchi F" first="F" last="Stocchi">F. Stocchi</name><affiliation><mods:affiliation>IRCSS Neuromed, Pozzilli, Italy</mods:affiliation></affiliation></author><author><name sortKey="Diroma, C" sort="Diroma, C" uniqKey="Diroma C" first="C" last="Diroma">C. Diroma</name><affiliation><mods:affiliation>Department of Neurology, University of Bari, Italy</mods:affiliation></affiliation></author><author><name sortKey="Lamberti, P" sort="Lamberti, P" uniqKey="Lamberti P" first="P" last="Lamberti">P. Lamberti</name><affiliation><mods:affiliation>Department of Neurology, University of Bari, Italy</mods:affiliation></affiliation></author><author><name sortKey="Sampaio, C" sort="Sampaio, C" uniqKey="Sampaio C" first="C" last="Sampaio">C. Sampaio</name><affiliation><mods:affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</mods:affiliation></affiliation></author><author><name sortKey="Meco, G" sort="Meco, G" uniqKey="Meco G" first="G" last="Meco">G. Meco</name><affiliation><mods:affiliation>Department of Neurological Sciences, La Sapienza University, Rome, Italy</mods:affiliation></affiliation></author><author><name sortKey="Barbosa, E" sort="Barbosa, E" uniqKey="Barbosa E" first="E" last="Barbosa">E. Barbosa</name><affiliation><mods:affiliation>Department of Neurology, University of São Paulo, São Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Bertoli Avella, A M" sort="Bertoli Avella, A M" uniqKey="Bertoli Avella A" first="A M" last="Bertoli-Avella">A M Bertoli-Avella</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Breedveld, G J" sort="Breedveld, G J" uniqKey="Breedveld G" first="G J" last="Breedveld">G J Breedveld</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Oostra, B A" sort="Oostra, B A" uniqKey="Oostra B" first="B A" last="Oostra">B A Oostra</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Pezzoli, G" sort="Pezzoli, G" uniqKey="Pezzoli G" first="G" last="Pezzoli">G. Pezzoli</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Bonifati, V" sort="Bonifati, V" uniqKey="Bonifati V" first="V" last="Bonifati">V. Bonifati</name><affiliation><mods:affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2005-11">2005-11</date><biblScope unit="volume">42</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="e65">e65</biblScope></imprint><idno type="ISSN">0022-2593</idno></series><idno type="istex">F93943A446D88EA8C4635BDE09A1CFC04C5ACD54</idno><idno type="DOI">10.1136/jmg.2005.035568</idno><idno type="href">jmedgenet-42-e65.pdf</idno><idno type="PMID">16272257</idno><idno type="local">042e065</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2593</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>G2019S</term><term>LD, linkage disequilibrium</term><term>LRRK2</term><term>Parkinson’s disease</term><term>SNP, single nucleotide polymorphism</term><term>founder</term><term>mutation</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.</div></front></TEI><istex><corpusName>bmj</corpusName><author><json:item><name>S Goldwurm</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>A Di Fonzo</name><affiliations><json:string>Centro Dino Ferrari, Department of Neurological Sciences, University of Milan, and Foundation “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena”, Milan</json:string></affiliations></json:item><json:item><name>E J Simons</name><affiliations><json:string>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</json:string></affiliations></json:item><json:item><name>C F Rohé</name><affiliations><json:string>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</json:string></affiliations></json:item><json:item><name>M Zini</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>M Canesi</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>S Tesei</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>A Zecchinelli</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>A Antonini</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>C Mariani</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>N Meucci</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>G Sacilotto</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>F Sironi</name><affiliations><json:string>Molecular Genetics Laboratory, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan</json:string></affiliations></json:item><json:item><name>G Salani</name><affiliations><json:string>Neuroimmunology Unit, San Raffaele Scientific Institute, Milan</json:string></affiliations></json:item><json:item><name>J Ferreira</name><affiliations><json:string>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</json:string></affiliations></json:item><json:item><name>H F Chien</name><affiliations><json:string>Department of Neurology, University of São Paulo, São Paulo, Brazil</json:string></affiliations></json:item><json:item><name>E Fabrizio</name><affiliations><json:string>Department of Neurological Sciences, La Sapienza University, Rome, Italy</json:string></affiliations></json:item><json:item><name>N Vanacore</name><affiliations><json:string>National Centre of Epidemiology, National Institute for Health, Rome</json:string></affiliations></json:item><json:item><name>A Dalla Libera</name><affiliations><json:string>Neurology Division, “Boldrini” Hospital, Thiene, Italy</json:string></affiliations></json:item><json:item><name>F Stocchi</name><affiliations><json:string>IRCSS Neuromed, Pozzilli, Italy</json:string></affiliations></json:item><json:item><name>C Diroma</name><affiliations><json:string>Department of Neurology, University of Bari, Italy</json:string></affiliations></json:item><json:item><name>P Lamberti</name><affiliations><json:string>Department of Neurology, University of Bari, Italy</json:string></affiliations></json:item><json:item><name>C Sampaio</name><affiliations><json:string>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</json:string></affiliations></json:item><json:item><name>G Meco</name><affiliations><json:string>Department of Neurological Sciences, La Sapienza University, Rome, Italy</json:string></affiliations></json:item><json:item><name>E Barbosa</name><affiliations><json:string>Department of Neurology, University of São Paulo, São Paulo, Brazil</json:string></affiliations></json:item><json:item><name>A M Bertoli-Avella</name><affiliations><json:string>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</json:string></affiliations></json:item><json:item><name>G J Breedveld</name><affiliations><json:string>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</json:string></affiliations></json:item><json:item><name>B A Oostra</name><affiliations><json:string>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</json:string></affiliations></json:item><json:item><name>G Pezzoli</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>V Bonifati</name><affiliations><json:string>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Electronic letters</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Genetic screening / counselling</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>LD, linkage disequilibrium</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SNP, single nucleotide polymorphism</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>mutation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>founder</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>LRRK2</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>G2019S</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (>50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p>0.002), and highest among probands with one affected parent (8.7%, 6/69) (p>0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.</abstract><qualityIndicators><score>7.47</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>9</keywordCount><abstractCharCount>1488</abstractCharCount><pdfWordCount>4818</pdfWordCount><pdfCharCount>31674</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>221</abstractWordCount></qualityIndicators><title>The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor</title><pmid><json:string>16272257</json:string></pmid><genre><json:string>other</json:string></genre><host><volume>42</volume><pages><first>e65</first></pages><issn><json:string>0022-2593</json:string></issn><issue>11</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1468-6244</json:string></eissn><title>Journal of Medical Genetics</title></host><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1136/jmg.2005.035568</json:string></doi><id>F93943A446D88EA8C4635BDE09A1CFC04C5ACD54</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/F93943A446D88EA8C4635BDE09A1CFC04C5ACD54/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/F93943A446D88EA8C4635BDE09A1CFC04C5ACD54/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/F93943A446D88EA8C4635BDE09A1CFC04C5ACD54/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor</title><respStmt xml:id="ISTEX-API" resp="Références bibliographiques récupérées via GROBID" name="ISTEX-API (INIST-CNRS)"></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>BMJ Publishing Group Ltd</publisher><availability><p>BMJ</p></availability><date>2005-11-04</date></publicationStmt><notesStmt><note>Correspondence to:
Dr V Bonifati
Department of Clinical Genetics, Erasmus MC Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands; v.bonifati@erasmusmc.nl</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor</title><author><persName><forename type="first">S</forename><surname>Goldwurm</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">A Di</forename><surname>Fonzo</surname></persName><affiliation>Centro Dino Ferrari, Department of Neurological Sciences, University of Milan, and Foundation “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena”, Milan</affiliation></author><author><persName><forename type="first">E J</forename><surname>Simons</surname></persName><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation></author><author><persName><forename type="first">C F</forename><surname>Rohé</surname></persName><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation></author><author><persName><forename type="first">M</forename><surname>Zini</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">M</forename><surname>Canesi</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">S</forename><surname>Tesei</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">A</forename><surname>Zecchinelli</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">A</forename><surname>Antonini</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">C</forename><surname>Mariani</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">N</forename><surname>Meucci</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">G</forename><surname>Sacilotto</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">F</forename><surname>Sironi</surname></persName><affiliation>Molecular Genetics Laboratory, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan</affiliation></author><author><persName><forename type="first">G</forename><surname>Salani</surname></persName><affiliation>Neuroimmunology Unit, San Raffaele Scientific Institute, Milan</affiliation></author><author><persName><forename type="first">J</forename><surname>Ferreira</surname></persName><affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</affiliation></author><author><persName><forename type="first">H F</forename><surname>Chien</surname></persName><affiliation>Department of Neurology, University of São Paulo, São Paulo, Brazil</affiliation></author><author><persName><forename type="first">E</forename><surname>Fabrizio</surname></persName><affiliation>Department of Neurological Sciences, La Sapienza University, Rome, Italy</affiliation></author><author><persName><forename type="first">N</forename><surname>Vanacore</surname></persName><affiliation>National Centre of Epidemiology, National Institute for Health, Rome</affiliation></author><author><persName><forename type="first">A Dalla</forename><surname>Libera</surname></persName><affiliation>Neurology Division, “Boldrini” Hospital, Thiene, Italy</affiliation></author><author><persName><forename type="first">F</forename><surname>Stocchi</surname></persName><affiliation>IRCSS Neuromed, Pozzilli, Italy</affiliation></author><author><persName><forename type="first">C</forename><surname>Diroma</surname></persName><affiliation>Department of Neurology, University of Bari, Italy</affiliation></author><author><persName><forename type="first">P</forename><surname>Lamberti</surname></persName><affiliation>Department of Neurology, University of Bari, Italy</affiliation></author><author><persName><forename type="first">C</forename><surname>Sampaio</surname></persName><affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</affiliation></author><author><persName><forename type="first">G</forename><surname>Meco</surname></persName><affiliation>Department of Neurological Sciences, La Sapienza University, Rome, Italy</affiliation></author><author><persName><forename type="first">E</forename><surname>Barbosa</surname></persName><affiliation>Department of Neurology, University of São Paulo, São Paulo, Brazil</affiliation></author><author><persName><forename type="first">A M</forename><surname>Bertoli-Avella</surname></persName><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation></author><author><persName><forename type="first">G J</forename><surname>Breedveld</surname></persName><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation></author><author><persName><forename type="first">B A</forename><surname>Oostra</surname></persName><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation></author><author><persName><forename type="first">G</forename><surname>Pezzoli</surname></persName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">V</forename><surname>Bonifati</surname></persName><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation></author></analytic><monogr><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="pISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2005-11"></date><biblScope unit="volume">42</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="e65">e65</biblScope></imprint></monogr><idno type="istex">F93943A446D88EA8C4635BDE09A1CFC04C5ACD54</idno><idno type="DOI">10.1136/jmg.2005.035568</idno><idno type="href">jmedgenet-42-e65.pdf</idno><idno type="PMID">16272257</idno><idno type="local">042e065</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2005-11-04</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.</p></abstract><textClass><keywords scheme="keyword"><list><head>hwp-journal-coll</head><item><term>Genetic screening / counselling</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><head>ABR</head><item><term>LD, linkage disequilibrium</term></item><item><term>SNP, single nucleotide polymorphism</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><head>KWD</head><item><term>Parkinson’s disease</term></item><item><term>mutation</term></item><item><term>founder</term></item><item><term>LRRK2</term></item><item><term>G2019S</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2005-11-04">Created</change><change when="2005-11">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-14">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/F93943A446D88EA8C4635BDE09A1CFC04C5ACD54/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Archiving and Interchange DTD v2.3 20070202//EN" URI="archivearticle.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="other"><front><journal-meta><journal-id journal-id-type="hwp">jmedgenet</journal-id><journal-id journal-id-type="nlm-ta">J Med Genet</journal-id><journal-title>Journal of Medical Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">J Med Genet</abbrev-journal-title><issn pub-type="ppub">0022-2593</issn><issn pub-type="epub">1468-6244</issn><publisher><publisher-name>BMJ Publishing Group Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">042e065</article-id><article-id pub-id-type="doi">10.1136/jmg.2005.035568</article-id><article-id pub-id-type="other">jmedgenet;42/11/e65</article-id><article-id pub-id-type="pmid">16272257</article-id><article-id pub-id-type="other">e65</article-id><article-id pub-id-type="other">jmg.2005.035568</article-id><article-categories><subj-group subj-group-type="heading"><subject>Electronic letters</subject></subj-group><subj-group subj-group-type="hwp-journal-coll"><subject>Genetic screening / counselling</subject></subj-group></article-categories><title-group><article-title>The G6055A (G2019S) mutation in <italic>LRRK2</italic> is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Goldwurm</surname><given-names>S</given-names></name><xref rid="AFF1">1</xref><xref rid="FN1">*</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Fonzo</surname><given-names>A Di</given-names></name><xref rid="AFF2">2</xref><xref rid="FN1">*</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Simons</surname><given-names>E J</given-names></name><xref rid="AFF5">5</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Rohé</surname><given-names>C F</given-names></name><xref rid="AFF5">5</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Zini</surname><given-names>M</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Canesi</surname><given-names>M</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Tesei</surname><given-names>S</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Zecchinelli</surname><given-names>A</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Antonini</surname><given-names>A</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Mariani</surname><given-names>C</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Meucci</surname><given-names>N</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Sacilotto</surname><given-names>G</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Sironi</surname><given-names>F</given-names></name><xref rid="AFF3">3</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Salani</surname><given-names>G</given-names></name><xref rid="AFF4">4</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Ferreira</surname><given-names>J</given-names></name><xref rid="AFF6">6</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Chien</surname><given-names>H F</given-names></name><xref rid="AFF7">7</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Fabrizio</surname><given-names>E</given-names></name><xref rid="AFF8">8</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Vanacore</surname><given-names>N</given-names></name><xref rid="AFF9">9</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Libera</surname><given-names>A Dalla</given-names></name><xref rid="AFF10">10</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Stocchi</surname><given-names>F</given-names></name><xref rid="AFF11">11</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Diroma</surname><given-names>C</given-names></name><xref rid="AFF12">12</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Lamberti</surname><given-names>P</given-names></name><xref rid="AFF12">12</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Sampaio</surname><given-names>C</given-names></name><xref rid="AFF6">6</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Meco</surname><given-names>G</given-names></name><xref rid="AFF8">8</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Barbosa</surname><given-names>E</given-names></name><xref rid="AFF7">7</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Bertoli-Avella</surname><given-names>A M</given-names></name><xref rid="AFF5">5</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Breedveld</surname><given-names>G J</given-names></name><xref rid="AFF5">5</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Oostra</surname><given-names>B A</given-names></name><xref rid="AFF5">5</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Pezzoli</surname><given-names>G</given-names></name><xref rid="AFF1">1</xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Bonifati</surname><given-names>V</given-names></name><xref rid="AFF5">5</xref></contrib><aff id="AFF1"><label>1</label>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</aff><aff id="AFF2"><label>2</label>Centro Dino Ferrari, Department of Neurological Sciences, University of Milan, and Foundation “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena”, Milan</aff><aff id="AFF3"><label>3</label>Molecular Genetics Laboratory, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan</aff><aff id="AFF4"><label>4</label>Neuroimmunology Unit, San Raffaele Scientific Institute, Milan</aff><aff id="AFF5"><label>5</label>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</aff><aff id="AFF6"><label>6</label>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</aff><aff id="AFF7"><label>7</label>Department of Neurology, University of São Paulo, São Paulo, Brazil</aff><aff id="AFF8"><label>8</label>Department of Neurological Sciences, La Sapienza University, Rome, Italy</aff><aff id="AFF9"><label>9</label>National Centre of Epidemiology, National Institute for Health, Rome</aff><aff id="AFF10"><label>10</label>Neurology Division, “Boldrini” Hospital, Thiene, Italy</aff><aff id="AFF11"><label>11</label>IRCSS Neuromed, Pozzilli, Italy</aff><aff id="AFF12"><label>12</label>Department of Neurology, University of Bari, Italy</aff></contrib-group><author-notes><corresp>Correspondence to:
Dr V Bonifati
Department of Clinical Genetics, Erasmus MC Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands; <ext-link xlink:href="v.bonifatierasmusmc.nl" ext-link-type="email" xlink:type="simple">v.bonifati@erasmusmc.nl</ext-link></corresp></author-notes><pub-date pub-type="ppub"><month>11</month><year>2005</year></pub-date><pub-date pub-type="epub"><day>4</day><month>11</month><year>2005</year></pub-date><volume>42</volume><volume-id pub-id-type="other">42</volume-id><volume-id pub-id-type="other">42</volume-id><issue>11</issue><issue-id pub-id-type="other">jmedgenet;42/11</issue-id><issue-id pub-id-type="other">11</issue-id><issue-id pub-id-type="other">42/11</issue-id><fpage>e65</fpage><history><date date-type="accepted"><day>27</day><month>06</month><year>2005</year></date><date date-type="received"><day>03</day><month>06</month><year>2005</year></date><date date-type="rev-recd"><day>22</day><month>06</month><year>2005</year></date></history><permissions><copyright-statement>Copyright 2005 Journal of Medical Genetics</copyright-statement><copyright-year>2005</copyright-year></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="jmedgenet-42-e65.pdf"></self-uri><abstract xml:lang="en"><p><bold>Background:</bold> Mutations in the gene <italic>Leucine-Rich Repeat Kinase 2</italic> (<italic>LRRK2</italic>) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease.</p><p><bold>Objective:</bold> To study recurrent <italic>LRRK2</italic> mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease.</p><p><bold>Results:</bold> Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early <italic>v</italic> late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years).</p><p><bold>Conclusions:</bold> G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.</p></abstract><kwd-group kwd-group-type="ABR" xml:lang="en"><kwd>LD, linkage disequilibrium</kwd><kwd>SNP, single nucleotide polymorphism</kwd></kwd-group><kwd-group kwd-group-type="KWD" xml:lang="en"><kwd>Parkinson’s disease</kwd><kwd>mutation</kwd><kwd>founder</kwd><kwd>LRRK2</kwd><kwd>G2019S</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor</title></titleInfo><name type="personal"><namePart type="given">S</namePart><namePart type="family">Goldwurm</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A Di</namePart><namePart type="family">Fonzo</namePart><affiliation>Centro Dino Ferrari, Department of Neurological Sciences, University of Milan, and Foundation “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena”, Milan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">E J</namePart><namePart type="family">Simons</namePart><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C F</namePart><namePart type="family">Rohé</namePart><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Zini</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Canesi</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Tesei</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Zecchinelli</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Antonini</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Mariani</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">N</namePart><namePart type="family">Meucci</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">G</namePart><namePart type="family">Sacilotto</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">F</namePart><namePart type="family">Sironi</namePart><affiliation>Molecular Genetics Laboratory, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">G</namePart><namePart type="family">Salani</namePart><affiliation>Neuroimmunology Unit, San Raffaele Scientific Institute, Milan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Ferreira</namePart><affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H F</namePart><namePart type="family">Chien</namePart><affiliation>Department of Neurology, University of São Paulo, São Paulo, Brazil</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">E</namePart><namePart type="family">Fabrizio</namePart><affiliation>Department of Neurological Sciences, La Sapienza University, Rome, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">N</namePart><namePart type="family">Vanacore</namePart><affiliation>National Centre of Epidemiology, National Institute for Health, Rome</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A Dalla</namePart><namePart type="family">Libera</namePart><affiliation>Neurology Division, “Boldrini” Hospital, Thiene, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">F</namePart><namePart type="family">Stocchi</namePart><affiliation>IRCSS Neuromed, Pozzilli, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Diroma</namePart><affiliation>Department of Neurology, University of Bari, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Lamberti</namePart><affiliation>Department of Neurology, University of Bari, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Sampaio</namePart><affiliation>Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">G</namePart><namePart type="family">Meco</namePart><affiliation>Department of Neurological Sciences, La Sapienza University, Rome, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">E</namePart><namePart type="family">Barbosa</namePart><affiliation>Department of Neurology, University of São Paulo, São Paulo, Brazil</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A M</namePart><namePart type="family">Bertoli-Avella</namePart><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">G J</namePart><namePart type="family">Breedveld</namePart><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B A</namePart><namePart type="family">Oostra</namePart><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">G</namePart><namePart type="family">Pezzoli</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">V</namePart><namePart type="family">Bonifati</namePart><affiliation>Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="other" displayLabel="other"></genre><subject><genre>hwp-journal-coll</genre><topic>Genetic screening / counselling</topic></subject><originInfo><publisher>BMJ Publishing Group Ltd</publisher><dateIssued encoding="w3cdtf">2005-11</dateIssued><dateCreated encoding="w3cdtf">2005-11-04</dateCreated><copyrightDate encoding="w3cdtf">2005</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">Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.</abstract><note type="author-notes">Correspondence to:
Dr V Bonifati
Department of Clinical Genetics, Erasmus MC Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands; v.bonifati@erasmusmc.nl</note><subject lang="en"><genre>ABR</genre><topic>LD, linkage disequilibrium</topic><topic>SNP, single nucleotide polymorphism</topic></subject><subject lang="en"><genre>KWD</genre><topic>Parkinson’s disease</topic><topic>mutation</topic><topic>founder</topic><topic>LRRK2</topic><topic>G2019S</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Medical Genetics</title></titleInfo><titleInfo type="abbreviated"><title>J Med Genet</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0022-2593</identifier><identifier type="eISSN">1468-6244</identifier><identifier type="PublisherID-hwp">jmedgenet</identifier><identifier type="PublisherID-nlm-ta">J Med Genet</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>42</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>e65</start></extent></part></relatedItem><identifier type="istex">F93943A446D88EA8C4635BDE09A1CFC04C5ACD54</identifier><identifier type="DOI">10.1136/jmg.2005.035568</identifier><identifier type="href">jmedgenet-42-e65.pdf</identifier><identifier type="PMID">16272257</identifier><identifier type="local">042e065</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright 2005 Journal of Medical Genetics</accessCondition><recordInfo><recordContentSource>BMJ</recordContentSource></recordInfo></mods></metadata><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/F93943A446D88EA8C4635BDE09A1CFC04C5ACD54/annexes/jpeg</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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