Parkin mutations and susceptibility alleles in late‐onset Parkinson's disease
Identifieur interne : 000715 ( Main/Corpus ); précédent : 000714; suivant : 000716Parkin mutations and susceptibility alleles in late‐onset Parkinson's disease
Auteurs : Sofia A. Oliveira ; William K. Scott ; Eden R. Martin ; Martha A. Nance ; Ray L. Watts ; Jean P. Hubble ; William C. Koller ; Rajesh Pahwa ; Matthew B. Stern ; Bradley C. Hiner ; William G. Ondo ; Fred H. Allen Jr. ; Burton L. Scott ; Christopher G. Goetz ; Gary W. Small ; Frank Mastaglia ; Jeffrey M. Stajich ; Fengyu Zhang ; Michael W. Booze ; Michelle P. Winn ; Lefkos T. Middleton ; Jonathan L. Haines ; Margaret A. Pericak-Vance ; Jeffery M. VanceSource :
- Annals of Neurology [ 0364-5134 ] ; 2003-05.
Abstract
Parkin, an E2‐dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late‐onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early‐onset and 2% of late‐onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late‐onset form of Parkinson disease. Ann Neurol 2003
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DOI: 10.1002/ana.10524
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Hiner</name><affiliation><mods:affiliation>Department of Neurology, Marshfield Clinic, Marshfield, WI</mods:affiliation></affiliation></author><author><name sortKey="Ondo, William G" sort="Ondo, William G" uniqKey="Ondo W" first="William G." last="Ondo">William G. Ondo</name><affiliation><mods:affiliation>Department of Neurology, Baylor College of Medicine, Houston, TX</mods:affiliation></affiliation></author><author><name sortKey="Allen Jr, Fred H" sort="Allen Jr, Fred H" uniqKey="Allen Jr F" first="Fred H." last="Allen Jr.">Fred H. Allen Jr.</name><affiliation><mods:affiliation>Carolina Neurologic Clinic, Charlotte, NC</mods:affiliation></affiliation></author><author><name sortKey="Scott, Burton L" sort="Scott, Burton L" uniqKey="Scott B" first="Burton L." last="Scott">Burton L. Scott</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Goetz, Christopher G" sort="Goetz, Christopher G" uniqKey="Goetz C" first="Christopher G." last="Goetz">Christopher G. Goetz</name><affiliation><mods:affiliation>Department of Neurological Sciences, Rush‐Presbyterian‐St. Luke's Hospital, Chicago, IL</mods:affiliation></affiliation></author><author><name sortKey="Small, Gary W" sort="Small, Gary W" uniqKey="Small G" first="Gary W." last="Small">Gary W. Small</name><affiliation><mods:affiliation>Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA</mods:affiliation></affiliation></author><author><name sortKey="Mastaglia, Frank" sort="Mastaglia, Frank" uniqKey="Mastaglia F" first="Frank" last="Mastaglia">Frank Mastaglia</name><affiliation><mods:affiliation>Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia</mods:affiliation></affiliation></author><author><name sortKey="Stajich, Jeffrey M" sort="Stajich, Jeffrey M" uniqKey="Stajich J" first="Jeffrey M." last="Stajich">Jeffrey M. Stajich</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Zhang, Fengyu" sort="Zhang, Fengyu" uniqKey="Zhang F" first="Fengyu" last="Zhang">Fengyu Zhang</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Booze, Michael W" sort="Booze, Michael W" uniqKey="Booze M" first="Michael W." last="Booze">Michael W. Booze</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Winn, Michelle P" sort="Winn, Michelle P" uniqKey="Winn M" first="Michelle P." last="Winn">Michelle P. Winn</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Middleton, Lefkos T" sort="Middleton, Lefkos T" uniqKey="Middleton L" first="Lefkos T." last="Middleton">Lefkos T. Middleton</name><affiliation><mods:affiliation>GlaxoSmithKline Research and Development, Greenford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Haines, Jonathan L" sort="Haines, Jonathan L" uniqKey="Haines J" first="Jonathan L." last="Haines">Jonathan L. Haines</name><affiliation><mods:affiliation>Program in Human Genetics, Vanderbilt University Medical Center, Nashville, TN</mods:affiliation></affiliation></author><author><name sortKey="Pericak Ance, Margaret A" sort="Pericak Ance, Margaret A" uniqKey="Pericak Ance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Vance, Jeffery M" sort="Vance, Jeffery M" uniqKey="Vance J" first="Jeffery M." last="Vance">Jeffery M. Vance</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:DFF83054383C21279E5B10EF84275578EB364FFF</idno><date when="2003" year="2003">2003</date><idno type="doi">10.1002/ana.10524</idno><idno type="url">https://api.istex.fr/document/DFF83054383C21279E5B10EF84275578EB364FFF/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000715</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Parkin mutations and susceptibility alleles in late‐onset Parkinson's disease</title><author><name sortKey="Oliveira, Sofia A" sort="Oliveira, Sofia A" uniqKey="Oliveira S" first="Sofia A." last="Oliveira">Sofia A. Oliveira</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Scott, William K" sort="Scott, William K" uniqKey="Scott W" first="William K." last="Scott">William K. Scott</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Martin, Eden R" sort="Martin, Eden R" uniqKey="Martin E" first="Eden R." last="Martin">Eden R. Martin</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Nance, Martha A" sort="Nance, Martha A" uniqKey="Nance M" first="Martha A." last="Nance">Martha A. Nance</name><affiliation><mods:affiliation>Struthers Parkinson Center, Golden Valley, MN</mods:affiliation></affiliation></author><author><name sortKey="Watts, Ray L" sort="Watts, Ray L" uniqKey="Watts R" first="Ray L." last="Watts">Ray L. Watts</name><affiliation><mods:affiliation>Department of Neurology, Emory University School of Medicine, Atlanta, GA</mods:affiliation></affiliation></author><author><name sortKey="Hubble, Jean P" sort="Hubble, Jean P" uniqKey="Hubble J" first="Jean P." last="Hubble">Jean P. Hubble</name><affiliation><mods:affiliation>Department of Neurology, Ohio State University, Columbus, OH</mods:affiliation></affiliation></author><author><name sortKey="Koller, William C" sort="Koller, William C" uniqKey="Koller W" first="William C." last="Koller">William C. Koller</name><affiliation><mods:affiliation>Department of Neurology, University of Miami School of Medicine, Miami, FL</mods:affiliation></affiliation></author><author><name sortKey="Pahwa, Rajesh" sort="Pahwa, Rajesh" uniqKey="Pahwa R" first="Rajesh" last="Pahwa">Rajesh Pahwa</name><affiliation><mods:affiliation>Department of Neurology, University of Kansas Medical Center, Kansas City, KS</mods:affiliation></affiliation></author><author><name sortKey="Stern, Matthew B" sort="Stern, Matthew B" uniqKey="Stern M" first="Matthew B." last="Stern">Matthew B. Stern</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania Health System, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Hiner, Bradley C" sort="Hiner, Bradley C" uniqKey="Hiner B" first="Bradley C." last="Hiner">Bradley C. Hiner</name><affiliation><mods:affiliation>Department of Neurology, Marshfield Clinic, Marshfield, WI</mods:affiliation></affiliation></author><author><name sortKey="Ondo, William G" sort="Ondo, William G" uniqKey="Ondo W" first="William G." last="Ondo">William G. Ondo</name><affiliation><mods:affiliation>Department of Neurology, Baylor College of Medicine, Houston, TX</mods:affiliation></affiliation></author><author><name sortKey="Allen Jr, Fred H" sort="Allen Jr, Fred H" uniqKey="Allen Jr F" first="Fred H." last="Allen Jr.">Fred H. Allen Jr.</name><affiliation><mods:affiliation>Carolina Neurologic Clinic, Charlotte, NC</mods:affiliation></affiliation></author><author><name sortKey="Scott, Burton L" sort="Scott, Burton L" uniqKey="Scott B" first="Burton L." last="Scott">Burton L. Scott</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Goetz, Christopher G" sort="Goetz, Christopher G" uniqKey="Goetz C" first="Christopher G." last="Goetz">Christopher G. Goetz</name><affiliation><mods:affiliation>Department of Neurological Sciences, Rush‐Presbyterian‐St. Luke's Hospital, Chicago, IL</mods:affiliation></affiliation></author><author><name sortKey="Small, Gary W" sort="Small, Gary W" uniqKey="Small G" first="Gary W." last="Small">Gary W. Small</name><affiliation><mods:affiliation>Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA</mods:affiliation></affiliation></author><author><name sortKey="Mastaglia, Frank" sort="Mastaglia, Frank" uniqKey="Mastaglia F" first="Frank" last="Mastaglia">Frank Mastaglia</name><affiliation><mods:affiliation>Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia</mods:affiliation></affiliation></author><author><name sortKey="Stajich, Jeffrey M" sort="Stajich, Jeffrey M" uniqKey="Stajich J" first="Jeffrey M." last="Stajich">Jeffrey M. Stajich</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Zhang, Fengyu" sort="Zhang, Fengyu" uniqKey="Zhang F" first="Fengyu" last="Zhang">Fengyu Zhang</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Booze, Michael W" sort="Booze, Michael W" uniqKey="Booze M" first="Michael W." last="Booze">Michael W. Booze</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Winn, Michelle P" sort="Winn, Michelle P" uniqKey="Winn M" first="Michelle P." last="Winn">Michelle P. Winn</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Middleton, Lefkos T" sort="Middleton, Lefkos T" uniqKey="Middleton L" first="Lefkos T." last="Middleton">Lefkos T. Middleton</name><affiliation><mods:affiliation>GlaxoSmithKline Research and Development, Greenford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Haines, Jonathan L" sort="Haines, Jonathan L" uniqKey="Haines J" first="Jonathan L." last="Haines">Jonathan L. Haines</name><affiliation><mods:affiliation>Program in Human Genetics, Vanderbilt University Medical Center, Nashville, TN</mods:affiliation></affiliation></author><author><name sortKey="Pericak Ance, Margaret A" sort="Pericak Ance, Margaret A" uniqKey="Pericak Ance M" first="Margaret A." last="Pericak-Vance">Margaret A. Pericak-Vance</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author><author><name sortKey="Vance, Jeffery M" sort="Vance, Jeffery M" uniqKey="Vance J" first="Jeffery M." last="Vance">Jeffery M. Vance</name><affiliation><mods:affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>New York</pubPlace><date type="published" when="2003-05">2003-05</date><biblScope unit="volume">53</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="624">624</biblScope><biblScope unit="page" to="629">629</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">DFF83054383C21279E5B10EF84275578EB364FFF</idno><idno type="DOI">10.1002/ana.10524</idno><idno type="ArticleID">ANA10524</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkin, an E2‐dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late‐onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early‐onset and 2% of late‐onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late‐onset form of Parkinson disease. Ann Neurol 2003</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Sofia A. Oliveira PhD</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>William K. Scott PhD</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Eden R. Martin PhD</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Martha A. Nance MD</name><affiliations><json:string>Struthers Parkinson Center, Golden Valley, MN</json:string></affiliations></json:item><json:item><name>Ray L. Watts MD</name><affiliations><json:string>Department of Neurology, Emory University School of Medicine, Atlanta, GA</json:string></affiliations></json:item><json:item><name>Jean P. Hubble MD</name><affiliations><json:string>Department of Neurology, Ohio State University, Columbus, OH</json:string></affiliations></json:item><json:item><name>William C. Koller MD</name><affiliations><json:string>Department of Neurology, University of Miami School of Medicine, Miami, FL</json:string></affiliations></json:item><json:item><name>Rajesh Pahwa MD</name><affiliations><json:string>Department of Neurology, University of Kansas Medical Center, Kansas City, KS</json:string></affiliations></json:item><json:item><name>Matthew B. Stern MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania Health System, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Bradley C. Hiner MD</name><affiliations><json:string>Department of Neurology, Marshfield Clinic, Marshfield, WI</json:string></affiliations></json:item><json:item><name>William G. Ondo MD</name><affiliations><json:string>Department of Neurology, Baylor College of Medicine, Houston, TX</json:string></affiliations></json:item><json:item><name>Fred H. Allen Jr. MD</name><affiliations><json:string>Carolina Neurologic Clinic, Charlotte, NC</json:string></affiliations></json:item><json:item><name>Burton L. Scott MD</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Christopher G. Goetz MD</name><affiliations><json:string>Department of Neurological Sciences, Rush‐Presbyterian‐St. Luke's Hospital, Chicago, IL</json:string></affiliations></json:item><json:item><name>Gary W. Small MD</name><affiliations><json:string>Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA</json:string></affiliations></json:item><json:item><name>Frank Mastaglia MD</name><affiliations><json:string>Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia</json:string></affiliations></json:item><json:item><name>Jeffrey M. Stajich PA‐C</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Fengyu Zhang PhD</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Michael W. Booze BS</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Michelle P. Winn MD</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Lefkos T. Middleton MD</name><affiliations><json:string>GlaxoSmithKline Research and Development, Greenford, United Kingdom</json:string></affiliations></json:item><json:item><name>Jonathan L. Haines PhD</name><affiliations><json:string>Program in Human Genetics, Vanderbilt University Medical Center, Nashville, TN</json:string></affiliations></json:item><json:item><name>Margaret A. Pericak‐Vance PhD</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item><json:item><name>Jeffery M. Vance MD, PhD</name><affiliations><json:string>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</json:string></affiliations></json:item></author><articleId><json:string>ANA10524</json:string></articleId><language><json:string>eng</json:string></language><abstract>Parkin, an E2‐dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late‐onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early‐onset and 2% of late‐onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late‐onset form of Parkinson disease. 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Udall Parkinson's Disease Research Center of Excellence - No. 5 P50 NS39764‐03;</note><note>Glaxo SmithKline</note><note>Portuguese Science and Technology Foundation - No. BPD/5733/2001;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Parkin mutations and susceptibility alleles in late‐onset Parkinson's disease</title><author><persName><forename type="first">Sofia A.</forename><surname>Oliveira</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">William K.</forename><surname>Scott</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Eden R.</forename><surname>Martin</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Martha A.</forename><surname>Nance</surname></persName><roleName type="degree">MD</roleName><affiliation>Struthers Parkinson Center, Golden Valley, MN</affiliation></author><author><persName><forename type="first">Ray L.</forename><surname>Watts</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Emory University School of Medicine, Atlanta, GA</affiliation></author><author><persName><forename type="first">Jean P.</forename><surname>Hubble</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Ohio State University, Columbus, OH</affiliation></author><author><persName><forename type="first">William C.</forename><surname>Koller</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Miami School of Medicine, Miami, FL</affiliation></author><author><persName><forename type="first">Rajesh</forename><surname>Pahwa</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Kansas Medical Center, Kansas City, KS</affiliation></author><author><persName><forename type="first">Matthew B.</forename><surname>Stern</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania Health System, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Bradley C.</forename><surname>Hiner</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Marshfield Clinic, Marshfield, WI</affiliation></author><author><persName><forename type="first">William G.</forename><surname>Ondo</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Baylor College of Medicine, Houston, TX</affiliation></author><author><persName><forename type="first">Fred H.</forename><surname>Allen Jr.</surname></persName><roleName type="degree">MD</roleName><affiliation>Carolina Neurologic Clinic, Charlotte, NC</affiliation></author><author><persName><forename type="first">Burton L.</forename><surname>Scott</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Christopher G.</forename><surname>Goetz</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurological Sciences, Rush‐Presbyterian‐St. Luke's Hospital, Chicago, IL</affiliation></author><author><persName><forename type="first">Gary W.</forename><surname>Small</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA</affiliation></author><author><persName><forename type="first">Frank</forename><surname>Mastaglia</surname></persName><roleName type="degree">MD</roleName><affiliation>Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia</affiliation></author><author><persName><forename type="first">Jeffrey M.</forename><surname>Stajich</surname></persName><roleName type="degree">PA‐C</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Fengyu</forename><surname>Zhang</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Michael W.</forename><surname>Booze</surname></persName><roleName type="degree">BS</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Michelle P.</forename><surname>Winn</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Lefkos T.</forename><surname>Middleton</surname></persName><roleName type="degree">MD</roleName><affiliation>GlaxoSmithKline Research and Development, Greenford, United Kingdom</affiliation></author><author><persName><forename type="first">Jonathan L.</forename><surname>Haines</surname></persName><roleName type="degree">PhD</roleName><affiliation>Program in Human Genetics, Vanderbilt University Medical Center, Nashville, TN</affiliation></author><author><persName><forename type="first">Margaret A.</forename><surname>Pericak‐Vance</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation></author><author><persName><forename type="first">Jeffery M.</forename><surname>Vance</surname></persName><roleName type="degree">MD, PhD</roleName><note type="correspondence"><p>Correspondence: Center for Human Genetics, Box 2903, Duke University Medical Center, Durham, NC 27710</p></note><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome 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Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early‐onset and 2% of late‐onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late‐onset form of Parkinson disease. 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Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early‐onset and 2% of late‐onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late‐onset form of Parkinson disease. 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type="family">Scott</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eden R.</namePart><namePart type="family">Martin</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Martha A.</namePart><namePart type="family">Nance</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Struthers Parkinson Center, Golden Valley, MN</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ray L.</namePart><namePart type="family">Watts</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Emory University School of Medicine, Atlanta, GA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean P.</namePart><namePart type="family">Hubble</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Ohio State University, Columbus, OH</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William C.</namePart><namePart type="family">Koller</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Miami School of Medicine, Miami, FL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rajesh</namePart><namePart type="family">Pahwa</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Kansas Medical Center, Kansas City, KS</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Matthew B.</namePart><namePart type="family">Stern</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania Health System, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bradley C.</namePart><namePart type="family">Hiner</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Marshfield Clinic, Marshfield, WI</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William G.</namePart><namePart type="family">Ondo</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Baylor College of Medicine, Houston, TX</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fred H.</namePart><namePart type="family">Allen Jr.</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Carolina Neurologic Clinic, Charlotte, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Burton L.</namePart><namePart type="family">Scott</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher G.</namePart><namePart type="family">Goetz</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurological Sciences, Rush‐Presbyterian‐St. Luke's Hospital, Chicago, IL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gary W.</namePart><namePart type="family">Small</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Frank</namePart><namePart type="family">Mastaglia</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeffrey M.</namePart><namePart type="family">Stajich</namePart><namePart type="termsOfAddress">PA‐C</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fengyu</namePart><namePart type="family">Zhang</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael W.</namePart><namePart type="family">Booze</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michelle P.</namePart><namePart type="family">Winn</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lefkos T.</namePart><namePart type="family">Middleton</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>GlaxoSmithKline Research and Development, Greenford, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jonathan L.</namePart><namePart type="family">Haines</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Program in Human Genetics, Vanderbilt University Medical Center, Nashville, TN</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Margaret A.</namePart><namePart type="family">Pericak‐Vance</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeffery M.</namePart><namePart type="family">Vance</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC</affiliation><description>Correspondence: Center for Human Genetics, Box 2903, Duke University Medical Center, Durham, NC 27710</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">New York</placeTerm></place><dateIssued encoding="w3cdtf">2003-05</dateIssued><dateCaptured encoding="w3cdtf">2002-09-13</dateCaptured><dateValid encoding="w3cdtf">2002-12-17</dateValid><copyrightDate encoding="w3cdtf">2003</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">1</extent><extent unit="tables">2</extent><extent unit="references">25</extent><extent unit="words">4452</extent></physicalDescription><abstract lang="en">Parkin, an E2‐dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late‐onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early‐onset and 2% of late‐onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late‐onset form of Parkinson disease. Ann Neurol 2003</abstract><note type="funding">Morris K. Udall Parkinson's Disease Research Center of Excellence - No. 5 P50 NS39764‐03; </note><note type="funding">Glaxo SmithKline</note><note type="funding">Portuguese Science and Technology Foundation - No. BPD/5733/2001; </note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title><subTitle>Official Journal of the American Neurological Association and the Child Neurology Society</subTitle></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Original Articles</topic></subject><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>53</number></detail><detail type="issue"><caption>no.</caption><number>5</number></detail><extent unit="pages"><start>624</start><end>629</end><total>6</total></extent></part></relatedItem><identifier type="istex">DFF83054383C21279E5B10EF84275578EB364FFF</identifier><identifier type="DOI">10.1002/ana.10524</identifier><identifier type="ArticleID">ANA10524</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2003 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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