title: Novel parkin mutations detected in patients with early-onset Parkinson's disease.
abstract: A multiethnic series of patients with early-onset Parkinson's disease (EOP) was studied to assess the frequency and nature of parkin/PARK2 gene mutations and to investigate phenotype-genotype relationships. Forty-six EOP probands with an onset age of < 45 years, and 14 affected relatives were ascertained from Italy, Brazil, Cuba, and Turkey. The genetic screening included direct sequencing and exon dosage using a new, cost-effective, real-time polymerase chain reaction method. Mutations were found in 33% of the indexes overall, and in 53% of those with family history compatible with autosomal recessive inheritance. Fifteen parkin alterations (10 exon deletions and five point mutations) were identified, including four novel mutations: Arg402Cys, Cys418Arg, IVS11-3C > G, and exon 8-9-10 deletion. Homozygous mutations, two heterozygous mutations, and a single heterozygous mutation were found in 8, 6, and 1 patient, respectively. Heterozygous exon deletions represented 28% of the mutant alleles. The patients with parkin mutations showed significantly earlier onset, longer disease duration, more frequently symmetric onset, and slower disease progression than the patients without mutations, in agreement with previous studies. This study confirms the frequent involvement of parkin and the importance of genetic testing in the diagnostic work-up of EOP.
authors.affiliation: Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
authors.forename: Aida M
authors.initials: AM
authors.lastname: Bertoli-Avella
authors.affiliation: University Hospital Carlos J. Finlay, Havana, Cuba.
authors.forename: José L
authors.initials: JL
authors.lastname: Giroud-Benitez
authors.affiliation: Department of Neurology, Adnan Menderes University, Aydin, Turkey.
authors.forename: Ali
authors.initials: A
authors.lastname: Akyol
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, Brazil.
authors.forename: Egberto
authors.initials: E
authors.lastname: Barbosa
authors.affiliation: Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
authors.forename: Onno
authors.initials: O
authors.lastname: Schaap
authors.affiliation: Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
authors.forename: Herma C
authors.initials: HC
authors.lastname: van der Linde
authors.affiliation: Neurological Institute IRCCS Mondino, Pavia and A. Avogadro University, Novara, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Martignoni
authors.affiliation: Department of Neuroscience, University of Turin, Turin, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lopiano
authors.affiliation: Department of Neurology, University of Bari, Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lamberti
authors.affiliation: Department of Neurology, University of Verona, Verona, Italy.
authors.forename: Emiliana
authors.initials: E
authors.lastname: Fincati
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Antonini
authors.affiliation: Department of Neurological Sciences, University La Sapienza, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Stocchi
authors.affiliation: Department of Neurology, University of Bologna, Bologna, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Montagna
authors.affiliation: Neurogenetics Unit, IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Squitieri
authors.affiliation: Department of Neurology, University of Florence, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Marini
authors.affiliation: Department of Neurosciences, Ophthalmology and Genetics, University of Genova, Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abbruzzese
authors.affiliation: Department of Neurological Sciences, University La Sapienza, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fabbrini
authors.affiliation: Neurology Division, Hospital Misericordia, Grosseto, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marconi
authors.affiliation: Neurology Division, Hospital Boldrini, Thiene, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Dalla Libera
authors.affiliation: Neurology Division, Hospital of Casarano, Casarano, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trianni
authors.affiliation: Neurology Division, INRCA Institute, Ancona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Guidi
authors.affiliation: Neurology Division, Hospital of Castrovillari, Castrovillari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: De Gaetano
authors.affiliation: Medical Genetics Service, Hospital de Clinicas, Porto Alegre, Brazil.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Boff Maegawa
authors.affiliation: Neurology Division, Hospital Piemonte, Messina, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: De Leo
authors.affiliation: Department of Neurology, University of Perugia, Perugia, Italy.
authors.forename: Virgilio
authors.initials: V
authors.lastname: Gallai
authors.affiliation: Division of Neurology, Hospital of Ivrea, Ivrea, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: de Rosa
authors.affiliation: National Centre of Epidemiology, National Institute for Health, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Vanacore
authors.affiliation: Department of Neurological Sciences, University La Sapienza, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Meco
authors.affiliation: Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.affiliation: Section Medical Genomics, Department of Human Genetics and Department of Biological Psychology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.|Department of Neurological Sciences, University La Sapienza, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
authors.affiliation: Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.|University Hospital Carlos J. Finlay, Havana, Cuba.
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D003362:Cost-Benefit Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D015723:Gene Library; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D015513:Oncogene Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000191:economics / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C105131:PARK7 protein, human