Novel parkin mutations detected in patients with early-onset Parkinson's disease.
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.
Bertoli-Avella
Aida M
AM
Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
Giroud-Benitez
José L
JL
University Hospital Carlos J. Finlay, Havana, Cuba.
Akyol
Ali
A
Department of Neurology, Adnan Menderes University, Aydin, Turkey.
Barbosa
Egberto
E
Department of Neurology, University of São Paulo, São Paulo, Brazil.
Schaap
Onno
O
Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
van der Linde
Herma C
HC
Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
Martignoni
Emilia
E
Neurological Institute IRCCS Mondino, Pavia and A. Avogadro University, Novara, Italy.
Lopiano
Leonardo
L
Department of Neuroscience, University of Turin, Turin, Italy.
Lamberti
Paolo
P
Department of Neurology, University of Bari, Bari, Italy.
Fincati
Emiliana
E
Department of Neurology, University of Verona, Verona, Italy.
Antonini
Angelo
A
Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.
Stocchi
Fabrizio
F
Department of Neurological Sciences, University La Sapienza, Rome, Italy.
Montagna
Pasquale
P
Department of Neurology, University of Bologna, Bologna, Italy.
Squitieri
Ferdinando
F
Neurogenetics Unit, IRCCS Neuromed, Pozzilli, Italy.
Marini
Paolo
P
Department of Neurology, University of Florence, Florence, Italy.
Abbruzzese
Giovanni
G
Department of Neurosciences, Ophthalmology and Genetics, University of Genova, Genova, Italy.
Fabbrini
Giovanni
G
Department of Neurological Sciences, University La Sapienza, Rome, Italy.
Marconi
Roberto
R
Neurology Division, Hospital Misericordia, Grosseto, Italy.
Dalla Libera
Alessio
A
Neurology Division, Hospital Boldrini, Thiene, Italy.
Trianni
Giorgio
G
Neurology Division, Hospital of Casarano, Casarano, Italy.
Guidi
Marco
M
Neurology Division, INRCA Institute, Ancona, Italy.
De Gaetano
Antonio
A
Neurology Division, Hospital of Castrovillari, Castrovillari, Italy.
Boff Maegawa
Gustavo
G
Medical Genetics Service, Hospital de Clinicas, Porto Alegre, Brazil.
De Leo
Antonino
A
Neurology Division, Hospital Piemonte, Messina, Italy.
Gallai
Virgilio
V
Department of Neurology, University of Perugia, Perugia, Italy.
de Rosa
Giulia
G
Division of Neurology, Hospital of Ivrea, Ivrea, Italy.
Vanacore
Nicola
N
National Centre of Epidemiology, National Institute for Health, Rome, Italy.
Meco
Giuseppe
G
Department of Neurological Sciences, University La Sapienza, Rome, Italy.
van Duijn
Cornelia M
CM
Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
Oostra
Ben A
BA
Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.
Heutink
Peter
P
Section Medical Genomics, Department of Human Genetics and Department of Biological Psychology, VU University Medical Center, Amsterdam, The Netherlands.
Bonifati
Vincenzo
V
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.
Genetic-Epidemiologic Unit, Department of Clinical Genetics and Department of Epidemiology & Biostatistics, Erasmus MC Rotterdam, The Netherlands.|University Hospital Carlos J. Finlay, Havana, Cuba.
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
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