title: Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease.
abstract: Early onset Parkinson's disease (EOPD) has been associated with mutations in the Parkin, DJ-1, PINK1, LRRK2, and SNCA genes. The aim of this study is to assess the contribution of these genes in a Dutch EOPD cohort and the phenotypic characteristics of the mutation carriers. A total of 187 unrelated Dutch EOPD patients (age at onset < or = 50 years) were phenotyped and screened for mutations in all exons of Parkin, DJ-1, and PINK1 by direct sequencing and gene dosage analysis. Additionally, analysis of the A30P mutation and exon dosage of SNCA and sequencing of exons 19,31,35,38,41, and 48 of LRRK2 was performed. Pathogenic variations could explain disease in 4% (7 of 187) of the patients including five patients carrying homozygous or compound heterozygous mutations in Parkin, one with a novel homozygous deletion in DJ-1 (P158Del) and one with a heterozygous mutation in LRRK2 (T2356I). We found seven novel mutations. The phenotypic characteristics of mutation carriers varied widely, comparable to the variability seen in sporadic EOPD. Parkin is the most frequently mutated gene in this EOPD cohort, followed by DJ-1, PINK1 and LRRK2. The low overall mutation frequency indicates that the extrapolation of mutation frequencies from other populations should be applied with caution.
authors.affiliation: Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. m.macedo@vumc.nl
authors.forename: Maria G
authors.initials: MG
authors.lastname: Macedo
authors.forename: Dagmar
authors.initials: D
authors.lastname: Verbaan
authors.forename: Yue
authors.initials: Y
authors.lastname: Fang
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: van Rooden
authors.forename: Martine
authors.initials: M
authors.lastname: Visser
authors.forename: Burcu
authors.initials: B
authors.lastname: Anar
authors.forename: Antonella
authors.initials: A
authors.lastname: Uras
authors.forename: Justus L
authors.initials: JL
authors.lastname: Groen
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rizzu
authors.forename: Jacobus J
authors.initials: JJ
authors.lastname: van Hilten
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009426:Netherlands / Q000453:epidemiology; D015513:Oncogene Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics; D020734:Parkinsonian Disorders / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055815:Young Adult; D051844:alpha-Synuclein / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C497604:SNCA protein, human; C111567:parkin protein; C495280:LRRK2 protein, human; C105131:PARK7 protein, human