title: DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease.
abstract: OBJECTIVE
  DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD).
  
  
  METHODS
  The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies.
  
  
  RESULTS
  We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD.
  
  
  CONCLUSIONS
  Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Olgiati
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Neurology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Janneke P M A
authors.initials: JP
authors.lastname: Rood
authors.affiliation: Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Saute
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, Brazil.
authors.forename: Hsin Fen
authors.initials: HF
authors.lastname: Chien
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.|Department of Psychiatry, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Bouwkamp
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Josja
authors.initials: J
authors.lastname: Graafland
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: Minneboo
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Frans W
authors.initials: FW
authors.lastname: Verheijen
authors.affiliation: Department of Neurology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Agnita J W
authors.initials: AJ
authors.lastname: Boon
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Anneke J A
authors.initials: AJ
authors.lastname: Kievit
authors.affiliation: Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Laura Bannach
authors.initials: LB
authors.lastname: Jardim
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Mandemakers
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, Brazil.
authors.forename: Egberto Reis
authors.initials: ER
authors.lastname: Barbosa
authors.affiliation: Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Carlos R M
authors.initials: CR
authors.lastname: Rieder
authors.affiliation: Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Klaus L
authors.initials: KL
authors.lastname: Leenders
authors.affiliation: BGI-Shenzhen, Shenzhen, China.|Department of Biology, University of Copenhagen, Copenhagen, Denmark.|Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.|Macau University of Science and Technology, Macau, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D034021:Auxilins / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D055815:Young Adult
chemical_list: D034021:Auxilins; C494652:DNAJC6 protein, human; D050956:HSP40 Heat-Shock Proteins