Simone Olgiati1, Marialuisa Quadri1, Mingyan Fang2, Janneke P M A Rood3, Jonas A Saute4, Hsin Fen Chien5, Christian G Bouwkamp1,6, Josja Graafland1, Michelle Minneboo1, Guido J Breedveld1, Jianguo Zhang2, Frans W Verheijen1, Agnita J W Boon3, Anneke J A Kievit1, Laura Bannach Jardim4,7, Wim Mandemakers1, Egberto Reis Barbosa5, Carlos R M Rieder8, Klaus L Leenders9, Jun Wang2,10,11,12, Vincenzo Bonifati1. 1. Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands. 2. BGI-Shenzhen, Shenzhen, China. 3. Department of Neurology, Erasmus MC, Rotterdam, the Netherlands. 4. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 5. Department of Neurology, University of São Paulo, São Paulo, Brazil. 6. Department of Psychiatry, Erasmus MC, Rotterdam, the Netherlands. 7. Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 8. Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 9. Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands. 10. Department of Biology, University of Copenhagen, Copenhagen, Denmark. 11. Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia. 12. Macau University of Science and Technology, Macau, China.
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. INTERPRETATION: 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.
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. INTERPRETATION: 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: Yvette C Wong; Kelvin Luk; Kerry Purtell; Samuel Burke Nanni; A Jon Stoessl; Louis-Eric Trudeau; Zhenyu Yue; Dimitri Krainc; Wolfgang Oertel; Jose A Obeso; Laura A Volpicelli-Daley Journal: Mov Disord Date: 2019-09-04 Impact factor: 10.338