DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease
Simone Olgiati MSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorMarialuisa Quadri PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorJanneke P.M.A. Rood MD
Department of Neurology, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorJonas A. Saute MD, PhD
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
Search for more papers by this authorHsin Fen Chien MD, PhD
Department of Neurology, University of São Paulo, São Paulo, Brazil
Search for more papers by this authorChristian G. Bouwkamp MSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Department of Psychiatry, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorJosja Graafland BSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorMichelle Minneboo BSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorGuido J. Breedveld BSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorThe International Parkinsonism Genetics Network
Search for more papers by this authorFrans W. Verheijen PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorAgnita J.W. Boon MD, PhD
Department of Neurology, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorAnneke J.A. Kievit MD, PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorLaura Bannach Jardim MD, PhD
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
Search for more papers by this authorWim Mandemakers PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorEgberto Reis Barbosa MD, PhD
Department of Neurology, University of São Paulo, São Paulo, Brazil
Search for more papers by this authorCarlos R.M. Rieder MD, PhD
Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
Search for more papers by this authorKlaus L. Leenders MD, PhD
Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands
Search for more papers by this authorJun Wang PhD
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
Search for more papers by this authorCorresponding Author
Vincenzo Bonifati MD, PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Address correspondence to Dr Vincenzo Bonifati, Department of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. E-mail: [email protected]; or, Dr Jun Wang, BGI-Shenzhen, Shenzhen 518083, China, E-mail: [email protected]Search for more papers by this authorSimone Olgiati MSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorMarialuisa Quadri PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorJanneke P.M.A. Rood MD
Department of Neurology, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorJonas A. Saute MD, PhD
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
Search for more papers by this authorHsin Fen Chien MD, PhD
Department of Neurology, University of São Paulo, São Paulo, Brazil
Search for more papers by this authorChristian G. Bouwkamp MSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Department of Psychiatry, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorJosja Graafland BSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorMichelle Minneboo BSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorGuido J. Breedveld BSc
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorThe International Parkinsonism Genetics Network
Search for more papers by this authorFrans W. Verheijen PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorAgnita J.W. Boon MD, PhD
Department of Neurology, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorAnneke J.A. Kievit MD, PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorLaura Bannach Jardim MD, PhD
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
Search for more papers by this authorWim Mandemakers PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Search for more papers by this authorEgberto Reis Barbosa MD, PhD
Department of Neurology, University of São Paulo, São Paulo, Brazil
Search for more papers by this authorCarlos R.M. Rieder MD, PhD
Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
Search for more papers by this authorKlaus L. Leenders MD, PhD
Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands
Search for more papers by this authorJun Wang PhD
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
Search for more papers by this authorCorresponding Author
Vincenzo Bonifati MD, PhD
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
Address correspondence to Dr Vincenzo Bonifati, Department of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. E-mail: [email protected]; or, Dr Jun Wang, BGI-Shenzhen, Shenzhen 518083, China, E-mail: [email protected]Search for more papers by this authorMembers of the network are listed in the Supplementary Material.
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. Ann Neurol 2016;79:244–256
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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| ana24553-sup-0002-suppvideo2.mpg8.3 MB |
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| ana24553-sup-0006-suppinfo.pdf120 KB |
Members of The International Parkinsonism Genetics Network are available as an online supplementary file. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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