Publication:
DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia

Issued Date

2020-08-01

Resource Type

Article

ISSN

15318257
08853185

DOI

10.1002/mds.28063

Other identifier(s)

2-s2.0-85085598880

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Movement Disorders. Vol.35, No.8 (2020), 1357-1368

Suggested Citation

Joanne Ng, Elisenda Cortès-Saladelafont, Lucia Abela, Pichet Termsarasab, Kshitij Mankad, Sniya Sudhakar, Kathleen M. Gorman, Simon J.R. Heales, Simon Pope, Lorenzo Biassoni, Barbara Csányi, John Cain, Karl Rakshi, Helen Coutts, Sandeep Jayawant, Rosalind Jefferson, Deborah Hughes, Àngels García-Cazorla, Detelina Grozeva, F. Lucy Raymond, Belén Pérez-Dueñas, Christian De Goede, Toni S. Pearson, Esther Meyer, Manju A. Kurian DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia. Movement Disorders. Vol.35, No.8 (2020), 1357-1368. doi:10.1002/mds.28063 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/58051

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Title

DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia

Author(s)

Joanne Ng
 Elisenda Cortès-Saladelafont
 Lucia Abela
 Pichet Termsarasab
 Kshitij Mankad
 Sniya Sudhakar
 Kathleen M. Gorman
 Simon J.R. Heales
 Simon Pope
 Lorenzo Biassoni
 Barbara Csányi
 John Cain
 Karl Rakshi
 Helen Coutts
 Sandeep Jayawant
 Rosalind Jefferson
 Deborah Hughes
 Àngels García-Cazorla
 Detelina Grozeva
 F. Lucy Raymond
 Belén Pérez-Dueñas
 Christian De Goede
 Toni S. Pearson
 Esther Meyer
 Manju A. Kurian

Other Contributor(s)

Reta Lila Weston Institute of Neurological Studies
 Vall d'Hebron Institut de Recerca
 Cambridge Institute for Medical Research
 CIBER Enfermedades Raras
 University of Oxford
 Washington University School of Medicine in St. Louis
 Lancashire Teaching Hospitals NHS Foundation Trust
 University College London
 National Hospital for Neurology and Neurosurgery
 Great Ormond Street Hospital for Children NHS Trust
 Faculty of Medicine, Ramathibodi Hospital, Mahidol University
 Icahn School of Medicine at Mount Sinai
 East Lancashire Hospitals NHS Trust
 UCL Great Ormond Street Institute of Child Health
 Royal Preston Hospital
 Royal Berkshire Hospital
 Wellcome Sanger Institute

Abstract

© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. Background: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism. Objective: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis. Methods: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G–associated kinase and synaptic proteins. Results: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. 123I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G–associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced. Conclusions: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G–associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G–associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keyword(s)

Medicine
 Neuroscience

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URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/58051

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Scopus 2020