DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia
Por:
Ng J, Cortés-Saladelafont E, Abela L, Termsarasab P, Mankad K, Sudhakar S, Gorman KM, Heales SJR, Pope S, Biassoni L, Csányi B, Cain J, Rakshi K, Coutts H, Jayawant S, Jefferson R, Hughes D, Garcia-Cazorla A, Grozeva D, Raymond FL, Pérez-Dueñas B, De Goede C, Pearson TS, Meyer E and Kurian MA
Publicada:
1 ago 2020
Ahead of Print:
1 may 2020
Resumen:
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. I-123-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. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Filiaciones:
Ng J:
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Gene Transfer Technology Group, UCL Institute for Women's Health, London, United Kingdom
Cortés-Saladelafont E:
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Abela L:
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Termsarasab P:
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
Division of Neurology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Mankad K:
Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
Sudhakar S:
Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
Gorman KM:
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
Heales SJR:
Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom
Pope S:
Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom
Biassoni L:
Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
Csányi B:
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Cain J:
Department of Nuclear Medicine and Imaging, Lancashire Teaching Hospitals, NHS Foundation Trust, Preston, United Kingdom
Rakshi K:
Department of Paediatrics, East Lancashire Hospital NHS Trust, Lancashire, United Kingdom
Coutts H:
Department of Paediatrics, East Lancashire Hospital NHS Trust, Lancashire, United Kingdom
Jayawant S:
Department of Paediatric Neurology, John Radcliffe Hospital, Oxford University, NHS Foundation Trust, London, United Kingdom
Jefferson R:
Department of Paediatrics, Royal Berkshire Hospital, NHS Foundation Trust, Reading, United Kingdom
Hughes D:
Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, Queen Square, London, United Kingdom
Garcia-Cazorla A:
Department of Neurology, Neurometabolic Unit and CIBERER Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Grozeva D:
Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
UK10K Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
Raymond FL:
Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
UK10K Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
Pérez-Dueñas B:
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Hospital Vall d'Hebron, Institut de Recerca (VHIR), Barcelona, Spain
De Goede C:
Department of Paediatric Neurology, Royal Preston Hospital, Lancashire Teaching Hospitals, NHS Foundation Trust, London, United Kingdom
Pearson TS:
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
Meyer E:
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Kurian MA:
Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
hybrid, Green Published, Green Accepted
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