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Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy
F. Hopfner, AK. Tietz, VC. Ruf, OA. Ross, S. Koga, D. Dickson, A. Aguzzi, J. Attems, T. Beach, A. Beller, WP. Cheshire, V. van Deerlin, P. Desplats, G. Deuschl, C. Duyckaerts, D. Ellinghaus, V. Evsyukov, ME. Flanagan, A. Franke, MP. Frosch, M....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural
Grantová podpora
U01 AG016976
NIA NIH HHS - United States
P50 AG005136
NIA NIH HHS - United States
P30 AG066509
NIA NIH HHS - United States
P01 AG066597
NIA NIH HHS - United States
U24 NS120854
NINDS NIH HHS - United States
U19 AG062418
NIA NIH HHS - United States
U54 NS110435
NINDS NIH HHS - United States
U01 AG032984
NIA NIH HHS - United States
P50 NS053488
NINDS NIH HHS - United States
U24 AG041689
NIA NIH HHS - United States
Medical Research Council - United Kingdom
PubMed
35997131
DOI
10.1002/mds.29164
Knihovny.cz E-zdroje
- MeSH
- alfa-synuklein metabolismus MeSH
- autoprotilátky MeSH
- celogenomová asociační studie MeSH
- lidé MeSH
- multisystémová atrofie * genetika patologie MeSH
- olivopontocerebelární atrofie * MeSH
- pitva MeSH
- proteiny nervové tkáně genetika MeSH
- striatonigrální degenerace * MeSH
- transkripční faktory genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Banner Sun Health Research Institute Sun City Arizona USA
Center for Neuropathology and Prion Research Ludwig Maximilians Universität Munich Germany
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Barcelona Spain
Department of Anatomical Pathology Alfred Health Melbourne Victoria Australia
Department of Biomedical Informatics Columbia University Irving Medical Center New York New York USA
Department of Clinical Genomics Mayo Clinic Jacksonville Florida USA
Department of Neuroimmunology Netherlands Institute for Neuroscience Amsterdam the Netherlands
Department of Neurology Emory University Atlanta Georgia USA
Department of Neurology Hannover Medical School Hannover Germany
Department of Neurology Kiel University Kiel Germany
Department of Neurology Ludwig Maximilians Universität München Munich Germany
Department of Neurology Massachusetts General Hospital Boston Massachusetts USA
Department of Neurology Mayo Clinic Jacksonville Florida USA
Department of Neurology Northwestern University Feinberg School of Medicine Chicago Illinois USA
Department of Neurology School of Medicine Johns Hopkins University Baltimore Maryland USA
Department of Neurology University Medical Center Goettingen Gottingen Germany
Department of Neurology University of Chicago Medicine Chicago Illinois USA
Department of Neuropathology University Hospital of Tübingen Tübingen Germany
Department of Neuroscience Mayo Clinic Jacksonville Florida USA
Department of Neurosurgery University Medical Center Goettingen Goettingen Germany
Department of Pathology Massachusetts General Hospital Boston Massachusetts USA
Department of Pathology Northwestern University Chicago Illinois USA
Department of Pathology University of British Columbia Vancouver British Columbia Canada
Department of Pathology University of California San Francisco California USA
Department of Pathology University of Sao Paulo Medical School Sao Paulo Brazil
Department of Pathology University of Washington Seattle Washington USA
Department of Pathology Vancouver General Hospital Vancouver British Columbia Canada
Division of Neurology Children's Hospital of Philadelphia Philadelphia Pennsylvania USA
DZNE German Center for Neurodegenerative Diseases Munich Germany
Global Health Institute University of California San Francisco California USA
Harvard Medical School Boston Massachusetts USA
Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain
Institut de Neurociències Maeztu Center University of Barcelona Barcelona Spain
Institute for Neuropathology University Medical Centre Göttingen Göttingen Germany
Institute of Clinical Molecular Biology Christian Albrechts University of Kiel Kiel Germany
Institute of Human Genetics JLU Gießen Giessen Germany
Institute of Neuropathology University Hospital Zürich Zürich Switzerland
Medical University of Vienna Austrian Reference Center for Human Prion Diseases Vienna Austria
Munich Cluster for Systems Neurology Munich Germany
Neurological Tissue Bank Biobanc Hospital Clínic IDIBAPS Barcelona Spain
Neurology Department Hospital Clinic IDIBAPS Barcelona Spain
Neuropathology Department CIEN Foundation Alzheimer's Centre Queen Sofía Foundation Madrid Spain
Paracelsus Elena Klinik Kassel Germany
Pathology University of Texas Southwestern Medical Center Dallas Texas USA
Section of Neurology Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden
Servicio de Neurología Hospital Ramón y Cajal de Madrid Madrid Spain
Zentrum für Systemische Neurowissenschaften Hannover Germany
Citace poskytuje Crossref.org
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