Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

TY - JOUR

T1 - Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

AU - Hopfner, Franziska

AU - Tietz, Anja K

AU - Ruf, Viktoria C

AU - Ross, Owen A

AU - Koga, Shunsuke

AU - Dickson, Dennis

AU - Aguzzi, Adriano

AU - Attems, Johannes

AU - Beach, Thomas

AU - Beller, Allison

AU - Cheshire, William P

AU - van Deerlin, Vivianna

AU - Desplats, Paula

AU - Deuschl, Günther

AU - Duyckaerts, Charles

AU - Ellinghaus, David

AU - Evsyukov, Valentin

AU - Flanagan, Margaret Ellen

AU - Franke, Andre

AU - Frosch, Matthew P

AU - Gearing, Marla

AU - Gelpi, Ellen

AU - van Gerpen, Jay A

AU - Ghetti, Bernardino

AU - Glass, Jonathan D

AU - Grinberg, Lea T

AU - Halliday, Glenda

AU - Helbig, Ingo

AU - Höllerhage, Matthias

AU - Huitinga, Inge

AU - Irwin, David John

AU - Keene, Dirk C

AU - Kovacs, Gabor G

AU - Lee, Edward B

AU - Levin, Johannes

AU - Martí, Maria J

AU - Mackenzie, Ian

AU - McKeith, Ian

AU - Mclean, Catriona

AU - Mollenhauer, Brit

AU - Neumann, Manuela

AU - Newell, Kathy L

AU - Pantelyat, Alex

AU - Pendziwiat, Manuela

AU - Peters, Annette

AU - Molina Porcel, Laura

AU - Rabano, Alberto

AU - Matěj, Radoslav

AU - Rajput, Alex

AU - Rajput, Ali

AU - Höglinger, G

N1 - © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PY - 2022/8/23

Y1 - 2022/8/23

N2 - 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.

AB - 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.

U2 - 10.1002/mds.29164

DO - 10.1002/mds.29164

M3 - Article

C2 - 35997131

SN - 0885-3185

VL - 37

SP - 2110

EP - 2121

JO - Movement disorders : official journal of the Movement Disorder Society

JF - Movement disorders : official journal of the Movement Disorder Society

ER -