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

被引：10

作者：

Hopfner, Franziska ^{[1
]}

Tietz, Anja K. ^{[2
]}

Ruf, Viktoria C. ^{[3
]}

Ross, Owen A. ^{[4
,5
]}

Koga, Shunsuke ^{[6
]}

Dickson, Dennis ^{[6
]}

Aguzzi, Adriano ^{[7
]}

Attems, Johannes ^{[8
]}

Beach, Thomas ^{[9
]}

Beller, Allison ^{[10
]}

Cheshire, William P. ^{[11
]}

van Deerlin, Vivianna ^{[12
]}

Desplats, Paula ^{[13
,14
]}

Deuschl, Guenther ^{[2
]}

Duyckaerts, Charles ^{[15
,16
]}

Ellinghaus, David ^{[17
,18
]}

Evsyukov, Valentin ^{[1
]}

Flanagan, Margaret Ellen ^{[19
,20
]}

Franke, Andre ^{[17
,18
]}

Frosch, Matthew P. ^{[21
,22
,23
]}

Gearing, Marla ^{[24
,25
]}

Gelpi, Ellen ^{[26
,27
]}

van Gerpen, Jay A. ^{[11
]}

Ghetti, Bernardino ^{[28
]}

Glass, Jonathan D. ^{[29
]}

Grinberg, Lea T. ^{[30
,31
,32
,33
]}

Halliday, Glenda ^{[34
,35
]}

Helbig, Ingo ^{[36
,37
,38
,39
,40
]}

Hollerhage, Matthias ^{[1
]}

Huitinga, Inge ^{[41
,42
]}

Irwin, David John ^{[40
]}

Keene, Dirk C. ^{[10
]}

Kovacs, Gabor G. ^{[26
,43
,44
,45
,46
]}

Lee, Edward B. ^{[47
]}

Levin, Johannes ^{[48
,49
,50
]}

Marti, Maria J. ^{[51
,52
,53
,54
]}

Mackenzie, Ian ^{[55
,56
]}

McKeith, Ian ^{[8
]}

Mclean, Catriona ^{[57
]}

Mollenhauer, Brit ^{[58
,59
]}

Neumann, Manuela ^{[60
,61
]}

Newell, Kathy L. ^{[28
]}

Pantelyat, Alex ^{[62
]}

Pendziwiat, Manuela ^{[17
,63
]}

Peters, Annette ^{[64
]}

Porcel, Laura Molina ^{[65
]}

Rabano, Alberto ^{[66
]}

Matej, Radoslav ^{[67
,68
]}

Rajput, Alex ^{[69
]}

Rajput, Ali ^{[70
]}

机构：

[1] Hannover Med Sch, Dept Neurol, Carl Neuberg Str 1, D-30625 Hannover, Germany

[2] Univ Kiel, Dept Neurol, Kiel, Germany

[3] Ludwig Maximilians Univ Munchen, Ctr Neuropathol & Prion Res, Munich, Germany

[4] Mayo Clin, Dept Neurosci, Jacksonville, FL USA

[5] Mayo Clin, Dept Clin Genom, Jacksonville, FL USA

[6] Mayo Clin, Dept Neurosci Neuropathol, Jacksonville, FL USA

[7] Univ Hosp Zurich, Inst Neuropathol, Zurich, Switzerland

[8] Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[9] Banner Sun Hlth Res Inst, Sun City, AZ USA

[10] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[11] Mayo Clin, Dept Neurol, Jacksonville, FL USA

[12] Univ Penn, Perelman Sch Med, Penn Neurodegenerat Genom Ctr, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[13] Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA

[14] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA

[15] Sorbonne Univ, Hop Pitie Salpetriere, AP HP,Inserm U1127 DMU Neurosci, Inst Cerveau,UMR 7225,Paris Brain Inst ICM,CNRS, Paris, France

[16] Hop La Pitie Salpetriere, Plateforme Ressources Biol, Brainbank NeuroCEB Neuropathol Network, Batiment Roger Baillet, Paris, France

[17] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[18] Univ Hosp Schleswig Holstein, Kiel, Germany

[19] Northwestern Univ, Feinberg Sch Med, Mesulam Ctr Cognit Neurol & Alzheimers Dis, Chicago, IL 60611 USA

[20] Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA

[21] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[22] Harvard Med Sch, Boston, MA 02115 USA

[23] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[24] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA

[25] Emory Univ, Sch Med, Dept Lab Med & Neurol, Atlanta, GA USA

[26] Med Univ Vienna, Dept Neurol, Div Neuropathol & Neurochem, Vienna, Austria

[27] Med Univ Vienna, Austrian Reference Ctr Human Prion Dis OERPE, Vienna, Austria

[28] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA

[29] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA

[30] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, Weill Inst Neurosci, San Francisco, CA USA

[31] Univ Calif San Francisco, Global Hlth Inst, San Francisco, CA 94143 USA

[32] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA

[33] Univ Sao Paulo, Med Sch, Dept Pathol, Sao Paulo, SP, Brazil

[34] Univ Sydney, Sch Med Sci, Sydney, NSW, Australia

[35] Univ Sydney, Brain & Mind Ctr, Sydney, NSW, Australia

[36] Columbia Univ, Irving Med Ctr, Dept Biomed Informat, New York, NY USA

[37] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA

[38] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA

[39] Childrens Hosp Philadelphia, Epilepsy NeuroGenet Initiat ENGIN, Philadelphia, PA 19104 USA

[40] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA

[41] Netherlands Inst Neurosci, Dept Neuroimmunol, Amsterdam, Netherlands

[42] Univ Amsterdam, Swammerdam Inst Life Sci, Brain Plast Grp, Amsterdam, Netherlands

[43] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[44] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada

[45] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada

[46] Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada

[47] Perelman Sch Med, Translat Neuropathol Res Lab, Dept Pathol & Lab Med, Philadelphia, PA USA

[48] DZNE German Ctr Neurodegenerat Dis, Munich, Germany

[49] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[50] Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany

来源：

MOVEMENT DISORDERS | 2022年 / 37卷 / 10期

基金：

英国医学研究理事会;

关键词：

multiple system atrophy; genome-wide association study; autopsy-confirmed; ZIC1; ZIC4; GENOME-WIDE ASSOCIATION; NATURAL-HISTORY; RISK LOCI; DISEASE; METAANALYSIS; DIAGNOSIS; SPECTRUM; DELETION; TAU;

D O I：

10.1002/mds.29164

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 x 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. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

引用

页码：2110 / 2121

页数：12

共 6 条

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