Kotaro Ogaki1, Shunsuke Koga1, Michael G Heckman1, Fabienne C Fiesel1, Maya Ando1, Catherine Labbé1, Oswaldo Lorenzo-Betancor1, Elisabeth L Moussaud-Lamodière1, Alexandra I Soto-Ortolaza1, Ronald L Walton1, Audrey J Strongosky1, Ryan J Uitti1, Allan McCarthy1, Timothy Lynch1, Joanna Siuda1, Grzegorz Opala1, Monika Rudzinska1, Anna Krygowska-Wajs1, Maria Barcikowska1, Krzysztof Czyzewski1, Andreas Puschmann1, Kenya Nishioka1, Manabu Funayama1, Nobutaka Hattori1, Joseph E Parisi1, Ronald C Petersen1, Neill R Graff-Radford1, Bradley F Boeve1, Wolfdieter Springer1, Zbigniew K Wszolek1, Dennis W Dickson1, Owen A Ross2. 1. From the Department of Neuroscience (K.O., S.K., F.C.F., M.A., C.L., O.L.-B., E.L.M.-L., A.I.S.-O., R.L.W., W.S., D.W.D., O.A.R.), the Division of Biomedical Statistics and Informatics (M.G.H.), and the Department of Neurology (A.J.S., R.J.U., N.R.G.-R., Z.K.W.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (K.O., M.A., K.N., M.F., N.H.), Juntendo University School of Medicine, Tokyo, Japan; the Dublin Neurological Institute at the Mater Misericordiae University Hospital (A.M., T.L.), Conway, and Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland; the Department of Neurology (J.S., G.O., M.R.), Medical University of Silesia, Katowice; the Department of Neurology (A.K.-W.), Jagiellonian University, Krakow; the Department of Neurodegenerative Disorders (M.B.), Medical Research Centre, Polish Academy of Sciences, Warsaw; the Department of Neurology (K.C.), Central Hospital of the Ministry of Interior and Administration, Warsaw, Poland; the Departments of Clinical Sciences and Neurology (A.P.), Lund University; the Department of Neurology (A.P.), Skåne University Hospital, Sweden; the Research Institute for Diseases of Old Age, Graduate School of Medicine (M.F., N.H.), Juntendo University, Tokyo, Japan; the Departments of Pathology and Laboratory Medicine (J.E.P.) and Neurology (R.C.P., B.F.B.), Mayo Clinic, Rochester, MN; the School of Medicine and Medical Science (O.A.R.), University College Dublin, Ireland; and Mayo Graduate School (O.A.R.), Neurobiology of Disease, Jacksonville, FL. 2. From the Department of Neuroscience (K.O., S.K., F.C.F., M.A., C.L., O.L.-B., E.L.M.-L., A.I.S.-O., R.L.W., W.S., D.W.D., O.A.R.), the Division of Biomedical Statistics and Informatics (M.G.H.), and the Department of Neurology (A.J.S., R.J.U., N.R.G.-R., Z.K.W.), Mayo Clinic, Jacksonville, FL; the Department of Neurology (K.O., M.A., K.N., M.F., N.H.), Juntendo University School of Medicine, Tokyo, Japan; the Dublin Neurological Institute at the Mater Misericordiae University Hospital (A.M., T.L.), Conway, and Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland; the Department of Neurology (J.S., G.O., M.R.), Medical University of Silesia, Katowice; the Department of Neurology (A.K.-W.), Jagiellonian University, Krakow; the Department of Neurodegenerative Disorders (M.B.), Medical Research Centre, Polish Academy of Sciences, Warsaw; the Department of Neurology (K.C.), Central Hospital of the Ministry of Interior and Administration, Warsaw, Poland; the Departments of Clinical Sciences and Neurology (A.P.), Lund University; the Department of Neurology (A.P.), Skåne University Hospital, Sweden; the Research Institute for Diseases of Old Age, Graduate School of Medicine (M.F., N.H.), Juntendo University, Tokyo, Japan; the Departments of Pathology and Laboratory Medicine (J.E.P.) and Neurology (R.C.P., B.F.B.), Mayo Clinic, Rochester, MN; the School of Medicine and Medical Science (O.A.R.), University College Dublin, Ireland; and Mayo Graduate School (O.A.R.), Neurobiology of Disease, Jacksonville, FL. ross.owen@mayo.edu.
Abstract
OBJECTIVE: To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations. METHODS: All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants. RESULTS: We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBD patients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the gene's mitochondrial targeting sequence. CONCLUSIONS: Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction.
OBJECTIVE: To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations. METHODS: All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants. RESULTS: We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBDpatients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the gene's mitochondrial targeting sequence. CONCLUSIONS: Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction.
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