Investigate single nucleotide variants and short tandem repeats in 39 genes related to spinocerebellar ataxia in clinical and pathologically defined cohorts of multiple system atrophy.
Exome sequencing was conducted in 28 clinical multiple system atrophy patients to identify single nucleotide variants in spinocerebellar ataxia-related genes. Novel variants were validated in two independent disease cohorts: 86 clinically diagnosed multiple system atrophy patients and 166 pathological multiple system atrophy cases. Expanded repeat alleles in spinocerebellar ataxia genes were evaluated in 36 clinically diagnosed multiple system atrophy patients, and CAG/CAA repeats in TATA-Box Binding Protein (TBP, causative of SCA17) were screened in 216 clinical and pathological multiple system atrophy patients and 346 controls.
No known pathogenic spinocerebellar ataxia single nucleotide variants or pathogenic range expanded repeat alleles of ATXN1, ATXN2, ATXN3, CACNA1A, AXTN7, ATXN8OS, ATXN10, PPP2R2B, and TBP were detected in any clinical multiple system atrophy patients. However, four novel variants were identified in four spinocerebellar ataxia-related genes across three multiple system atrophy patients. Additionally, four multiple system atrophy patients (1.6%) and one control (0.3%) carried an intermediate length 41 TBP CAG/CAA repeat allele (OR = 4.11, P = 0.21). There was a significant association between the occurrence of a repeat length of longer alleles (> 38 repeats) and an increased risk of multiple system atrophy (OR = 1.64, P = 0.03).
Occurrence of TBP CAG/CAA repeat length of longer alleles (> 38 repeats) is significantly associated with increased multiple system atrophy risk. This discovery warrants further investigation and supports a possible genetic overlap of multiple system atrophy with SCA17.
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All relevant data generated or analysed during this study are included in this published article (and its supplementary information files). Full datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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We would like to thank all those who have contributed to our research, particularly the patients and families who donated brain and blood samples for this work. We are grateful to all patients, family members, and caregivers who agreed to brain donation. Without their donation these studies would not have been possible. We also acknowledge expert technical assistance of Virginia Phillips for histology and Monica Castanedes-Casey for immunohistochemistry and Audrey Strongosky for her assistance in blood sample collection and brain donation arrangements. Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and the Mayo Clinic Lewy Body Dementia Association (LBDA) Research Center of Excellence and a LBD Center WithOut Walls (U54 NS110435). Samples included in this study were clinical controls or brain donors to the Mayo Clinic Brain Bank in Jacksonville, which is supported by CurePSP and the Tau Consortium. SK is supported by a Jaye F. and Betty F. Dyer Foundation Fellowship in Progressive supranuclear palsy research and CorticoBasal Degeneration Solutions Research Grant. ZKW is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, and the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. The funding organizations and sponsors had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and the Mayo Clinic Lewy Body Dementia Association (LBDA) Research Center of Excellence and a LBD Center WithOut Walls (U54 NS110435). SK is supported by a Jaye F. and Betty F. Dyer Foundation Fellowship in Progressive supranuclear palsy research and CorticoBasal Degeneration Solutions Research Grant.
Conflict of interest
Anna I. Wernick, Ronald L. Walton, Alexandra I. Soto-Beasley, Shunsuke Koga, and Rebecca R. Valentino report no disclosures. Michael G. Heckman is a Statistical Editor of Parkinsonism & Related Disorders, and is on the editorial board of Molecular Neurodegeneration. Lukasz M. Milanowski is supported by the Polish National Agency for Academic Exchange Iwanowska’s Programme PPN/IWA/2018/1/00006/U/00001/01. Dorota Hoffman-Zacharska report no disclosures. Dariusz Koziorowski report no disclosures. Anhar Hassan is on the editorial board of Parkinsonism and Related Disorders, and receives research support from Intrabio. Ryan J. Uitti is an Associate Editor of Neurology. William P. Cheshire is an Associate Editor of Clinical Autonomic Research and is on the editorial boards of Autonomic Neuroscience and Parkinsonism and Related Disorders. Wolfgang Singer received research support from NIH (R01NS092625, U54NS065736), FDA (R01FD004789), Sturm Foundation, and Mayo Funds. He is associate editor of Clinical Autonomic Research and serves on the editorial board of Autonomic Neuroscience. He has advisory board and consulting agreements with Lundbeck, Catalyst, and Astellas. Zbigniew K. Wszolek receives research support from P50-NS072187, NIH/NIA (primary) and NIH/NINDS (secondary) 1U01AG045390-01A1, Mayo Clinic Center for Regenerative Medicine, the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, The Sol Goldman Charitable Trust, and Donald G. and Jodi P. Heeringa, the Haworth Family Professorship in Neurodegenerative Diseases fund, and by the Albertson Parkinson's Research Foundation. He serves as Co-Editor-in-Chief of Neurologia i Neurochirurgia Polska and is on the editorial boards of European Journal of Clinical and Experimental Medicine, Clinical and Experimental Medical Letters, and Wiadomosci Lekarskie; holds and has contractual rights for receipt of future royalty payments from patents for “A Novel Polynucleotide Involved in Heritable Parkinson’s Disease”; and received royalties from publishing Parkinsonism and Related Disorders (Elsevier, 2016, 2017) and the European Journal of Neurology (Wiley Blackwell, 2016, 2017). ZKW serves as PI or Co-PI on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). He serves as PI of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as Co-PI of the Mayo Clinic APDA Center for Advanced Research. Dennis W. Dickson (DWD) receives support from P50-AG016574, P50-NS072187, P01-AG003949, and CurePSP: Foundation for PSP | CBD and Related Disorders. DWD is an editorial board member of Acta Neuropathologica, Annals of Neurology, Brain, Brain Pathology, and Neuropathology and is Editor in Chief of American Journal of Neurodegenerative Disease and International Journal of Clinical and Experimental Pathology. Phillip A. Low receives support from Supported by NIH (P01NS44233, U54NS065736, R01 FD004789, R01 NS092625, Cure MSA Foundation, Sturm and Mayo Funds. Owen A. Ross (OAR) receives support from R01-NS078086, P50-NS072187, and U54 NS100693, The Little Family Foundation, and the Michael J. Fox Foundation. OAR is an editorial board member of American Journal of Neurodegenerative Disease and Molecular Neurodegeneration.
Written consent from each subject or next-of-kin was collected for all patients included in this study and IRB approval was obtained from the Mayo Clinic institutional review board for ethical conduct of research.
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Supplementary Table 1 aGenes likely responsible for SCA but require further confirmation. 1: Gene was screened for known pathogenic point mutations and novel point mutations via exome sequencing (N = 28). 2: Gene was screened for repeats by duplication analysis; however, duplication analysis was not possible for BEAN and DAB1 due to the absence of a positive control (DOCX 19 KB)
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Wernick, A.I., Walton, R.L., Soto-Beasley, A.I. et al. Frequency of spinocerebellar ataxia mutations in patients with multiple system atrophy. Clin Auton Res 31, 117–125 (2021). https://doi.org/10.1007/s10286-020-00759-1
- Multiple system atrophy
- Spinocerebellar ataxia