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Whole Exome Sequencing Identifies Novel DYT1 Dystonia- 2 Associated Genome Variants As Potential Disease Modifiers 3 4 Chih-Fen Hu1*, G

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Whole Exome Sequencing Identifies Novel DYT1 Dystonia- 2 Associated Genome Variants As Potential Disease Modifiers 3 4 Chih-Fen Hu1*, G bioRxiv preprint doi: https://doi.org/10.1101/2020.03.15.993113; this version posted March 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Whole exome sequencing identifies novel DYT1 dystonia- 2 associated genome variants as potential disease modifiers 3 4 Chih-Fen Hu1*, G. W. Gant Luxton2, Feng-Chin Lee1, Chih-Sin Hsu3, Shih-Ming 5 Huang4, Jau-Shyong Hong5, San-Pin Wu6* 6 7 1 Department of Pediatrics, Tri-Service General Hospital, National Defense Medical 8 Center, Taipei, Taiwan 9 2 Department of Genetics, Cell Biology, and Development, University of Minnesota, 10 Minneapolis, MN, United States 11 3 Center for Precision Medicine and Genomics, Tri-Service General Hospital, 12 National Defense Medical Center, Taipei, Taiwan 13 4 Department and Graduate Institute of Biochemistry, National Defense Medical 14 Center, Taipei, Taiwan 15 5 Neurobiology Laboratory, National Institute of Environmental Health Sciences, 16 National Institutes of Health, Research Triangle Park, NC, United States 17 6 Reproductive and Developmental Biology Laboratory, National Institute of 18 Environmental Health Sciences, National Institutes of Health, Research Triangle 19 Park, NC, United States 20 21 * Correspondence: 22 1. Chih-Fen Hu, Department of Pediatrics, Tri-Service General Hospital, National 23 Defense Medical Center, Taipei 114, Taiwan, Email: 24 [email protected]; [email protected] 25 2. San-Pin Wu, Reproductive and Developmental Biology Laboratory, National 26 Institute of Environmental Health Sciences, National Institutes of Health, 27 Research Triangle Park, NC 27709, United States, Email: 28 [email protected] 29 30 31 32 33 Funding information: This research was funded by Tri-Service General Hospital, 34 grant number TSGH-C108-021 (C.F.H.), TSGH-C108-022 (C.F.H.) and National 35 Institutes of Health GM129374 (G.W.G.L.), Z99-ES999999 (S.P.W.). 36 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.15.993113; this version posted March 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 37 Abstract 38 DYT1 dystonia is a neurological movement disorder characterized by painful 39 sustained muscle contractions resulting in abnormal twisting and postures. In a 40 subset of patients, it is caused by a loss-of-function mutation (ΔE302/303; or ΔE) in 41 the luminal ATPases associated with various cellular activities (AAA+) protein 42 torsinA encoded by the TOR1A gene. The low penetrance of the ΔE mutation (~30- 43 40%) suggests the existence of unknown genetic modifiers of DYT1 dystonia. To 44 identify these modifiers, we performed whole exome sequencing (WES) of blood 45 leukocyte DNA isolated from two DYT1 dystonia patients, three asymptomatic 46 carriers of the ΔE mutation, and an unaffected adult relative. A total of 264 DYT1 47 dystonia-associated variants (DYT1 variants) were identified in 195 genes. 48 Consistent with the emerging view of torsinA as an important regulator of the 49 cytoskeleton, endoplasmic reticulum homeostasis, and lipid metabolism, we found 50 DYT1 variants in genes that encode proteins implicated in these processes. 51 Moreover, 40 DYT1 variants were detected in 32 genes associated with 52 neuromuscular and neuropsychiatric disorders. The DYT1 variants described in this 53 work represent exciting new targets for future studies designed to increase our 54 understanding of the pathophysiology and pathogenesis of DYT1 dystonia. 55 56 57 58 59 60 Keywords: DYT1 dystonia; TOR1A; torsinA; neurogenetics; whole exome 61 sequencing 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.15.993113; this version posted March 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 62 1. INTRODUCTION 63 Dystonias are a heterogeneous collection of hyperkinetic neurological movement 64 disorders that are characterized by involuntary muscle contractions resulting in 65 abnormal repetitive movements and postures (Alberto Albanese et al., 2013; Fahn, 66 1988). Dystonias can be acquired as the result of environmental insults (i.e. central 67 nervous system infection, toxins, and traumatic brain injury) (Alberto Albanese et al., 68 2013; A. Albanese, Di Giovanni, & Lalli, 2019) as well as inherited due to genetic 69 mutations (Weisheit, Pappas, & Dauer, 2018). While several causative genes are 70 known, the mechanisms underlying their contribution to dystonia pathogenesis 71 and/or pathophysiology remain unclear. 72 73 Early onset torsion dystonia, or DYT1 dystonia, is the most common and severe 74 inherited dystonia (Petrucci & Valente, 2013). It is a primary torsion dystonia, as 75 dystonia is the only clinical symptom present in patients and it is inherited in a 76 monogenic fashion. The majority of DYT1 dystonia cases are caused by the 77 autosomal dominantly inherited deletion of a GAG codon 78 (c.904_906/907_909ΔGAG) from the TOR1A gene, which removes a glutamic acid 79 residue (ΔE302/303; or ΔE) from the C-terminus of the encoded luminal ATPase 80 torsinA (Neuwald, Aravind, Spouge, & Koonin, 1999; L. J. Ozelius et al., 1997). The 81 ΔE mutation is considered a loss-of-function mutation because homozygous torsinA- 82 knockout and homozygous torsinAΔE-knockin mice both die perinatally and exhibit 83 neurons with abnormal blebbing of the inner nuclear membrane into the perinuclear 84 space of the nuclear envelope (Goodchild, Kim, & Dauer, 2005). In addition, the ΔE 85 mutation impairs the ability of torsinA to interact with its major binding partners the 86 inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1) and the 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.15.993113; this version posted March 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 87 endoplasmic reticulum/outer nuclear membrane protein luminal domain-like LAP1 88 (LULL1) (Naismith, Dalal, & Hanson, 2009), which stimulates the ability of torsinA to 89 hydrolyze ATP above negligible background levels in vitro (Zhao, Brown, Chase, 90 Eisele, & Schlieker, 2013). 91 92 Surprisingly, only ~30-40% of individuals heterozygous for the ΔE develop DYT1 93 dystonia despite the presence of abnormalities in brain metabolism and the 94 cerebellothalamocortical pathway in all carriers (Argyelan et al., 2009; Eidelberg et 95 al., 1998; Niethammer, Carbon, Argyelan, & Eidelberg, 2011; Premi et al., 2016; 96 Trost et al., 2002). Collectively, these clinical findings demonstrate that the presence 97 of the ΔE mutation results in abnormal brain function regardless of whether or not 98 an individual develops DYT1 dystonia. Moreover, they suggest the hypothesis that 99 the penetrance of the ΔE mutation may be influenced by additional as-of-yet 100 unknown genetic factors. 101 102 Consistent with this hypothesis, recent research shows that genetic background 103 modulates the phenotype of a mouse model of DYT1 dystonia (Tanabe, Martin, & 104 Dauer, 2012). In addition, expression profiling in peripheral blood harvested from 105 human DYT1 dystonia patients harboring the ΔE mutation and asymptomatic 106 carriers revealed a genetic signature that could correctly predict disease state 107 (Walter et al., 2010). The functional classification of transcripts that were differentially 108 regulated in DYT1 dystonia patients relative to unaffected carriers identified a variety 109 of potentially impacted biological pathways, including cell adhesion, cytoskeleton 110 organization and biogenesis, development of the nervous system, G-protein receptor 111 signaling, and vesicle-mediated pathway/protein transport. Since these biological 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.15.993113; this version posted March 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 112 pathways have all been previously associated with torsinA function (Cascalho, 113 Jacquemyn, & Goodchild, 2017; Gonzalez-Alegre, 2019; Laudermilch & Schlieker, 114 2016; Weisheit et al., 2018), we hypothesize that the penetrance of the ΔE mutation 115 and therefore the development of DYT1 dystonia may depend upon the presence or 116 absence of variants in genes that encode proteins that influence biological pathways 117 associated with torsinA function. Below, we describe the use of WES to identify 118 genetic variants in DYT1 dystonia patients but neither unaffected ΔE mutation 119 carriers nor the unaffected control. 120 121 2. MATERIALS AND METHODS 122 2.1 Human Subjects. This study recruited 11 human subjects, including two patients 123 from two separate families of Taiwanese ancestry. All subjects (or legal guardians) 124 gave their written informed consent for participation and the study was approved by 125 the Institutional Review Board of the Tri-Service General Hospital at the National 126 Defense Medical Center in Taipei, Taiwan (IRB# 1-107-05-164). Detailed clinical 127 information was obtained from corresponding clinicians and medical records. 128 129 2.2 Purification of genomic DNA from Isolated Human Blood Leukocytes. 130 Genomic DNA was purified from human leukocytes using the MagPurix®
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