Cali, E

Houlden, H

Rocca, C

Sullivan, R

Vandrovcova, J

Wood, NW

Yau, WY

English

UCL Discovery

NOTCH2NLC Intermediate-length Repeat Expansion and Parkinson’s Disease in Patients of European Descent  Wai Yan Yau1* FRACP, Roisin Sullivan1* MSc, Clarissa Rocca1 MSc, Elisa Cali1 MD, Jana Vandrovcova1 PhD, Nicholas W Wood2,3 FRCP, PhD, Henry Houlden1,3 FRCP, PhD  1 Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, United Kingdom  2 Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, United Kingdom 3 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom *Both authors contribute equally to this study  Page count: 6 Word count: 336 Number of figure: 1       This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as doi:10.1002/ana.26003This article is protected by copyright. All rights reserved. Out of 1011 sporadic Parkinson’s Disease (PD) patients of Chinese ethnicity, Shi et al. identified 11 patients with intermediate-length GGC repeat expansions (41-64 repeats) in NOTCH2NLC1. Interestingly, the skin samples in 2 of these patients demonstrated phospho-alpha-synuclein deposition rather than the typical inclusion bodies of neuronal intranuclear inclusion disease. We aimed to validate the association between this intermediate-length repeat expansions and PD in an ethnically different cohort.   We estimated the NOTCH2NLC GGC allele sizes in 825 PD patients of European descent—in whom pathogenic repeat expansions were previously excluded2—by amplifying the genomic DNA region containing the repeat using polymerase chain reaction primers specific for NOTCH2NLC3. The genomic DNA of all patients were from the National Institute of Neurological Disorders and Stroke Human Genetics and Cell Line Repository, United States. The study was approved by the joint ethics committee of University College London Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, United Kingdom (UCL: 19/LO/1796).   In our PD cohort, we did not identify any patient with intermediate-length repeat expansions. The estimated repeat sizes ranged from 10 to 38 in our patients (Figure 1). Our study is limited by a lack of a control group. In addition, use of long-read sequencing may also achieve better estimates of GGC repeat sizes and ascertain the presence of repeat interruption. However, these factors should not impact on the result of this study.  This article is protected by copyright. All rights reserved. Despite of the negative screen in our cohort, another case-control study in 1000 Chinese sporadic PD patients identified that 1% of them carried intermediate-length GGC repeat expansions in NOTCH2NLC4. Furthermore, gray-zone GGC alleles (41-54 repeats) at FMR1—another neurodegenerative disease caused by polyglycine expansions—are also associated with increased risk of PD in women5. Shi et al. posited NOTCH2NLC protein upregulation and autophagy dysfunction as the potential pathomechanism in PD patients with intermediate-length GGC repeat expansions1. Therefore, the role of intermediate-length GGC in NOTCH2NLC as a genetic risk factor of PD remains to be confirmed and requires further studies with larger longitudinal clinic-pathological cohorts.   Acknowledgement This study used a Parkinson’s disease panel from the NINDS Repository. The submitters who contributed samples are acknowledged in detailed descriptions of each panel: NDPT083, NDPT085, NDPT087, NDPT088, NDPT089, NDPT101, NDPT102, NDPT104, NDPT105. We are grateful to Professor Shoji Tsuji from Department of Neurology of the University of Tokyo providing us with genomic DNA of the positive control. W.Y.Y. receives a PhD studentship from Ataxia UK and Rosetrees Trust and funding from a Nicholas Blair MDSANZ travelling fellowship. R.S. receives funding from MRC. We are grateful to the Medical Research Council (MRC), The Wellcome Trust Synaptopathies award, MRC Centre grant (G0601943), Ataxia UK, The Rosetrees Trust, Brain Research UK, UCL ODA/LMIC award, The MSA Trust, MDUK, The Muscular Dystrophy Association (MDA). This research was This article is protected by copyright. All rights reserved.also supported by the UCL/UCLH National Institute for Health Research University College London Hospitals Biomedical Research Centre.  Author contributions WYY, RS, NWW and HH contributed to conception and design of the study; WYY, RS, CR, EC and JV contributed to the acquisition and analysis of data; WYY and RS contributed to drafting the text and preparing the figures.  Potential conflicts of interest The authors declare no competing interests.  Data availability The data supporting the findings of this study are available from the corresponding author upon reasonable request.            This article is protected by copyright. All rights reserved.  References 1. Shi CH, Fan Y, Yang J, et al. NOTCH2NLC Intermediate-Length Repeat Expansions Are Associated with Parkinson Disease. Ann Neurol. 2020 Oct 5. 2. Yau WY, Vandrovcova J, Sullivan R, et al. Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients With Movement Disorders. Mov Disord. 2020 Oct 7. 3. Ishiura H, Shibata S, Yoshimura J, et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet. 2019 Aug;51(8):1222-32. 4. Ma D, Tan YJ, Ng ASL, et al. Association of NOTCH2NLC Repeat Expansions With Parkinson Disease. JAMA Neurol. 2020 Aug 24;77(12):1-5. 5. Loesch DZ, Tassone F, Mellick GD, et al. Evidence for the role of FMR1 gray zone alleles as a risk factor for parkinsonism in females. Mov Disord. 2018 Jul;33(7):1178-81.          This article is protected by copyright. All rights reserved.  Figure legend Figure 1. Distribution of the GGC repeat length of NOTCH2NLC in the 825 Parkinson’s disease patients of European descent.      This article is protected by copyright. All rights reserved. Figure 1. Distribution of the GGC repeat length of NOTCH2NLC in the 825 white patients with Parkinson’s Disease. 380x215mm (72 x 72 DPI) Accepted ArticleThis article is protected by copyright. All rights reserved.

NOTCH2NLC Intermediate-length Repeat Expansion and Parkinson's Disease in Patients of European Descent

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NOTCH2NLC Intermediate-length Repeat Expansion and Parkinson's Disease in Patients of European Descent

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