The Effect of SMN Gene Dosage on ALS Risk and Disease Severity

• Type of Material: Article
• Authors: Matthieu Moisse, Universiteit Leuven; Ramona A. J. Zwamborn, Utrecht University; Joke van Vugt, Utrecht University; Rick van Der Spek, Utrecht University; Wouter van Rheenen, Utrecht University; Brendan Kenna, Utrecht University; Kristel Van Eijk, Utrecht University; Kevin Kenna, Utrecht University; Philippe Corcia, CHRU Tours; Philippe Couratier, CHRU Tours; Patrick Vourc'h, Université de Tours; Orla Hardiman, Trinity College Dublin; Russell McLaughin, Trinity College Dublin; Marc Gotkine, Hadassah Hebrew University; Vivian Drory, Tel Aviv Sourasky Medical Center; Nicole Ticozzi, IRCCS Istituto Auxologico Italiano; Vincenzo Silani, IRCCS Istituto Auxologico Italiano; Mamede de Carvalho, University of Lisbon; Jesús S. Mora Pardina, Hospital San Rafael; Monica Povedano, HUB IDIBELL; Peter M. Andersen, Umea University; Markus Weber, ALS Clinic; Nazli A. Basak, Koc University; Xiao Chen, Illumina Inc; Michael A. Eberle, Illumina Inc; Ammar Al-Chalabi, Kings College London; Chris Shaw, Kings College London; Pamela J. Shaw, University of Sheffield; Karen E. Morrison, Queens University Belfast; John E. Landers, University of Massachusetts; Jonathan Glass, Emory University; Wim Robberecht, Universiteit Leuven; Michael van Es, Utrecht University; Leonard van den Berg, Utrecht University; Jan Veldink, Utrecht University; Philip Van Damme, Universiteit Leuven
• Language: English
• Date: 2021-01-15
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2021 the Authors. nnals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/ana.26009
• Title of Journal or Parent Work: Annals of Neurology
• Volume: 89
• Issue: 4
• Start Page: 686
• End Page: 697
• Grant/Funding Information: This study represents independent research part funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre. Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust.; R.McL. is supported by Science Foundation Ireland (17/CDA/4737).; Samples were sequenced as part of Project MinE. Project MinE Belgium was supported by a grant from IWT (no. 140935), FWO‐Vlaanderen (G0B2819N), the ALS Liga België, the National Lottery of Belgium, and the KU Leuven Opening the Future Fund; This is in part an EU Joint Programme ‐ Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND ‐ www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1, the Netherlands, ZONMW, grant no. 733051071, BRAIN‐MEND), and through the Motor Neurone Disease Association.; Funding was provided to J.E.L. by the NIH/NINDS (R01NS073873) and the ALS Association. V.S. receives or has received research supports from the Italian Ministry of Health (Grant RF‐201302355764), Fondazione Italiana di Ricerca per la SLA – AriSLA (Grant Exomefals and Novals), Fondazione Regionale per la Ricerca Biomedica Regione Lombardia (Project no. 2015–0023), and E‐RARE JTC (Project Repetomics).; This study was supported by the ALS Foundation Netherlands. The collaboration project is co‐funded by the PPP Allowance made available by Health ~ Holland, Top Sector Life Sciences & Health, to stimulate public‐private partnerships.
• Keywords: Science & Technology; Neurosciences & Neurology; Neurosciences; Life Sciences & Biomedicine; Clinical Neurology
• Research Categories: Psychology, Psychobiology; Biology, Neuroscience; Biology, Genetics

Abstract

Objective The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. Methods In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation‐dependent probe amplification data. Results The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston‐Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston‐Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). Interpretation In our well‐powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686–697