The Effect of SMN Gene Dosage on ALS Risk and Disease Severity
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University of Massachusetts Medical School eScholarship@UMMS Open Access Publications by UMMS Authors 2021-04-01 The Effect of SMN Gene Dosage on ALS Risk and Disease Severity Matthieu Moisse KU Leuven - University of Leuven Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Amino Acids, Peptides, and Proteins Commons, Genetics and Genomics Commons, Molecular and Cellular Neuroscience Commons, Nervous System Diseases Commons, and the Neurology Commons Repository Citation Moisse M, Landers JE, Van Damme P. (2021). The Effect of SMN Gene Dosage on ALS Risk and Disease Severity. Open Access Publications by UMMS Authors. https://doi.org/10.1002/ana.26009. Retrieved from https://escholarship.umassmed.edu/oapubs/4668 Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Publications by UMMS Authors by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. RESEARCH ARTICLE The Effect of SMN Gene Dosage on ALS Risk and Disease Severity Matthieu Moisse, PhD ,1,2 Ramona A. J. Zwamborn, MSc,3 Joke van Vugt, PhD ,3 Rick van der Spek, MD ,3 Wouter van Rheenen, PhD ,3 Brendan Kenna, PhD,3 Kristel Van Eijk, PhD,3 Kevin Kenna, PhD,3 Philippe Corcia, MD ,4,5 Philippe Couratier, MD ,4 Patrick Vourc’h, PhD ,5 Orla Hardiman, MD ,6 Russell McLaughin, PhD ,7 Marc Gotkine, MBBS ,8 Vivian Drory, MD,9 Nicola Ticozzi, MD ,10,11 Vincenzo Silani, MD ,10,11 Mamede de Carvalho, MD ,12 Jesús S. Mora Pardina, MD ,13 Monica Povedano, MD,14 Peter M. Andersen, MD ,15 Markus Weber, MD,16 Nazli A. Bas¸ak, PhD ,17 Xiao Chen, PhD ,18 Michael A. Eberle, PhD ,18 Ammar Al-Chalabi, PhD ,19 Chris Shaw, MD,19 Pamela J. Shaw, MD ,20 Karen E. Morrison, MD ,21 John E. Landers, PhD ,22 Jonathan D. Glass, MD ,23 Wim Robberecht, MD,1,24 Michael van Es, MD ,3 Leonard van den Berg, MD ,3 † † Jan Veldink, MD ,3 Philip Van Damme, MD, 1,2,24 and Project MinE Sequencing Consortium25 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 View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.26009 Received Sep 11, 2020, and in revised form Dec 29, 2020. Accepted for publication Dec 30, 2020. Address correspondence to Prof. Philip Van Damme, Neurology Department, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] † These authors contributed equally to this work. From the 1Departments of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven – University of Leuven, Leuven, Belgium; 2Laboratory of Neurobiology, VIB, Center for Brain and Disease Research, Leuven, Belgium; 3Department of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands; 4Centre SLA, CHRU de Tours, Tours, France; 5UMR 1253, iBrain, Université de Tours, Inserm, Tours, France; 6Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Republic of Ireland; 7Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Republic of Ireland; 8The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 9Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel Aviv, Israel; 10Department of Neurology, Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; 11Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy; 12Instituto de Fisiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; 13ALS Unit, Hospital San Rafael, Madrid, Spain; 14Servei de Neurologia, HUB-IDIBELL, Barcelona, Spain; 15Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden; 16Neuromuscular Diseases Unit/ALS Clinic, St. Gallen, Switzerland; 17Koç University, School of Medicine, KUTTAM-NDAL, Istanbul, Turkey; 18Illumina Inc., San Diego, CA; 19Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK; 20Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK; 21School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast, UK; 22Department of Neurology, University of Massachusetts Medical School, Worcester, MA; 23Department Neurology, Emory University School of Medicine, Atlanta, GA; 24Department of Neurology, University Hospitals Leuven, Leuven, Belgium; and 25Project MinE Sequencing Consortium, Utrecht, The Netherlands Additional supporting information can be found in the online version of this article. 686 © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Moisse et al: The Effect of SMN Gene Dosage 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 dif- ferences (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 myotrophic lateral sclerosis (ALS) and spinal muscu- experimental compound therapies, aiming to increase the Alar atrophy (SMA) are both motor neuron disorders expression of the SMN locus.19,20 Nusinersen works leading to progressive muscle weakness and death of through blocking the binding of heterogeneous nuclear patients, mostly due to respiratory failure.1,2 ribonucleoproteins (hnRNPs) at a splicing silencer ele- ALS is an adult-onset disease with an estimated life- ment, named ISS-N1, leading to exon 7 inclusion and time risk of 1 in 400. Approximately 50% of patients die increases full length SMN protein levels.2,19 within 3 to 5 years after onset, but there is a high level of Onasemnogene abeparvovec adds a functional copy of variability between patients in age at onset and progression SMN1 to the genome using a self-complementary adeno- rate, with 5% of the patients surviving more than associated viral serotype 9, increasing the SMN protein 10 years.3,4 Patients are typically categorized into familial levels.20 ALS representing 10 to 20% of patients and sporadic These recent therapeutic breakthroughs in SMA ALS. Genetically, 66% of familial and 10% sporadic could have large consequences for ALS as well, if a con- patients are explained by a mutation in one of the 25 vincing role for SMN in ALS could be established. genes that have been associated with ALS, with mutations Previous studies investigating the effect of the CNs in SOD1, TARDBP, FUS, and C9orf72 being the most of SMN on disease risk and progression of ALS have – common causes.1 To date, several clinical and genetic fac- reported conflicting results.6 15 According to some studies, tors have been put forward as disease modifiers, for exam- loss of SMN1 is associated with ALS risk,8,9,12 whereas ple, sex, age at onset, site of onset, diagnostic delay, others found that duplication of SMN1 associated with – presence of frontotemporal dementia, C9orf72 repeat ALS risks.6,7,11 13 Others did not find any association expansions and SNPs in or near UNC13A, and between ALS and the number of SMN1 copies.10,14,15 CAMTA1.5 In addition, copy number (CN) variation in Likewise for SMN2, some found a homozygous deletion SMN, the gene that is deleted in childhood onset SMA, to be protective,8 whereas others found the deletion to be has been extensively studied as disease modifier with many more frequent in ALS and reducing the survival time of – conflicting reports.6 15 these patients.9,10,15 In addition, here, several other publi- – SMA is a monogenic disease usually caused by a cations failed to find any association.6,7,11 14 homozygous loss of SMN1 and modulated by the number In this large study, we aimed to use the whole of SMN2 copies present.16 In 95% of the cases, both genome sequencing (WGS) data from Project MinE, copies of SMN1 are missing or affected by a gene conver- which contains 6,375 patients with ALS and 2,412 con- sion, the remaining 5% of the patients have a mutation trols to evaluate the effect of SMN CNs in the context of on their remaining copy of SMN1.17 The SMN genes are ALS risk and clinical phenotype.21 This is the largest ALS located on q13.2 of chromosome 5, a locus that under- cohort in which SMN genes have been analyzed in the went an inverted duplication of about 500 kb.18 SMN2 is hope to find a definitive answer.