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

Matthieu Moisse (1) , Ramona Zwamborn (2) , Joke Vugt (2) , Rick Spek (2) , Wouter Rheenen (2) , Brendan Kenna (2) , Kristel van Eijk (2) , Kevin Kenna (2) , Philippe Corcia (3) , Philippe Couratier (4, 5) , Patrick Vourc'H (6) , Orla Hardiman (7) , Russell Mclaughin (8) , Marc Gotkine (9) , Vivian Drory (9) , Nicola Ticozzi (10) , Vincenzo Silani (11) , Mamede Carvalho (12) , Jesús Mora Pardina (13) , Monica Povedano , Peter Andersen (14) , Markus Weber , Nazli Başak , Xiao Chen (15) , Michael Eberle (15) , Ammar Al‐chalabi (16) , Chris Shaw (16) , Pamela Shaw (17) , Karen Morrison (18) , John Landers (19) , Jonathan Glass (20) , Wim Robberecht (21) , Michael Es (2) , Leonard Berg (2) , Jan Veldink (2) , Philip van Damme (21)

1 Université de Leuven
2 Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht
3 SLA CHRU Tours - Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours]
4 NET - Neuroépidémiologie Tropicale
5 Service de Neurologie [CHU Limoges]
6 UMR U 1253
7 Department of Neurology, The Adelaide and Meath Hospital, Trinity College Dublin
8 Trinity College
9 Tel Aviv Sourasky Medical Center [Te Aviv]
10 Department of Neurology, IRCCS San Raffaele, Milano
11 Department of Neurology, IRCCS San Raffaele, Milano
12 Université de Lisbonne
13 Sant Rafael Hospital
14 Umeå University Hospital
15 Illumina Incorporated [San Diego, CA, USA]
16 Maurice Wohl Clinical Neuroscience Institut
17 SITraN - Sheffield Institute for Translational Neuroscience
18 QUB - Queen's University [Belfast]
19 UMASS - University of Massachusetts Medical School [Worcester]
20 Emory University School of Medicine
21 University Hospitals Leuven [Leuven]

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.

Domaines: Santé publique et épidémiologie

Matthieu Moisse, Ramona Zwamborn, Joke Vugt, Rick Spek, Wouter Rheenen, et al.. The Effect of SMN Gene Dosage on ALS Risk and Disease Severity. Annals of Neurology, 2021, 89 (4), pp.686-697. ⟨10.1002/ana.26009⟩. ⟨hal-03350820⟩