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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, * 
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.
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Soumis le : mardi 21 septembre 2021 - 15:41:02
Dernière modification le : jeudi 12 mai 2022 - 09:12:09

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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, Wiley, 2021, 89 (4), pp.686-697. ⟨10.1002/ana.26009⟩. ⟨hal-03350820⟩



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