Department of Neurology
Amino Acids, Peptides, and Proteins | Genetics and Genomics | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology
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.
motor neuron gene, SMN, amyotrophic lateral sclerosis
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Copyright © 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 http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
Moisse M, Zwamborn RAJ, van Vugt J, van der Spek R, van Rheenen W, Kenna B, Van Eijk K, Kenna K, Corcia P, Couratier P, Vourc'h P, Hardiman O, McLaughin R, Gotkine M, Drory V, Ticozzi N, Silani V, de Carvalho M, Mora Pardina JS, Povedano M, Andersen PM, Weber M, Başak NA, Chen X, Eberle MA, Al-Chalabi A, Shaw C, Shaw PJ, Morrison KE, Landers JE, Glass JD, Robberecht W, van Es M, van den Berg L, Veldink J, Van Damme P; Project MinE Sequencing Consortium. The Effect of SMN Gene Dosage on ALS Risk and Disease Severity. Ann Neurol. 2021 Apr;89(4):686-697. doi: 10.1002/ana.26009. Epub 2021 Jan 15. PMID: 33389754; PMCID: PMC8048961. Link to article on publisher's site
Annals of neurology
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
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