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.

The Effect of SMN Gene Dosage on ALS Risk and Disease Severity / M. Moisse, R.A.J. Zwamborn, J. van Vugt, R. van der Spek, W. van Rheenen, B. Kenna, K. Van Eijk, K. Kenna, P. Corcia, P. Couratier, P. Vourc'h, O. Hardiman, R. McLaughin, M. Gotkine, V. Drory, N. Ticozzi, V. Silani, M. de Carvalho, J.S. Mora Pardina, M. Povedano, P.M. Andersen, M. Weber, N.A. Basak, X. Chen, M.A. Eberle, A. Al-Chalabi, C. Shaw, P.J. Shaw, K.E. Morrison, J.E. Landers, J.D. Glass, W. Robberecht, M. van Es, L. van den Berg, J. Veldink, P. Van Damme. - In: ANNALS OF NEUROLOGY. - ISSN 0364-5134. - 89:4(2021), pp. 686-697. [10.1002/ana.26009]

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

N. Ticozzi;V. Silani;
2021

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.
Settore MED/26 - Neurologia
Settore MED/03 - Genetica Medica
Article (author)
File in questo prodotto:
File Dimensione Formato  
Moisse M Ann Neurol 2021.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 2.1 MB
Formato Adobe PDF
2.1 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/832000
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 3
social impact