The Effect of SMN Gene Dosage on ALS Risk and Disease Severity.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
29
12
2020
received:
11
09
2020
accepted:
30
12
2020
pubmed:
4
1
2021
medline:
26
5
2021
entrez:
3
1
2021
Statut:
ppublish
Résumé
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. 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. 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). 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.
Identifiants
pubmed: 33389754
doi: 10.1002/ana.26009
pmc: PMC8048961
doi:
Substances chimiques
SMN1 protein, human
0
SMN2 protein, human
0
Survival of Motor Neuron 1 Protein
0
Survival of Motor Neuron 2 Protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
686-697Subventions
Organisme : Medical Research Council
ID : MR/L501529/1
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R56 NS073873
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS073873
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : ALCHALABI-DOBSON/APR14/829-791
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0600974
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R024804/1
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Références
Korean J Lab Med. 2010 Feb;30(1):93-6
pubmed: 20197730
Genet Med. 2020 May;22(5):945-953
pubmed: 32066871
Neurology. 2001 Mar 27;56(6):749-52
pubmed: 11274309
N Engl J Med. 2017 Nov 2;377(18):1713-1722
pubmed: 29091557
Neurology. 2002 Nov 12;59(9):1456-60
pubmed: 12427907
Genet Med. 2017 Aug;19(8):936-944
pubmed: 28125085
Eur J Neurol. 2020 Oct;27(10):1918-1929
pubmed: 32526057
Yonsei Med J. 2012 Jan;53(1):53-7
pubmed: 22187232
Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):436-40
pubmed: 19922137
Neurology. 2005 Sep 27;65(6):820-5
pubmed: 16093455
J Clin Invest. 2019 Nov 1;129(11):4817-4831
pubmed: 31589162
J Med Genet. 2014 Jun;51(6):419-24
pubmed: 24706941
Hum Mutat. 2005 Jan;25(1):64-71
pubmed: 15580564
J Neurol Sci. 2014 May 15;340(1-2):63-8
pubmed: 24630593
Lancet Neurol. 2020 Apr;19(4):317-325
pubmed: 32199097
Eur J Hum Genet. 2018 Oct;26(10):1537-1546
pubmed: 29955173
Neurology. 2012 Mar 13;78(11):776-80
pubmed: 22323753
J Neurol. 2002 Sep;249(9):1211-9
pubmed: 12242541
Cell Rep. 2017 Feb 7;18(6):1484-1498
pubmed: 28178525
BMC Musculoskelet Disord. 2015 Feb 07;16:11
pubmed: 25888055
Ann Neurol. 2014 Feb;75(2):287-97
pubmed: 24382602
Stat Med. 2002 Aug 15;21(15):2175-97
pubmed: 12210632
Ann Neurol. 2002 Feb;51(2):243-6
pubmed: 11835381
Dis Model Mech. 2017 May 1;10(5):537-549
pubmed: 28468939
PLoS One. 2015 Oct 15;10(10):e0139950
pubmed: 26468953
Genes Dev. 2010 Aug 1;24(15):1634-44
pubmed: 20624852
Eur J Hum Genet. 2012 May;20(5):588-91
pubmed: 22274580
Neurology. 2006 Oct 10;67(7):1147-50
pubmed: 16931506
Eur J Med Genet. 2018 Nov;61(11):685-698
pubmed: 29313812
JAMA Neurol. 2016 Jul 1;73(7):812-20
pubmed: 27244217
Hum Genet. 2001 Mar;108(3):255-66
pubmed: 11354640
Neurology. 2006 Apr 11;66(7):1067-73
pubmed: 16481599
Bioinformatics. 2019 Jun 1;35(11):1978-1980
pubmed: 30376034
Bioinformatics. 2019 Nov 1;35(22):4754-4756
pubmed: 31134279
Cell Rep. 2017 Dec 26;21(13):3767-3780
pubmed: 29281826