CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis.
ALS
CGG repeat expansion
LRP12
OPDM
RNA foci
iPSCs
motor neuron
pTDP-43
repeat disease
skeletal muscle
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
06 07 2023
06 07 2023
Historique:
received:
25
03
2023
revised:
25
05
2023
accepted:
25
05
2023
pmc-release:
06
01
2024
medline:
10
7
2023
pubmed:
21
6
2023
entrez:
20
6
2023
Statut:
ppublish
Résumé
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.
Identifiants
pubmed: 37339631
pii: S0002-9297(23)00198-2
doi: 10.1016/j.ajhg.2023.05.014
pmc: PMC10357476
pii:
doi:
Substances chimiques
C9orf72 Protein
0
LRP12 protein, human
0
Low Density Lipoprotein Receptor-Related Protein-1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1086-1097Informations de copyright
Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
EMBO J. 2010 Apr 7;29(7):1248-61
pubmed: 20186122
Lancet Neurol. 2022 May;21(5):480-493
pubmed: 35334233
Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9
pubmed: 11464847
Am J Hum Genet. 2022 Mar 3;109(3):533-541
pubmed: 35148830
Nat Neurosci. 2020 Mar;23(3):386-397
pubmed: 32066985
Cell Stem Cell. 2009 Sep 4;5(3):332-42
pubmed: 19733544
Am J Hum Genet. 2020 Jun 4;106(6):793-804
pubmed: 32413282
Genome Res. 2001 May;11(5):863-74
pubmed: 11337480
Nat Methods. 2011 May;8(5):409-12
pubmed: 21460823
Cell Rep. 2015 Feb 3;10(4):537-50
pubmed: 25640179
Autophagy. 2021 Nov;17(11):3306-3322
pubmed: 33632058
Genome Biol. 2019 Mar 19;20(1):58
pubmed: 30890163
Neuron. 2011 Oct 20;72(2):257-68
pubmed: 21944779
Life Sci Alliance. 2018 May 16;1(2):e201800070
pubmed: 30456350
Neuropathol Appl Neurobiol. 2019 Feb;45(1):19-40
pubmed: 30357887
Bioinformatics. 2020 May 1;36(10):3236-3238
pubmed: 32053166
Am J Hum Genet. 2007 Jun;80(6):1090-102
pubmed: 17503327
Biomolecules. 2021 Feb 16;11(2):
pubmed: 33669384
Stem Cells. 2013 Mar;31(3):458-66
pubmed: 23193063
Acta Neuropathol Commun. 2020 Nov 25;8(1):204
pubmed: 33239111
JAMA Neurol. 2022 Jul 1;79(7):693-701
pubmed: 35604654
Cell Rep. 2016 Nov 1;17(6):1482-1490
pubmed: 27806289
Dev Biol. 2014 Jul 1;391(1):81-8
pubmed: 24709321
Neuron. 2011 Oct 20;72(2):245-56
pubmed: 21944778
Neurology. 2001 Jul 10;57(1):127-30
pubmed: 11445641
Clin Neurophysiol. 2008 Mar;119(3):497-503
pubmed: 18164242
Science. 1991 Jun 21;252(5013):1711-4
pubmed: 1675488
Nat Genet. 2019 Aug;51(8):1222-1232
pubmed: 31332380
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Nat Genet. 2000 May;25(1):12-3
pubmed: 10802644
Stem Cell Res. 2018 May;29:189-196
pubmed: 29729503
Brain. 2021 Jul 28;144(6):1819-1832
pubmed: 33693509
Nature. 2010 Aug 26;466(7310):1069-75
pubmed: 20740007
Acta Neuropathol Commun. 2020 Jun 3;8(1):75
pubmed: 32493488
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Curr Opin Neurol. 2021 Aug 1;34(4):541-546
pubmed: 33990099
Cell. 2007 Nov 30;131(5):861-72
pubmed: 18035408
Science. 2013 Mar 15;339(6125):1335-8
pubmed: 23393093
Nat Neurosci. 2010 Oct;13(10):1171-80
pubmed: 20835252
JAMA Neurol. 2021 Jul 1;78(7):853-863
pubmed: 34047774
Science. 2006 Oct 6;314(5796):130-3
pubmed: 17023659
J Vis Exp. 2019 May 1;(147):
pubmed: 31107442
Neurol Genet. 2020 Jan 16;6(1):e396
pubmed: 32042923
Ann Neurol. 2022 Sep;92(3):512-526
pubmed: 35700120
Sci Transl Med. 2012 Aug 1;4(145):145ra104
pubmed: 22855461