Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy.
EEF1A2
de novo
dyskinesia
epilepsy
yeast complementation assay
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
18
09
2019
revised:
14
02
2020
accepted:
13
03
2020
pubmed:
21
3
2020
medline:
6
11
2021
entrez:
21
3
2020
Statut:
ppublish
Résumé
Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.
Identifiants
pubmed: 32196822
doi: 10.1002/humu.24015
pmc: PMC7292794
mid: NIHMS1583672
doi:
Substances chimiques
EEF1A2 protein, human
0
Peptide Elongation Factor 1
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
1263-1279Subventions
Organisme : NICHD NIH HHS
ID : P50 HD103524
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS106298
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS069605
Pays : United States
Organisme : NINDS NIH HHS
ID : R00 NS089858
Pays : United States
Informations de copyright
© 2020 Wiley Periodicals, Inc.
Références
Genet Med. 2015 Jul;17(7):578-86
pubmed: 25356970
Mol Genet Genomic Med. 2016 Apr 03;4(4):465-74
pubmed: 27441201
J Cell Sci. 2013 Apr 15;126(Pt 8):1744-52
pubmed: 23444377
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W382-8
pubmed: 15980494
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
J Med Genet. 2016 Mar;53(3):190-9
pubmed: 26740508
N Engl J Med. 2012 Nov 15;367(20):1921-9
pubmed: 23033978
J Biochem. 2006 Sep;140(3):393-9
pubmed: 16877446
Am J Hum Genet. 2016 Jun 2;98(6):1249-1255
pubmed: 27236917
Clin Genet. 2015 Apr;87(4):356-61
pubmed: 24697219
J Biol Chem. 2003 Oct 31;278(44):43443-51
pubmed: 12920118
Yeast. 2000 Apr;16(6):553-60
pubmed: 10790693
Mol Cell Biol. 2007 Mar;27(5):1974-89
pubmed: 17178834
PLoS One. 2009 Jul 28;4(7):e6315
pubmed: 19636410
Am J Hum Genet. 2019 Aug 1;105(2):267-282
pubmed: 31327507
Science. 2016 Jan 29;351(6272):aad3867
pubmed: 26823435
J Biol Chem. 1992 Jan 15;267(2):699-702
pubmed: 1730661
Mol Cell. 2010 Oct 22;40(2):280-93
pubmed: 20965422
Epilepsia. 2013 Jul;54(7):1270-81
pubmed: 23647072
J Cell Sci. 2016 Dec 15;129(24):4521-4533
pubmed: 27852836
Sci Signal. 2015 Mar 10;8(367):ra27
pubmed: 25759478
PLoS Genet. 2013;9(8):e1003709
pubmed: 23990802
Nucleic Acids Res. 2014 Nov 10;42(20):12939-48
pubmed: 25326326
Mol Cell Biol. 2005 Jan;25(1):403-13
pubmed: 15601860
J Biol Chem. 2011 Oct 21;286(42):36568-79
pubmed: 21849502
Gene. 1995 Apr 14;156(1):119-22
pubmed: 7737504
Sci Rep. 2017 Apr 05;7:46019
pubmed: 28378778
J Mol Biol. 1999 Dec 17;294(5):1351-62
pubmed: 10600390
J Bacteriol. 1983 Jan;153(1):163-8
pubmed: 6336730
Wiley Interdiscip Rev RNA. 2012 Jul-Aug;3(4):543-55
pubmed: 22555874
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Epilepsia. 2017 Apr;58(4):512-521
pubmed: 28276062
Int J Biochem Cell Biol. 2004 Jul;36(7):1341-7
pubmed: 15109577
Brain Dev. 2016 May;38(5):520-4
pubmed: 26682508
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4463-8
pubmed: 9539760
J Biol Chem. 2007 Sep 28;282(39):28951-9
pubmed: 17640869
Methods Enzymol. 2008;451:89-107
pubmed: 19185716
Eur J Biochem. 1993 Aug 1;215(3):549-54
pubmed: 8354261
Nat Genet. 2013 Jul;45(7):825-30
pubmed: 23708187
Cell Rep. 2013 Nov 14;5(3):727-37
pubmed: 24209753
J Biol Chem. 2014 Jul 25;289(30):20928-38
pubmed: 24936063
Curr Genet. 1985;9(8):693-7
pubmed: 3916735
Yeast. 1999 Oct;15(14):1541-53
pubmed: 10514571
Elife. 2014 Sep 16;3:e03164
pubmed: 25233275
Brain Res Dev Brain Res. 2004 Mar 22;149(1):1-8
pubmed: 15013623
NPJ Genom Med. 2018 Aug 13;3:22
pubmed: 30109124
Nat Commun. 2014 Nov 24;5:5595
pubmed: 25418537
Hum Mol Genet. 2017 Sep 15;26(18):3545-3552
pubmed: 28911200