The GRIA3 c.2477G > A Variant Causes an Exaggerated Startle Reflex, Chorea, and Multifocal Myoclonus.
AMPA receptor
GRIA3
chorea
glutamate receptor
myoclonus
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
27
09
2019
revised:
24
02
2020
accepted:
03
03
2020
pubmed:
6
5
2020
medline:
28
4
2021
entrez:
6
5
2020
Statut:
ppublish
Résumé
Hemizygous mutations in GRIA3 encoding the GluA3 subunit of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor are known to be associated with neurodevelopmental disorders, including intellectual disability, hypotonia, an autism spectrum disorder, sleep disturbances, and epilepsy in males. To describe a new and consistent phenotype in 4 affected male patients associated with an undescribed deleterious variant in GRIA3. We evaluated a large French family in which segregate a singular phenotype according to an apparent X-linked mode of inheritance. Molecular analyses using next generation sequencing and in vitro functional studies using 2-electrode voltage clamp recordings on Xenopus laevis oocytes and a β-lactamase reporter assay in transfected human embryonic kidney (HEK293) cells were performed. In addition to mild intellectual disability and dysarthria, affected patients presented a tightly consistent early-onset movement disorder combining an exaggerated startle reflex with generalized chorea and multifocal myoclonus. The unreported GRIA3 missense variant c.2477G > A; p.(Gly826Asp) affecting the fourth transmembrane domain of the protein was identified in index patients and their unaffected mothers. Functional studies revealed that variant receptors show decreased current response evoked by agonist (ie, kainic acid and glutamate) and reduced expression on the cell surface in favor of pathogenicity by a loss-of-function mechanism. Taken together, our results suggest that apart from known GRIA3-related disorders, an undescribed mutation-specific singular movement disorder does exist. We thus advocate considering GRIA3 mutations in the differential diagnosis of hyperekplexia and generalized chorea with myoclonus. © 2020 International Parkinson and Movement Disorder Society.
Sections du résumé
BACKGROUND
Hemizygous mutations in GRIA3 encoding the GluA3 subunit of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor are known to be associated with neurodevelopmental disorders, including intellectual disability, hypotonia, an autism spectrum disorder, sleep disturbances, and epilepsy in males.
OBJECTIVE
To describe a new and consistent phenotype in 4 affected male patients associated with an undescribed deleterious variant in GRIA3.
METHODS
We evaluated a large French family in which segregate a singular phenotype according to an apparent X-linked mode of inheritance. Molecular analyses using next generation sequencing and in vitro functional studies using 2-electrode voltage clamp recordings on Xenopus laevis oocytes and a β-lactamase reporter assay in transfected human embryonic kidney (HEK293) cells were performed.
RESULTS
In addition to mild intellectual disability and dysarthria, affected patients presented a tightly consistent early-onset movement disorder combining an exaggerated startle reflex with generalized chorea and multifocal myoclonus. The unreported GRIA3 missense variant c.2477G > A; p.(Gly826Asp) affecting the fourth transmembrane domain of the protein was identified in index patients and their unaffected mothers. Functional studies revealed that variant receptors show decreased current response evoked by agonist (ie, kainic acid and glutamate) and reduced expression on the cell surface in favor of pathogenicity by a loss-of-function mechanism.
CONCLUSIONS
Taken together, our results suggest that apart from known GRIA3-related disorders, an undescribed mutation-specific singular movement disorder does exist. We thus advocate considering GRIA3 mutations in the differential diagnosis of hyperekplexia and generalized chorea with myoclonus. © 2020 International Parkinson and Movement Disorder Society.
Identifiants
pubmed: 32369665
doi: 10.1002/mds.28058
pmc: PMC9190290
mid: NIHMS1811513
doi:
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
1224-1232Subventions
Organisme : NINDS NIH HHS
ID : R01 NS036654
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD082373
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS065371
Pays : United States
Organisme : NINDS NIH HHS
ID : R24 NS092989
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS111619
Pays : United States
Informations de copyright
© 2020 International Parkinson and Movement Disorder Society.
Références
Nature. 2013 Sep 12;501(7466):217-21
pubmed: 23934111
Brain Dev. 2017 Apr;39(4):306-311
pubmed: 27843043
Genomics. 1999 Dec 15;62(3):356-68
pubmed: 10644433
Brain. 2019 Jan 1;142(1):80-92
pubmed: 30544257
Am J Hum Genet. 2016 Oct 6;99(4):802-816
pubmed: 27616483
Parkinsonism Relat Disord. 2019 Jul;64:145-149
pubmed: 30975617
Am J Med Genet A. 2007 Jul 1;143A(13):1448-55
pubmed: 17568425
Traffic. 2013 Jul;14(7):778-84
pubmed: 23574269
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18163-8
pubmed: 17989220
Eur J Hum Genet. 2013 Jan;21(1):112-4
pubmed: 22669415
Am J Hum Genet. 2017 Dec 7;101(6):1013-1020
pubmed: 29220673
Nature. 1989 Dec 7;342(6250):643-8
pubmed: 2480522
Nat Genet. 2016 Nov;48(11):1349-1358
pubmed: 27694961
Hum Mol Genet. 2017 Oct 15;26(20):3869-3882
pubmed: 29016847
Nat Commun. 2018 Sep 14;9(1):3748
pubmed: 30217972
Brain. 2019 Oct 1;142(10):3009-3027
pubmed: 31504254
PLoS Genet. 2017 Jan 17;13(1):e1006536
pubmed: 28095420
Orphanet J Rare Dis. 2014 Apr 11;9:49
pubmed: 24721225
Mov Disord. 2019 Nov;34(11):1602-1613
pubmed: 31584223
Am J Med Genet A. 2013 Jun;161A(6):1370-5
pubmed: 23637084
Science. 1990 Aug 3;249(4968):556-60
pubmed: 2166337
Hum Mutat. 2012 Feb;33(2):355-8
pubmed: 22124977
Mol Syndromol. 2013 Jun;4(5):213-26
pubmed: 23885228
Pharmacol Rev. 2010 Sep;62(3):405-96
pubmed: 20716669
Am J Hum Genet. 2016 Dec 1;99(6):1261-1280
pubmed: 27839871
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2018 Apr 10;35(2):257-260
pubmed: 29653005
Mol Pharmacol. 2017 Apr;91(4):317-330
pubmed: 28126851
Gene. 2015 Aug 1;567(1):98-102
pubmed: 25956375
Mov Disord Clin Pract. 2018 Nov 09;6(1):34-39
pubmed: 30746413
Nucleic Acids Res. 2012 Jan;40(Database issue):D84-90
pubmed: 22086963
Am J Med Genet A. 2009 Jun;149A(6):1280-9
pubmed: 19449417
Nature. 2009 Dec 10;462(7274):745-56
pubmed: 19946266