Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
18
08
2018
accepted:
07
01
2019
entrez:
26
1
2019
pubmed:
27
1
2019
medline:
23
10
2019
Statut:
epublish
Résumé
Infants and children with dominant de novo mutations in GNAO1 exhibit movement disorders, epilepsy, or both. Children with loss-of-function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17). Gain-of-function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM). There is no animal model with a human mutant GNAO1 allele. Here we develop a mouse model carrying a human GNAO1 mutation (G203R) and determine whether the clinical features of patients with this GNAO1 mutation, which includes both epilepsy and movement disorder, would be evident in the mouse model. A mouse Gnao1 knock-in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock-in (Gnao1+/G184S), which has not been found in patients, was also studied for comparison. Gnao1+/G203R mutant mice are viable and gain weight comparably to controls. Homozygotes are non-viable. Grip strength was decreased in both males and females. Male Gnao1+/G203R mice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. Male Gnao1+/G203R mice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock-in also showed movement-related behavioral phenotypes but females were more strongly affected than males. Gnao1+/G203R mice phenocopy children with heterozygous GNAO1 G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies of GNAO1-related movement disorders.
Sections du résumé
BACKGROUND
Infants and children with dominant de novo mutations in GNAO1 exhibit movement disorders, epilepsy, or both. Children with loss-of-function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17). Gain-of-function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM). There is no animal model with a human mutant GNAO1 allele.
OBJECTIVES
Here we develop a mouse model carrying a human GNAO1 mutation (G203R) and determine whether the clinical features of patients with this GNAO1 mutation, which includes both epilepsy and movement disorder, would be evident in the mouse model.
METHODS
A mouse Gnao1 knock-in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock-in (Gnao1+/G184S), which has not been found in patients, was also studied for comparison.
RESULTS
Gnao1+/G203R mutant mice are viable and gain weight comparably to controls. Homozygotes are non-viable. Grip strength was decreased in both males and females. Male Gnao1+/G203R mice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. Male Gnao1+/G203R mice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock-in also showed movement-related behavioral phenotypes but females were more strongly affected than males.
CONCLUSIONS
Gnao1+/G203R mice phenocopy children with heterozygous GNAO1 G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies of GNAO1-related movement disorders.
Identifiants
pubmed: 30682176
doi: 10.1371/journal.pone.0211066
pii: PONE-D-18-22930
pmc: PMC6347370
doi:
Substances chimiques
GNAO1 protein, human
0
GNAO1 protein, mouse
EC 3.6.5.1
GTP-Binding Protein alpha Subunits, Gi-Go
EC 3.6.5.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Retracted Publication
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0211066Commentaires et corrections
Type : RetractionIn
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
PLoS Genet. 2018 Jul 9;14(7):e1007503
pubmed: 29985941
Nat Biotechnol. 2013 Sep;31(9):827-32
pubmed: 23873081
J Neurol Neurosurg Psychiatry. 2018 Feb;89(2):221-222
pubmed: 28668776
Mamm Genome. 2014 Jun;25(5-6):202-10
pubmed: 24700286
Zhongguo Dang Dai Er Ke Za Zhi. 2018 Feb;20(2):154-157
pubmed: 29429466
J Vis Exp. 2013 Jun 02;(76):
pubmed: 23770643
Eur J Hum Genet. 2016 Jan;24(1):129-34
pubmed: 25966631
Front Biosci. 2008 May 01;13:4544-57
pubmed: 18508528
Neuropediatrics. 2017 Oct;48(5):371-377
pubmed: 28628939
Exp Neurol. 2014 Sep;259:44-56
pubmed: 24681088
Biochem Pharmacol. 1998 Nov 15;56(10):1287-93
pubmed: 9825727
Neuropediatrics. 2016 Jan;47(1):1-2
pubmed: 26800375
Mol Pharmacol. 2009 May;75(5):1222-30
pubmed: 19225179
Behav Brain Res. 2013 Mar 15;241:32-7
pubmed: 23219967
Pharmacol Biochem Behav. 2013 Jan;103(3):582-8
pubmed: 23103202
Genome Biol. 2016 Jul 05;17(1):148
pubmed: 27380939
Clin Chim Acta. 2015 Dec 7;451(Pt B):292-6
pubmed: 26485252
J Neurosci. 1994 Apr;14(4):2327-38
pubmed: 8158271
Methods Enzymol. 2004;389:229-43
pubmed: 15313569
Sci Rep. 2017 Nov 7;7(1):14678
pubmed: 29116142
Neurosignals. 2009;17(1):23-41
pubmed: 19212138
Pharmacol Biochem Behav. 2004 Jul;78(3):513-22
pubmed: 15251260
Epileptic Disord. 2017 Mar 1;19(1):67-75
pubmed: 28202424
Biotechniques. 2000 Jul;29(1):52, 54
pubmed: 10907076
Pediatr Neurol. 2016 Jun;59:81-4
pubmed: 27068059
Br J Pharmacol. 2003 Mar;138(5):775-86
pubmed: 12642378
Pediatr Neurol. 2016 Jul;60:83-7
pubmed: 27343026
Nat Biotechnol. 2016 Feb;34(2):184-191
pubmed: 26780180
J Biol Chem. 1998 Mar 6;273(10):5780-4
pubmed: 9488712
Toxicol Lett. 2007 Mar 30;169(3):205-13
pubmed: 17317045
Am J Hum Genet. 2013 Sep 5;93(3):496-505
pubmed: 23993195
Curr Protoc Neurosci. 2012;Chapter 9:Unit9.37
pubmed: 23042503
PLoS One. 2016 Jan 25;11(1):e0147887
pubmed: 26807827
Neurol Genet. 2017 Mar 21;3(2):e143
pubmed: 28357411
Neurobiol Dis. 2018 Aug;116:131-141
pubmed: 29758257
Clin Neuropharmacol. 1999 Nov-Dec;22(6):318-26
pubmed: 10626091
J Child Neurol. 2016 Dec;31(14):1598-1601
pubmed: 27625011
Genet Med. 2015 Oct;17(10):774-81
pubmed: 25590979
Naunyn Schmiedebergs Arch Pharmacol. 2004 Mar;369(3):287-93
pubmed: 14963640
J Vis Exp. 2014 Sep 29;(91):51785
pubmed: 25286313
Neurology. 2017 Aug 22;89(8):762-770
pubmed: 28747448
Physiol Rev. 2005 Oct;85(4):1159-204
pubmed: 16183910
J Physiol. 2002 Dec 1;545(2):355-73
pubmed: 12456817
Learn Mem. 2011 Dec 21;19(1):26-34
pubmed: 22190729
J Biol Chem. 1998 May 22;273(21):12794-7
pubmed: 9582306
J Neurosci. 2004 Apr 21;24(16):4070-81
pubmed: 15102922
Genetics. 2015 Jun;200(2):423-30
pubmed: 25819794
Am J Hum Genet. 2014 Oct 2;95(4):360-70
pubmed: 25262651
J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):637-9
pubmed: 15026515
Orphanet J Rare Dis. 2016 Apr 12;11:38
pubmed: 27072799
Genet Med. 2018 Apr;20(5):486-494
pubmed: 28817111
J Cell Biol. 2008 Mar 10;180(5):1021-35
pubmed: 18332222
Oncotarget. 2017 Oct 25;9(35):23846-23847
pubmed: 29844856
Mov Disord. 2013 Jun 15;28(7):990-1000
pubmed: 23893455
J Child Neurol. 2018 May;33(6):413-416
pubmed: 29661126
Mol Pharmacol. 1994 Mar;45(3):524-31
pubmed: 8145737
J Child Neurol. 2016 Feb;31(2):211-4
pubmed: 26060304
Mov Disord. 2013 Jun 15;28(7):982-9
pubmed: 23893454
Neuropharmacology. 1999 Nov;38(11):1657-66
pubmed: 10587081
Learn Mem. 2011 Aug 30;18(9):598-604
pubmed: 21878527
Neurobiol Dis. 2012 Oct;48(1):66-78
pubmed: 22659308
Childs Nerv Syst. 2016 Sep;32(9):1567-8
pubmed: 27278281
Science. 2005 Mar 11;307(5715):1625-30
pubmed: 15705806