A Gain-of-Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype.
chorea
dopamine D2 receptor
dystonia
hyperkinetic movement disorder
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:
03 2021
03 2021
Historique:
revised:
03
10
2020
received:
28
05
2020
accepted:
26
10
2020
pubmed:
18
11
2020
medline:
24
4
2021
entrez:
17
11
2020
Statut:
ppublish
Résumé
We describe a 4-generation Dutch pedigree with a unique dominantly inherited clinical phenotype of a combined progressive chorea and cervical dystonia carrying a novel heterozygous dopamine D2 receptor (DRD2) variant. The objective of this study was to identify the genetic cause of the disease and to further investigate the functional consequences of the genetic variant. After detailed clinical and neurological examination, whole-exome sequencing was performed. Because a novel variant in the DRD2 gene was found as the likely causative gene defect in our pedigree, we sequenced the DRD2 gene in a cohort of 121 Huntington-like cases with unknown genetic cause (Germany). Moreover, functional characterization of the DRD2 variant included arrestin recruitment, G protein activation, and G protein-mediated inhibition of adenylyl cyclase determined in a cell model, and G protein-regulated inward-rectifying potassium channels measured in midbrain slices of mice. We identified a novel heterozygous variant c.634A > T, p.Ile212Phe in exon 5 of DRD2 that cosegregated with the clinical phenotype. Screening of the German cohort did not reveal additional putative disease-causing variants. We demonstrated that the D2 Our results support an association between the novel p.Ile212Phe variant in DRD2, its modified D2 receptor activity, and the hyperkinetic movement disorder reported in the 4-generation pedigree. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Sections du résumé
BACKGROUND
We describe a 4-generation Dutch pedigree with a unique dominantly inherited clinical phenotype of a combined progressive chorea and cervical dystonia carrying a novel heterozygous dopamine D2 receptor (DRD2) variant.
OBJECTIVES
The objective of this study was to identify the genetic cause of the disease and to further investigate the functional consequences of the genetic variant.
METHODS
After detailed clinical and neurological examination, whole-exome sequencing was performed. Because a novel variant in the DRD2 gene was found as the likely causative gene defect in our pedigree, we sequenced the DRD2 gene in a cohort of 121 Huntington-like cases with unknown genetic cause (Germany). Moreover, functional characterization of the DRD2 variant included arrestin recruitment, G protein activation, and G protein-mediated inhibition of adenylyl cyclase determined in a cell model, and G protein-regulated inward-rectifying potassium channels measured in midbrain slices of mice.
RESULT
We identified a novel heterozygous variant c.634A > T, p.Ile212Phe in exon 5 of DRD2 that cosegregated with the clinical phenotype. Screening of the German cohort did not reveal additional putative disease-causing variants. We demonstrated that the D2
CONCLUSIONS
Our results support an association between the novel p.Ile212Phe variant in DRD2, its modified D2 receptor activity, and the hyperkinetic movement disorder reported in the 4-generation pedigree. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Identifiants
pubmed: 33200438
doi: 10.1002/mds.28385
pmc: PMC8049080
doi:
Substances chimiques
Receptors, Dopamine D2
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
729-739Subventions
Organisme : BLRD VA
ID : I01 BX003279
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS117713
Pays : United States
Organisme : NIDA NIH HHS
ID : K99 DA044287
Pays : United States
Organisme : NIDA NIH HHS
ID : F31 DA047007
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Références
J Neural Transm (Vienna). 2010 Dec;117(12):1359-69
pubmed: 21076988
Front Mol Neurosci. 2011 Nov 01;4:38
pubmed: 22065948
Neurol Clin Pract. 2015 Apr;5(2):143-149
pubmed: 29443187
J Exp Neurosci. 2018 May 31;12:1179069518779829
pubmed: 29899667
Neuron. 2016 May 18;90(4):824-38
pubmed: 27196975
Neuron. 2013 Jun 5;78(5):807-12
pubmed: 23764286
Nat Rev Neurosci. 2010 May;11(5):301-15
pubmed: 20389305
Ann Neurol. 2000 Mar;47(3):369-73
pubmed: 10716258
Front Neuroanat. 2011 Sep 06;5:58
pubmed: 21922001
J Neurosci. 1998 May 1;18(9):3470-9
pubmed: 9547254
Neuropsychopharmacology. 2015 Jun;40(7):1609-18
pubmed: 25578797
Neurology. 2002 Oct 22;59(8):1187-96
pubmed: 12391346
Mol Neurobiol. 1998 Winter;17(1-3):109-35
pubmed: 9887449
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5173-6
pubmed: 10220438
Nature. 1995 Oct 5;377(6548):424-8
pubmed: 7566118
Neuron. 2004 Jun 24;42(6):939-46
pubmed: 15207238
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12218-23
pubmed: 16103364
J Biol Chem. 2014 Nov 28;289(48):33663-75
pubmed: 25336643
J Neurosci. 2007 Feb 21;27(8):2074-80
pubmed: 17314302
Mol Psychiatry. 2020 Sep;25(9):2086-2100
pubmed: 30120413
Neurol Clin. 2015 Feb;33(1):1-17
pubmed: 25432720
Mol Pharmacol. 2009 Jan;75(1):113-23
pubmed: 18809670
Nat Protoc. 2006;1(1):337-45
pubmed: 17406254
Annu Rev Physiol. 2007;69:483-510
pubmed: 17305471
Pharmacol Biochem Behav. 1994 Dec;49(4):985-95
pubmed: 7886117
Proc Natl Acad Sci U S A. 2015 May 12;112(19):E2517-26
pubmed: 25918399
Pharmacol Res. 2016 Sep;111:1-16
pubmed: 27178731
J Clin Psychiatry. 1999 Dec;60(12):819-23
pubmed: 10665627
J Cereb Blood Flow Metab. 2015 Nov;35(11):1812-8
pubmed: 26058690