TY - JOUR
T1 - A Gain-of-Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype
AU - van der Weijden, Marlous C.M.
AU - Rodriguez-Contreras, Dayana
AU - Delnooz, Cathérine C.S.
AU - Robinson, Brooks G.
AU - Condon, Alec F.
AU - Kielhold, Michelle L.
AU - Stormezand, Gilles N.
AU - Ma, Kai Yu
AU - Dufke, Claudia
AU - Williams, John T.
AU - Neve, Kim A.
AU - Tijssen, Marina A.J.
AU - Verbeek, Dineke S.
N1 - Funding Information:
MD‐PhD scholarship from the University Medical Center Groningen (M.V.W.); Rosalind Franklin Fellowship from the University of Groningen (D.S.V.); K99DA044287 (B.G.R.) and F31DA047007 (A.F.C.) training awards from the U.S. Public Health Service; and grants from the Netherlands Organization for Health Research and Development ZonMW Topsubsidie (91218013) (M.A.J.), the European Fund for Regional Development from the European Union (01492947) and the province of Friesland (M.A.J.), the Dystonia Medical Research Foundation (M.A.J.), the Stichting Wetenschapsfonds Dystonie Vereniging (M.A.J.), the Fonds Psychische Gezondheid (M.A.J.), the Phelps Stichting (M.A.J.), an unrestricted grant from Actelion (M.A.J.); and a Merit Review Award BX003279 from the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development (K.A.N.).
Publisher Copyright:
© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PY - 2021/3
Y1 - 2021/3
N2 - 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 D2S/L-I212F receptor exhibited increased agonist potency and constitutive activation of G proteins in human embryonic kidney 239 cells as well as significantly reduced arrestin3 recruitment. We further showed that the D2S-I212F receptor exhibited aberrant receptor function in mouse midbrain slices. 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.
AB - 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 D2S/L-I212F receptor exhibited increased agonist potency and constitutive activation of G proteins in human embryonic kidney 239 cells as well as significantly reduced arrestin3 recruitment. We further showed that the D2S-I212F receptor exhibited aberrant receptor function in mouse midbrain slices. 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.
KW - chorea
KW - dopamine D2 receptor
KW - dystonia
KW - hyperkinetic movement disorder
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U2 - 10.1002/mds.28385
DO - 10.1002/mds.28385
M3 - Article
C2 - 33200438
AN - SCOPUS:85096699851
VL - 36
SP - 729
EP - 739
JO - Movement Disorders
JF - Movement Disorders
SN - 0885-3185
IS - 3
ER -