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 - 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
SN - 0885-3185
VL - 36
SP - 729
EP - 739
JO - Movement Disorders
JF - Movement Disorders
IS - 3
ER -