Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
Expertise Center Movement Disorders Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Mov Disord. 2021 Mar;36(3):729-739. doi: 10.1002/mds.28385. Epub 2020 Nov 16.
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 -I F 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 D2 -I F receptor exhibited aberrant receptor function in mouse midbrain slices.
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.
我们描述了一个具有独特显性遗传临床表型的 4 代荷兰家系，该家系表现为合并进行性舞蹈病和颈肌张力障碍，携带一种新型杂合多巴胺 D2 受体（DRD2）变异。
本研究的目的是确定疾病的遗传原因，并进一步研究遗传变异的功能后果。
在详细的临床和神经检查后，进行了全外显子组测序。因为在我们的家系中，发现 DRD2 基因中的一种新型变异可能是导致疾病的基因缺陷，所以我们在一个由 121 名具有未知遗传原因的亨廷顿样病例组成的队列中对 DRD2 基因进行了测序（德国）。此外，通过细胞模型测定 arrestin 募集、G 蛋白激活和 G 蛋白介导的腺苷酸环化酶抑制，以及在小鼠中脑切片中测量 G 蛋白调节的内向整流钾通道，对 DRD2 变异的功能特征进行了研究。
我们在 DRD2 的外显子 5 中发现了一个新的杂合变异 c.634A > T，p.Ile212Phe，该变异与临床表型共分离。对德国队列的筛查没有发现其他潜在的致病变异。我们证明，D2 -I F 受体在人胚肾 239 细胞中表现出增加的激动剂效力和 G 蛋白的组成性激活，以及显著减少的 arrestin3 募集。我们进一步表明，D2 -I F 受体在小鼠中脑切片中表现出异常的受体功能。
我们的研究结果支持 DRD2 中的新型 p.Ile212Phe 变异与报道的 4 代家系中的多动障碍之间存在关联，该变异改变了 D2 受体的活性。
