A Gain-of-Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype.
A Gain-of-Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype.
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多巴胺D2受体功能获得变异与进行性舞蹈症和肌张力障碍表型
DOI：
10.1002/mds.28385
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Verbeek DS
中科院分区：
文献类型：
--
作者：
van der Weijden MCM;Rodriguez-Contreras D;Delnooz CCS;Robinson BG;Condon AF;Kielhold ML;Stormezand GN;Ma KY;Dufke C;Williams JT;Neve KA;Tijssen MAJ;Verbeek DS
我们描述了一个四代荷兰家系，该家系具有独特的显性遗传临床表型，即进行性舞蹈病和颈部肌张力障碍的组合，携带一种新型杂合多巴胺D2受体（DRD 2）变体。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学检查后，进行了全外显子组测序。由于在我们的家系中发现了DRD 2基因中的一种新变体作为可能的致病基因缺陷，我们对121例遗传原因未知的亨廷顿样病例（德国）的DRD 2基因进行了测序。此外，DRD 2变体的功能表征包括在细胞模型中测定的抑制蛋白募集、G蛋白活化和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定的G蛋白调节的内向整流钾通道。我们在DRD 2基因第5外显子发现了一个新的杂合变异体c.634A > T，p.Ile212Phe，与临床表型共分离。德国队列的筛查未发现其他推定的致病变异。我们证明，D2 S/L-I212 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arrestin 3募集。我们进一步表明，D2 S-I212 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DRD 2中的新型p.Ile212Phe变体，其修饰的D2受体活性和4代家系中报告的多动性运动障碍之间的关联。版权所有2020作者。运动障碍由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版。
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 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. 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.
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DOI：
10.1073/pnas.0502698102
发表时间：
2005-08-23
影响因子：
11.1
作者：
Charvin, D;Vanhoutte, P;Caboche, J
通讯作者：
Caboche, J
DOI：
10.1073/pnas.1502740112
发表时间：
2015-05-12
影响因子：
11.1
作者：
Urs, Nikhil M.;Bido, Simone;Caron, Marc G.
通讯作者：
Caron, Marc G.
影响因子：
2.9
作者：
Del'guidice T;Lemasson M;Beaulieu JM
通讯作者：
Beaulieu JM
DOI：
10.1212/cpj.0000000000000113
发表时间：
2015-04-01
期刊：
Neurology. Clinical practice
影响因子：
--
作者：
Cummins, Gemma;Zandi, Michael;Barker, Roger A
通讯作者：
Barker, Roger A
影响因子：
5.3
作者：
Pallanti, S;Quercioli, L;Pazzagli, A
通讯作者：
Pazzagli, A