Reply to: "Childhood Onset Chorea Caused by a Recurrent De Novo DRD2 Variant".
Reply to: "Childhood Onset Chorea Caused by a Recurrent De Novo DRD2 Variant".
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回复：“由复发性新发 DRD2 变异引起的儿童期舞蹈病”。
DOI：
10.1002/mds.28635
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Tijssen,MarinaAJ
中科院分区：
文献类型：
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作者：
vanderWeijden,MarlousCM;Rodriguez-Contreras,Dayana;Neve,KimA;Verbeek,DinekeS;Tijssen,MarinaAJ
下载日期：01-02-2025 影响从物种到无脊椎动物都完全保守的氨基酸残基（图 1），并被所有计算机预测工具预测为致病性。根据美国医学遗传学和基因组学指南，它被解释为可能致病。 3 对两个家族三人组的数据分析没有发现任何其他潜在的候选变异，包括其他从头或双等位基因可能致病的变异或与单基因运动障碍相关的其他基因的变异。支持其致病作用，p。 Met374Arg 位于蛋白质第六跨膜结构域中，该结构域形成 D2R 激动剂结合口袋核心的一部分。该残基 (p. Met374Leu) 的突变被证明决定了无配体 D2R 向活性状态的转变，4 表明类似的机制可能适用于 p. Met374Leu。 Met374Arg。 p。 Ile212Phe 变体还被证明会导致激动剂效力和组成型激活增加，1 表明致病性 DRD2 变体具有功能获得性。总之，这些病例强调 DRD2 变异应纳入基因原因不明的早发性多动性运动障碍的诊断检查中。与之前报道的病例相比，我们的系列将发病年龄扩大到早至4个月，并表明发育迟缓、肌阵挛、认知和神经精神功能障碍可能是表型的一部分。
Download date: 01-02-2025 affects an amino acid residue completely conserved across species down to invertebrates (Fig. 1), and is predicted pathogenic by all in silico prediction tools. It was interpreted as likely pathogenic according to American College of Medical Genetics and Genomics guidelines. 3 Analysis of data from both family trios did not identify any other potential candidate variants, including other de novo or biallelic likely pathogenic variants or variants in other genes linked to monogenic movement disorders. Supporting its pathogenic role, p. Met374Arg is located in the protein sixth transmembrane domain, which forms part of the binding pocket core for D2R agonists. A mutation at this residue (p. Met374Leu) was shown to determine a shift of the ligand-free D2R toward the active state, 4 suggesting a similar mechanism may apply to p. Met374Arg. The p. Ile212Phe variant was also shown to cause increased agonist potency and constitutive activation, 1 suggesting that pathogenic DRD2 variants are gain-of-function. In conclusion, these cases highlight that variants in DRD2 should be included in the diagnostic workup of genetically unexplained early-onset hyperkinetic movement disorders. Compared with the previously reported cases, our series expands the age of onset to as early as 4 months and shows that developmental delay, myoclonus, and cognitive and neuropsychiatric dysfunction can be part of the phenotype.