TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study
TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study
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TMEM151A 变异体导致阵发性运动源性运动障碍：一项大样本研究
DOI：
10.1002/mds.28865
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发表时间：
2021-11-24
影响因子：
8.6
通讯作者：
Cao, Li
中科院分区：
文献类型：
--
作者：
Tian, Wo-Tu;Zhan, Fei-Xia;Cao, Li
背景发作性运动性运动障碍(PKD)是最常见的发作性运动障碍类型。只有三分之一的PKD患者被归因于富含脯氨酸的跨膜蛋白2(PRRT2)突变。目的探讨PKD的潜在致病基因。方法对196例PRRT2阴性的PKD先证者进行全外显子测序。应用病例对照分析方法中的基因排序、鉴定和预测工具对候选基因进行筛选。随后对另外325例PRRT2阴性的PKD先证者进行了Sanger测序。结果与对照组相比，PKD患者的跨膜蛋白151(TMEM151A)变异主要呈聚集性分布。在521例先证者中，25例检出24个杂合子突变，占4.80%，其中18个为错义突变，6个为无义突变。在29例TMEM151A型患者中，男女之比为2.63：1，平均发病年龄为12.93±3.15岁。与PRRT2突变携带者相比，TMEM151A相关PKD在散发性纯表型PKD患者中更为常见。TMEM151a阳性组和PRRT2阳性组在发作类型和治疗结果方面无显著差异。结论通过对大规模WES资料的病例对照分析，我们巩固了引起PKD的TMEM151A突变，拓宽了PKD的基因分型范围。与TMEM151A型相关的PKD在散发性病例中更为常见，并倾向于表现为纯表型且发病较晚。需要进行广泛的功能研究，以加强我们对TMEM151A相关PKD发病机制的理解。(C)2021年国际帕金森病和运动障碍协会
Background Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. Objective We aimed to explore the potential causative gene for PKD. Methods A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. Results Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 +/- 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. Conclusions We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. (c) 2021 International Parkinson and Movement Disorder Society