Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.
Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.
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PRRT2 鉴定为阵发性运动诱发性运动障碍的致病基因
DOI：
10.1093/brain/awr289
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Tang BS
中科院分区：
文献类型：
--
作者：
Wang JL;Cao L;Li XH;Hu ZM;Li JD;Zhang JG;Liang Y;San-A;Li N;Chen SQ;Guo JF;Jiang H;Shen L;Zheng L;Mao X;Yan WQ;Zhou Y;Shi YT;Ai SX;Dai MZ;Zhang P;Xia K;Chen SD;Tang BS
阵发性运动诱发性运动障碍是一种阵发性运动障碍，其特征是突然自主运动引起的异常不自主运动的反复、短暂发作。尽管包括 16 号染色体的着丝粒周围区域在内的多个位点已与阵发性运动诱发性运动障碍相关，但致病基因尚未确定。在这里，我们通过外显子组测序和连锁分析相结合，将富含脯氨酸的跨膜蛋白 2 (PRRT2) 鉴定为阵发性运动诱发性运动障碍的致病基因。在患有常染色体显性遗传性阵发性运动障碍的两个家族的 27 名成员中，对包含 16 号染色体着丝粒周围的 11 个标记进行了遗传连锁图谱分析。然后，对这两个家庭的三名患者进行了全外显子组测序。通过结合定义的连锁区域 (16p12.1–q12.1) 和外显子组测序结果，我们在一个家族中鉴定出插入突变 c.649_650InsC (p.P217fsX7)，在另一个家族中鉴定出无义突变 c.487C>T (p.Q163X)。为了证实我们的发现，我们对另外三个患有阵发性运动诱发性运动障碍的家族的 PRRT2 外显子和侧翼内含子进行了测序。在其中两个家族中发现了 c.649_650InsC (p.P217fsX7) 突变，而在另一个患有阵发性运动诱发性运动障碍的家族中发现了错义突变 c.796C>T (R266W)。所有这些突变都与每个家族的表型完全共分离。在 500 名地理血统相匹配的正常未受影响个体中，没有发现任何这些突变。因此，我们已经确定 PRRT2 是阵发性运动源性运动障碍的第一个致病基因，需要进一步研究以了解这种疾病的发病机制。
Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1–q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder.
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影响因子：
6.4
作者：
Banaschewski, Tobias;Becker, Katja;Scherag, Susann;Franke, Barbara;Coghill, David
通讯作者：
Coghill, David
影响因子：
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作者：
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作者：
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Wang, Jun
影响因子：
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作者：
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通讯作者：
CHUN, RWM
影响因子：
8.6
作者：
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通讯作者：
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