Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression
Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression
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PRRT2 突变导致阵发性运动障碍，临床表达存在显着差异
DOI：
10.1136/jmedgenet-2011-100653
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发表时间：
2012-02-01
影响因子：
4
通讯作者：
Zhang, Xue
中科院分区：
文献类型：
--
作者：
Liu, Qing;Qi, Zhan;Zhang, Xue
背景阵发性运动障碍（Paroxysmal dyskinesias，PD）是一组临床和遗传异质性的发作性运动障碍，包括运动诱发性PD（kinesigenic PD，PKD）、运动诱发性PD（exercise induced PD，PED）和非运动诱发性PD（non-kinesigenic PD，PNKD）。这些疾病都是以常染色体显性遗传，遗传不完全。几种PD相关的遗传性疾病，包括PKD和家族性婴儿惊厥伴阵发性舞蹈手足徐动症（ICCA），定位于16号染色体上的同一区域。独立的遗传学研究最近发现，PKD可能是由富含脯氨酸的跨膜蛋白2基因（PRRT 2）的功能缺失突变引起的。我们测试了其他形式的PD也是由于PRRT 2突变的假设。方法/结果对6个汉族家系和15例散发性PD相关表型病例的PRRT 2基因全基因组进行测序。先前报道的突变，c.649dupC（p.R217Pfs*7），被发现在两个家庭与PKD，一个家庭与ICCA，一个家庭与PNKD样表型，和两个散发病例与PED。在另一个ICCA家族中，发现了一个新的移码突变c.904dupG（p.D302Gfs*38）。在两例散发性PKD病例中还检测到错义突变c.913G→A（p.G305R）和同义替换c.1011C→T（p.G337G）。结论PKD、ICCA和其他PD相关表型属于同一表型谱，均由PRRT 2基因突变引起。这强调了PRRT 2突变的表型后果的复杂性。
Background Paroxysmal dyskinesias (PDs), a clinically and genetically heterogeneous group of episodic movement disorders, include kinesigenic PD (PKD), exercise-induced PD (PED) and non-kinesigenic PD (PNKD). These disorders are all transmitted as autosomal dominant traits with incomplete penetrance. Several PD-related genetic disorders, including PKD and familial infantile convulsions with paroxysmal choreoathetosis (ICCA), mapped to the same region on chromosome 16. Independent genetic studies have recently revealed that PKD can be caused by loss-of-function mutations in the proline-rich transmembrane protein 2 gene (PRRT2). We tested the hypothesis that other forms of PDs are also due to PRRT2 mutations. Methods/results The whole genomic region of PRRT2 was sequenced in six Han Chinese families and 15 sporadic cases of PD-related phenotypes. The previously reported mutation, c.649dupC (p.R217Pfs*7), was found in two families with PKD, one family with ICCA, one family with PNKD-like phenotype, and two sporadic cases with PED. In an additional ICCA family, a novel frameshift mutation, c.904dupG (p.D302Gfs*38), was identified. A missense mutation, c.913G→A (p.G305R), and a synonymous substitution, c.1011C→T (p.G337G), were also detected in two sporadic PKD cases. Conclusion This study shows that PKD, ICCA and some other PD-related phenotypes are part of the same phenotypic spectrum, caused by mutations in PRRT2. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.