A novel PRRT2 pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures.
A novel PRRT2 pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures.
复制标题
DOI：
10.1101/mcs.a002287
复制
发表时间：
2018-03
影响因子：
1.8
通讯作者：
Brenner SE
中科院分区：
文献类型：
--
作者：
Lu JG;Bishop J;Cheyette S;Zhulin IB;Guo S;Sobreira N;Brenner SE
阵发性动态性运动障碍（PKD）是一种罕见的神经系统疾病，其特征是运动障碍的反复发作而不改变意识，通常由自主运动的开始引发。全外显子组测序揭示了PRRT2（富含脯氨酸的跨膜蛋白）的一组致病变异，该基因在突触调节中具有功能，但人们对其知之甚少。在这里，我们报告了在PKD和良性家族性婴儿癫痫（BFIS）家族中以常染色体显性模式遗传的一种新的PRRT2致病变异的发现。在靶向Sanger测序未发现先前描述的PRRT2致病变异的存在后，我们对先证者及其受影响的祖父进行了全外显子组测序。这导致了一种新的PRRT2变体的发现，NM_001256442:exon3: c.c c959t /NP_660282.2:p。A320V，改变了位于M2跨膜区氨基酸位置320的一个进化上保守的丙氨酸。Sanger测序进一步证实了该变异在4个受影响的家庭成员（祖父、父亲、兄弟和先证者）中存在，而在2个未受影响的家庭成员（祖父和母亲）中不存在。这一新发现的变异进一步强化了PRRT2在PKD、BFIS和其他可能的运动障碍中的重要性。未来使用动物模型和人类多能干细胞模型的功能研究将为PRRT2的作用以及该变体在调节神经发育和/或功能中的意义提供新的见解。
Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent attacks of dyskinetic movements without alteration of consciousness that are often triggered by the initiation of voluntary movements. Whole-exome sequencing has revealed a cluster of pathogenic variants in PRRT2 (proline-rich transmembrane protein), a gene with a function in synaptic regulation that remains poorly understood. Here, we report the discovery of a novel PRRT2 pathogenic variant inherited in an autosomal dominant pattern in a family with PKD and benign familial infantile seizures (BFIS). After targeted Sanger sequencing did not identify the presence of previously described PRRT2 pathogenic variants, we carried out whole-exome sequencing in the proband and her affected paternal grandfather. This led to the discovery of a novel PRRT2 variant, NM_001256442:exon3:c.C959T/NP_660282.2:p.A320V, altering an evolutionarily conserved alanine at the amino acid position 320 located in the M2 transmembrane region. Sanger sequencing further confirmed the presence of this variant in four affected family members (paternal grandfather, father, brother, and proband) and its absence in two unaffected ones (paternal grandmother and mother). This newly found variant further reinforces the importance of PRRT2 in PKD, BFIS, and possibly other movement disorders. Future functional studies using animal models and human pluripotent stem cell models will provide new insights into the role of PRRT2 and the significance of this variant in regulating neural development and/or function.