Identification of a novel homozygous mutation Arg459Pro in SYNJ1 gene of an Indian family with autosomal recessive juvenile Parkinsonism
Identification of a novel homozygous mutation Arg459Pro in SYNJ1 gene of an Indian family with autosomal recessive juvenile Parkinsonism
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DOI：
10.1016/j.parkreldis.2016.07.014
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发表时间：
2016-10-01
影响因子：
4.1
通讯作者：
Thelma, B. K.
中科院分区：
文献类型：
--
作者：
Kirola, Laxmi;Behari, Madhuri;Thelma, B. K.
背景资料：最近在两个意大利和一个伊朗常染色体隐性遗传性青少年帕金森综合征（ARJP）家系中发现了Synaptojanin 1（SYNJ 1，21q22.2）基因的一个新的纯合错义突变（c.773G > A，p.Arg258Gln）。在其他人群中帕金森症表型相关的这种突触基因的贡献仍然unidentified.Methods：一个ARJP家族与两个受影响的兄弟姐妹，其特点是频繁震颤与运动迟缓和僵硬招募在这项研究中。两个兄弟姐妹都表现出强烈的运动障碍和肌张力障碍的管理Syndopa。对该家族进行PARKIN、PINK 1和DJ 1的突变和外显子剂量变异分析。结果：在该家系中发现了一个新的SYNJ 1纯合突变（c.1376C > G，p.Arg459Pro）。通过PCR-Sanger-测序筛选的285例额外的帕金森病（PD）样本（32例家族性，81例早发性和172例晚发性）中未观察到这种p.Arg459Pro突变。它也不存在于dbSNP、1000 Genomes、ExAC、NHLBI-ESP数据库和我们实验室中可用的>250个种族匹配的外显子组中。精氨酸残基在物种间高度保守，并被几种二氧化硅工具预测为破坏性的。与以前的突变p.Arg258Gln，p.Arg459Pro也存在于囊1结构域的SYNJ 1，其中p.Arg258Gln突变已经被描述为损害磷酸酶activity.Conclusions：我们报告另一个新的突变在SYNJ 1的印度血缘ARJP家庭。在该基因中发现额外的突变进一步支持SYNJ 1参与不同种族的PD发病机制。(C)2016爱思唯尔有限公司版权所有
Background: A novel homozygous missense mutation (c.773G > A, p.Arg258Gln) in Synaptojanin 1 (SYNJ1, 21q22.2) has recently been reported in two Italian and one Iranian consanguineous families with autosomal recessive juvenile Parkinsonism (ARJP). Contribution of this synaptic gene related to Parkinsonism phenotypes in other populations still remains unidentified.Methods: An ARJP family with two affected siblings characterized by frequent tremor with bradykinesia and rigidity was recruited in this study. Both siblings showed intense dyskinesia and dystonia on administration of Syndopa. The family was analyzed for both mutations and exon dosage variations in PARKIN, PINK1 and DJ1. Further, whole exome sequencing was performed in two affected and one unaffected sibling in the family.Results: We identified a novel homozygous mutation (c.1376C > G, p.Arg459Pro) in SYNJ1 segregating in this family. This p.Arg459Pro mutation was not observed in 285 additional Parkinson disease (PD) samples (32 familial, 81 early onset and 172 late onset) screened by PCR-Sanger-sequencing. It was also absent in dbSNP, 1000 Genomes, ExAC, NHLBI-ESP database and in >250 ethnically matched exomes available in our laboratory. The arginine residue is highly conserved across species and predicted to be damaging by several in silica tools. As with the previous mutation p.Arg258Gln, p.Arg459Pro is also present in Sac 1 domain of SYNJ1 wherein p.Arg258Gln mutation has already been described to impair the phosphatase activity.Conclusions: We report another novel mutation in SYNJ1 of an Indian consanguineous ARJP family. Finding an additional mutation in this gene further supports the involvement of SYNJ1 in PD pathogenesis across different ethnicities. (C) 2016 Elsevier Ltd. All rights reserved.