A Novel SYNJ1 Mutation in a Tunisian Family with Juvenile Parkinson's Disease Associated with Epilepsy
A Novel SYNJ1 Mutation in a Tunisian Family with Juvenile Parkinson's Disease Associated with Epilepsy
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DOI：
10.1007/s12031-018-1167-2
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发表时间：
2018-10-01
影响因子：
3.1
通讯作者：
Mhiri, Chokri
中科院分区：
文献类型：
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作者：
Ben Romdhan, Sawssan;Sakka, Salma;Mhiri, Chokri
SYNJ 1基因突变在少数非典型帕金森病家系中有报道。该基因编码Synaptojanin 1，一种在突触囊泡的磷酸化和再循环中起主要作用的酶。在这项研究中，我们报告了两个兄弟姐妹，从一个血缘突尼斯家庭，提出少年PD。两兄弟分别在16岁和21岁时出现轻度帕金森症。1例患者自7岁起出现全身强直阵挛性癫痫发作。在这两种情况下，没有睡眠或自主神经功能障碍和精神障碍的证据，但他们发展了中度认知障碍。对小剂量左旋多巴治疗反应良好，无运动障碍和运动波动。我们设计了一个基于NGS的22个目前最流行的帕金森病相关基因的筛选。遗传学研究发现SYNJ 1基因中存在一种新的复合杂合突变（p.Leu1406Phefs*42和p.Lys1321Glu）。p.Lys1321Glu突变位于富含脯氨酸的结构域，导致蛋白质的3D结构发生显著变化（RMS=12.58埃）。p.Leu1406Phefs*42突变破坏了AP 2结合位点，随后使神经元中的突触和囊泡内吞再循环失效。这是第一个报告的突变在C-末端结构域的Synaptojanin 1蛋白导致轻度青少年PD与全身性癫痫发作，认知功能障碍，以及良好的反应，左旋多巴治疗。
Mutations in SYNJ1 gene have been described in few families with juvenile atypical Parkinson disease (PD). This gene encodes for Synaptojanin 1, an enzyme playing a major role in the phosphorylation and the recycling of synaptic vesicles. In this study, we report two siblings, from a consanguineous Tunisian family, presenting juvenile PD. Both siblings developed mild Parkinsonism at 16 and 21years old respectively. One patient had generalized tonic-clonic seizures since the age of 7years. There was no evidence of sleep or autonomic dysfunctions and psychiatric disorders in both cases, but they developed a moderate cognitive impairment. They kept a good respond to low doses of levodopa treatment with no dyskinesia or motor fluctuations. We designed an NGS-based screening of 22 currently most prevalent parkinsonism-associated genes. Genetic study revealed a novel compound heterozygous mutation (p.Leu1406Phefs*42 and p.Lys1321Glu) in SYNJ1 gene. The p.Lys1321Glu mutation is located in the proline-rich domain and leads to a significant change in the 3D structure of the protein (RMS=12.58 angstrom). The p.Leu1406Phefs*42 mutation disrupt the AP2 binding sites and subsequently disable synaptic and vesicle endocytic recycling in neurons. This is the first report of mutation in the C-terminal domain of Synaptojanin 1 protein causing mild juvenile PD with generalized seizures, cognitive impairment, and good respond to levodopa treatment.