Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Hum Mutat. 2013 Sep;34(9):1200-7. doi: 10.1002/humu.22372. Epub 2013 Jul 19.
This study aimed to elucidate the genetic causes underlying early-onset Parkinsonism (EOP) in a consanguineous Iranian family. To attain this, homozygosity mapping and whole-exome sequencing were performed. As a result, a homozygous mutation (c.773G>A; p.Arg258Gln) lying within the NH2 -terminal Sac1-like inositol phosphatase domain of polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1), which has been implicated in the regulation of endocytic traffic at synapses, was identified as the disease-segregating mutation. This mutation impaired the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro. We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. Our finding not only opens new avenues of investigation in the synaptic dysfunction mechanisms associated with Parkinsonism, but also suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.
本研究旨在阐明一个伊朗近亲家族中早发性帕金森病（EOP）的遗传原因。为此，进行了纯合子作图和全外显子组测序。结果，发现了一个位于多磷酸肌醇磷酸酶突触结合蛋白 1（SYNJ1）的 NH2-末端 Sac1 样肌醇磷酸酶结构域内的纯合突变（c.773G>A;p.Arg258Gln），该突变与突触处的内吞运输调节有关，被鉴定为疾病分离突变。该突变损害了 SYNJ1 对其 Sac1 结构域底物的体外磷酸酶活性。我们得出结论，这里鉴定的 SYNJ1 突变可能是由于其磷酸酶活性的缺陷和随后的突触功能障碍导致我们的患者出现 EOP 表型。我们的发现不仅为与帕金森病相关的突触功能障碍机制的研究开辟了新途径，而且还表明磷酸肌醇代谢是帕金森病的一个新的治疗靶点。
