The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures.
The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures.
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DOI：
10.1002/humu.22372
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发表时间：
2013-09
期刊：
影响因子：
3.9
通讯作者：
Paisan-Ruiz, Coro
中科院分区：
文献类型：
--
作者：
Krebs, Catharine E.;Karkheiran, Siamak;Powell, James C.;Cao, Mian;Makarov, Vladimir;Darvish, Hossein;Di Paolo, Gilbert;Walker, Ruth H.;Shahidi, Gholam Ali;Buxbaum, Joseph D.;De Camilli, Pietro;Yue, Zhenyu;Paisan-Ruiz, Coro
本研究旨在阐明伊朗近亲家庭中早发性帕金森病（EOP）的遗传原因。为了实现这一目标，进行了纯合性作图和全外显子组测序。结果，位于多磷酸肌醇磷酸酶 synaptojanin 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) 被鉴定为疾病隔离突变，该突变与突触内吞运输的调节有关。这种突变在体外损害了 SYNJ1 对其 Sac1 结构域底物的磷酸酶活性。我们得出的结论是，此处确定的 SYNJ1 突变是造成我们患者中出现的 EOP 表型的原因，可能是由于其磷酸酶活性缺陷以及随之而来的突触功能受损。我们的发现不仅为帕金森病相关突触功能障碍机制的研究开辟了新途径，而且表明磷酸肌醇代谢可以作为帕金森病的新治疗靶点。
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 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.
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DOI：
10.1083/jcb.150.3.589
发表时间：
2000-08-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harris TW;Hartwieg E;Horvitz HR;Jorgensen EM
通讯作者：
Jorgensen EM
影响因子：
4
作者：
Casey, Jillian P.;Nobbs, Michael;Ennis, Sean
通讯作者：
Ennis, Sean
影响因子：
15.9
作者：
Hughes, Claire R.;Guasti, Leonardo;Metherell, Louise A.
通讯作者：
Metherell, Louise A.
影响因子：
25
作者：
Berman, Diego E.;Dall'Armi, Claudia;Di Paolo, Gilbert
通讯作者：
Di Paolo, Gilbert
影响因子：
4.8
作者：
Jha, A;Agostinelli, NR;Traub, LM
通讯作者：
Traub, LM