Dyment David A, Smith Amanda C, Humphreys Peter, Schwartzentruber Jeremy, Beaulieu Chandree L, Bulman Dennis E, Majewski Jacek, Woulfe John, Michaud Jean, Boycott Kym M
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Neurobiol Aging. 2015 Feb;36(2):1222.e1-5. doi: 10.1016/j.neurobiolaging.2014.09.005. Epub 2014 Sep 6.
The tauopathies are a heterogeneous group of neurodegenerative disorders characterized by the shared presence of tau aggregates and neurofibrillary tangles within the central nervous system. Here, we present a child with a severe neurodegenerative disorder characterized by intractable seizures and significant tau-immunoreactive neurofibrillary degeneration localized predominantly to the substantia nigra on neuropathology with absence of beta-amyloid plaques and Lewy or Pick bodies. Whole-exome sequencing identified a homozygous truncating mutation in Synaptojanin 1 (SYNJ1). Quantitative polymerase chain reaction and Western blot experiments demonstrated diminished SYNJ1 messenger RNA and protein. Knockout Synj1(-/-) mice have convulsions and die early in life. More recently, homozygous missense mutations have been reported in 2 families with early-onset parkinsonism and seizures. Our findings broaden the spectrum of disease associated with alteration of SYNJ1 and further implicate defects in synaptic vesicle recycling in the tauopathies.
tau蛋白病是一组异质性神经退行性疾病，其特征是中枢神经系统内共同存在tau蛋白聚集体和神经原纤维缠结。在此，我们报告一名患有严重神经退行性疾病的儿童，其特征为顽固性癫痫发作，且神经病理学检查显示主要定位于黑质的显著tau免疫反应性神经原纤维变性，不存在β淀粉样斑块以及路易小体或Pick小体。全外显子测序在突触素1（SYNJ1）中鉴定出一个纯合截短突变。定量聚合酶链反应和蛋白质印迹实验表明SYNJ1信使核糖核酸和蛋白质减少。敲除Synj1(-/-)小鼠会出现惊厥并在生命早期死亡。最近，在2个早发性帕金森病和癫痫家系中报告了纯合错义突变。我们的研究结果拓宽了与SYNJ1改变相关的疾病谱，并进一步表明tau蛋白病中存在突触小泡循环缺陷。
