Hardies Katia, Cai Yiying, Jardel Claude, Jansen Anna C, Cao Mian, May Patrick, Djémié Tania, Hachon Le Camus Caroline, Keymolen Kathelijn, Deconinck Tine, Bhambhani Vikas, Long Catherine, Sajan Samin A, Helbig Katherine L, Suls Arvid, Balling Rudi, Helbig Ingo, De Jonghe Peter, Depienne Christel, De Camilli Pietro, Weckhuysen Sarah
Brain. 2016 Sep;139(Pt 9):2420-30. doi: 10.1093/brain/aww180. Epub 2016 Jul 19.
SYNJ1 encodes a polyphosphoinositide phosphatase, synaptojanin 1, which contains two consecutive phosphatase domains and plays a prominent role in synaptic vesicle dynamics. Autosomal recessive inherited variants in SYNJ1 have previously been associated with two different neurological diseases: a recurrent homozygous missense variant (p.Arg258Gln) that abolishes Sac1 phosphatase activity was identified in three independent families with early onset parkinsonism, whereas a homozygous nonsense variant (p.Arg136*) causing a severe decrease of mRNA transcript was found in a single patient with intractable epilepsy and tau pathology. We performed whole exome or genome sequencing in three independent sib pairs with early onset refractory seizures and progressive neurological decline, and identified novel segregating recessive SYNJ1 defects. A homozygous missense variant resulting in an amino acid substitution (p.Tyr888Cys) was found to impair, but not abolish, the dual phosphatase activity of SYNJ1, whereas three premature stop variants (homozygote p.Trp843* and compound heterozygote p.Gln647Argfs6/p.Ser1122Thrfs3) almost completely abolished mRNA transcript production. A genetic follow-up screening in a large cohort of 543 patients with a wide phenotypical range of epilepsies and intellectual disability revealed no additional pathogenic variants, showing that SYNJ1 deficiency is rare and probably linked to a specific phenotype. While variants leading to early onset parkinsonism selectively abolish Sac1 function, our results provide evidence that a critical reduction of the dual phosphatase activity of SYNJ1 underlies a severe disorder with neonatal refractory epilepsy and a neurodegenerative disease course. These findings further expand the clinical spectrum of synaptic dysregulation in patients with severe epilepsy, and emphasize the importance of this biological pathway in seizure pathophysiology.
SYNJ1编码一种多磷酸肌醇磷酸酶——突触素1,它含有两个连续的磷酸酶结构域,在突触小泡动力学中起重要作用。此前,SYNJ1中的常染色体隐性遗传变异与两种不同的神经疾病相关:在三个早发性帕金森病的独立家系中,发现了一种反复出现的纯合错义变异(p.Arg258Gln),该变异消除了Sac1磷酸酶活性;而在一名患有顽固性癫痫和tau病理的患者中,发现了一种导致mRNA转录物严重减少的纯合无义变异(p.Arg136*)。我们对三对患有早发性难治性癫痫和进行性神经功能衰退的独立同胞进行了全外显子组或基因组测序,确定了新的分离隐性SYNJ1缺陷。发现一种导致氨基酸替代的纯合错义变异(p.Tyr888Cys)会损害但不会消除SYNJ1的双磷酸酶活性,而三种过早终止变异(纯合子p.Trp843和复合杂合子p.Gln647Argfs6/p.Ser1122Thrfs*3)几乎完全消除了mRNA转录物的产生。在一大组543名具有广泛癫痫和智力残疾表型范围的患者中进行的基因随访筛查未发现其他致病变异,表明SYNJ1缺乏症很罕见,可能与特定表型有关。虽然导致早发性帕金森病的变异选择性地消除了Sac1功能,但我们的结果提供了证据,表明SYNJ1双磷酸酶活性的严重降低是导致新生儿难治性癫痫和神经退行性疾病病程的严重疾病的基础。这些发现进一步扩大了严重癫痫患者突触失调的临床谱,并强调了这一生物学途径在癫痫病理生理学中的重要性。