Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline

Katia Hardies, Yiying Cai, Claude Jardel, Anna C. Jansen, Mian Cao, Patrick May, Tania Djémié, Caroline Hachon Le Camus, Kathelijn Keymolen, Tine Deconinck, Vikas Bhambhani, Catherine Long, Samin A. Sajan, Katherine L. Helbig, Arvid Suls, Rudi Balling, Ingo Helbig, Peter De Jonghe, Christel Depienne, Pietro De CamilliSarah Weckhuysen, Federico Zara, Pasquale Striano

Research output: Contribution to journalArticlepeer-review


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.Gln647Argfs∗6/p.Ser1122Thrfs∗3) 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.

Original languageEnglish
Pages (from-to)2420-2430
Number of pages11
Issue number9
Publication statusPublished - Sep 1 2016


  • early onset epilepsy
  • neurodegenerative disorder
  • recessive disorder
  • SYNJ1
  • SYNJ1 dual phosphatase activity

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology


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