title: Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline.
abstract: 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.
authors.forename: Katia
authors.initials: K
authors.lastname: Hardies
authors.forename: Yiying
authors.initials: Y
authors.lastname: Cai
authors.forename: Claude
authors.initials: C
authors.lastname: Jardel
authors.forename: Anna C
authors.initials: AC
authors.lastname: Jansen
authors.forename: Mian
authors.initials: M
authors.lastname: Cao
authors.forename: Patrick
authors.initials: P
authors.lastname: May
authors.forename: Tania
authors.initials: T
authors.lastname: Djémié
authors.forename: Caroline
authors.initials: C
authors.lastname: Hachon Le Camus
authors.forename: Kathelijn
authors.initials: K
authors.lastname: Keymolen
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhambhani
authors.forename: Catherine
authors.initials: C
authors.lastname: Long
authors.forename: Samin A
authors.initials: SA
authors.lastname: Sajan
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Helbig
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003241:Consanguinity; D000069279:Drug Resistant Epilepsy / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D009419:Nerve Tissue Proteins; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C089504:polyphosphoinositide phosphatase; C097702:synaptojanin
keywords: SYNJ1; SYNJ1 dual phosphatase activity; early onset epilepsy; neurodegenerative disorder; recessive disorder