Reference : Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and ...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Systems Biomedicine
http://hdl.handle.net/10993/28021
Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline
English
Hardies, Katia []
Cai, Yiying []
Jardel, Claude []
Jansen, Anna C. []
Cao, Mian []
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Djémié, Tania []
Hachon Le Camus, Caroline []
Keymolen, Kathelijn []
Deconinck, Tine []
Bhambhani, Vikas []
Long, Catherine []
Sajan, Samin A. []
Helbig, Katherine L. []
Suls, Arvid []
Balling, Rudi mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Helbig, Ingo []
De Jonghe, Peter []
Depienne, Christel []
De Camilli, Pietro []
Weckhuysen, Sarah []
19-Jul-2016
Brain : A Journal of Neurology
Oxford University Press
Yes (verified by ORBilu)
International
0006-8950
1460-2156
Oxford
United Kingdom
[en] Genetics ; Epilepsy ; SYNJ1
[en] 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) ; University of Luxembourg: High Performance Computing - ULHPC
Researchers
http://hdl.handle.net/10993/28021
10.1093/brain/aww180
http://brain.oxfordjournals.org/content/early/2016/07/18/brain.aww180

File(s) associated to this reference

Fulltext file(s):

FileCommentaryVersionSizeAccess
Limited access
brain.aww180.full.pdfPublisher postprint656.07 kBRequest a copy

Bookmark and Share SFX Query

All documents in ORBilu are protected by a user license.