ArticleBrain : a journal of neurology2016
Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline.
Article in Brain : a journal of neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 1 of them a synthesis that pooled it.
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Who cites it
55 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.
- Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review.International journal of molecular sciences · 2021Pooled it
- Dystrophic changes of nigrostriatal axons harboring aProceedings of the National Academy of Sciences of the United States of America · 2026Article
- The power of five - inositol polyphosphate 5-phosphatase gene mutations at the intersection of development and disease.FEBS letters · 2026Review
- Behavioral screening defines the molecular Parkinsonism-related subgroups in Drosophila.Nature communications · 2026Article
- Roles in physiology and disease of the inositol phosphatase synaptojanin 1.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026Review
- Subcellular Cartography of the Phosphoinositide Multiverse.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026Review
- A phosphoinositide switch from PI(4,5)PScience advances · 2025Article
- Synaptojanin-1 supports VPS35-dependent trafficking of dopamine D2 autoreceptors at presynaptic terminals.Research square · 2025Article
- Discovery and Characterization of a Selective Inhibitor of Synaptojanin1 5‑Phosphatase Activity.ACS pharmacology & translational science · 2025Article
- Genetic Sketch of Parkinson's Disease in India.Annals of Indian Academy of Neurology · 2025Article
- Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders.Journal of inherited metabolic disease · 2025Review
- Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Identification of SYNJ1 in a Complex Case of Juvenile Parkinsonism Using a Multiomics Approach.International journal of molecular sciences · 2024Article
- Diverse Functions of Parkin in Midbrain Dopaminergic Neurons.Movement disorders : official journal of the Movement Disorder Society · 2024Review
- Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Case report: Novel variants cause developmental and epileptic encephalopathy in three unrelated families from Mali.Frontiers in genetics · 2024Article
- Emerging perspectives on precision therapy for Parkinson's disease: multidimensional evidence leading to a new breakthrough in personalized medicine.Frontiers in aging neuroscience · 2024Review
- Review
- Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons.bioRxiv : the preprint server for biology · 2023Article
- Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission.Journal of neurochemistry · 2023Article
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22 authors at 10 institutions in 5 countries.
Funding
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.
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