SYNJ1 – Young‐Onset Parkinson Disease

Synaptojanin 1 (SYNJ1) encodes a dual‐function phosphoinositide phosphatase critical for synaptic vesicle endocytosis. Biallelic loss‐of‐function variants in SYNJ1 have been repeatedly observed in patients with autosomal recessive young‐onset Parkinson disease (YOPD), defining a distinct phenotype now catalogued as MONDO:0017279. The clinical presentation includes early‐onset parkinsonism often accompanied by dystonia and variable seizures.

Genetic evidence for a strong gene–disease relationship derives from three independent consanguineous families harboring the same homozygous variant c.773G>A (p.Arg258Gln). This variant segregates with disease in an Iranian kindred (two affected siblings) (PMID:23804563), an Italian family (PMID:23804577), and a Sicilian pedigree with two affected sibs (PMID:24816432), totaling six affected individuals with confirmed segregation under an autosomal recessive model.

Additional support comes from a cohort of 90 YOPD patients in India, where rare SNV/InDels in SYNJ1 were detected among monogenic cases (PMID:35810474). A large case–control burden analysis of 8 165 PD cases versus 70 363 controls identified an excess of rare nonsynonymous variants in the Sac1 domain of SYNJ1 in early‐onset patients (SKAT-O Pfdr=0.040) (PMID:38853950).

Functional assays in multiple model systems have elucidated the mechanism of pathogenicity. Haploinsufficiency of SYNJ1 in mice leads to age‐dependent motor deficits, α-synuclein accumulation, impaired autophagy, and dopaminergic terminal degeneration (PMID:32356558). In vitro studies demonstrate that loss of 5′‐phosphatase activity impairs synaptic vesicle recycling and endolysosomal homeostasis, and exacerbates deficits when combined with LRRK2 G2019S (PMID:29054882; PMID:39117637; PMID:37072173).

No robust conflicting evidence has been reported; some intronic variants occur at higher frequency in controls and may represent modifiers rather than primary causes. The aggregate of genetic segregation, independent replication, and consistent functional concordance supports a Strong clinical validity classification.

Key Take-home: SYNJ1 biallelic loss‐of‐function variants cause autosomal recessive young‐onset Parkinson disease via impaired phosphoinositide phosphatase activity and synaptic vesicle trafficking, underpinning their diagnostic utility in early‐onset parkinsonism.

References

• Molecular genetics & genomic medicine • 2018 • SYNJ1 gene associated with neonatal onset of neurodegenerative disorder and intractable seizure. PMID:29179256
• Advanced biology • 2022 • Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India. PMID:35810474
• Human mutation • 2013 • The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. PMID:23804563
• Human mutation • 2013 • Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. PMID:23804577
• Neurogenetics • 2014 • PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family. PMID:24816432
• Brain : a journal of neurology • 2016 • Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline. PMID:27435091
• The Journal of neuroscience • 2017 • Parkinson's Disease-Associated LRRK2 Hyperactive Kinase Mutant Disrupts Synaptic Vesicle Trafficking in Ventral Midbrain Neurons. PMID:29054882
• Human molecular genetics • 2020 • Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice. PMID:32356558
• NPJ Parkinson's disease • 2024 • Parkinson's disease gene, Synaptojanin1, dysregulates the surface maintenance of the dopamine transporter. PMID:39117637
• medRxiv : the preprint server for health sciences • 2024 • Are rare heterozygous SYNJ1 variants associated with Parkinson's disease? PMID:38853950

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