SYNJ1 – early-onset Parkinson disease 20

Early-onset Parkinson disease 20 (PARK20) is an autosomal recessive parkinsonism defined by onset in the third decade with bradykinesia, rigidity and poor levodopa response, often accompanied by atypical features such as dystonia, dementia, drooling and seizures. Biallelic loss-of-function variants in SYNJ1 (HGNC:11503), encoding the dual Sac1/5-phosphatase synaptojanin-1, underlie PARK20, implicating disrupted phosphoinositide metabolism in dopaminergic pathways. Affected individuals typically present with early dyskinesia, facial dystonia and progressive cognitive impairment.

The pathogenic association was first reported in a consanguineous Iranian family where two siblings with early-onset parkinsonism harboured homozygous c.773G>A (p.Arg258Gln) in SYNJ1 and segregated with disease (PMID:23804563). Two subsequent independent pedigrees—one Sicilian and a third Italian family—each showed the same homozygous p.Arg258Gln change in two affected siblings, totaling four probands across three families (PMID:24816432). These data confirm autosomal recessive inheritance and robust segregation of a recurrent missense allele.

Genetic evidence includes recurrent homozygous missense variants clustered in the N-terminal Sac1 domain, particularly p.Arg258Gln, absent from population databases and not observed in heterozygotes. No truncating SYNJ1 alleles have been reported in PARK20, consistent with a hypomorphic missense mechanism. Segregation in multiple kindreds and absence in controls support a high genetic validity.

Functional assays demonstrate that p.Arg258Gln abolishes Sac1 phosphatase activity against phosphoinositide substrates in vitro, impairing synaptic vesicle uncoating and endocytosis in neuronal cultures (PMID:23804563). LRRK2 G2019S neurons and SYNJ1 haploinsufficient models exhibit convergent synaptic vesicle trafficking defects, linking SYNJ1 loss to known PD pathways (PMID:29054882).

Animal models corroborate the mechanism: synj1 zebrafish mutants show fatigue of ribbon synapses and postural deficits (PMID:33584199), while Synj1+/- mice develop age-dependent dopaminergic terminal degeneration, α-synuclein accumulation and autophagy impairment in the midbrain (PMID:32356558). These in vivo findings mirror human PARK20 phenotypes and substantiate a loss-of-function pathogenesis.

In summary, robust genetic and experimental data support a Strong ClinGen classification for the SYNJ1–early-onset Parkinson disease 20 association. Four probands in three families with concordant segregation, recurrent p.Arg258Gln alleles and concordant functional deficits establish high clinical validity. Key take-home: autosomal recessive SYNJ1 mutations disrupt synaptic phosphoinositide metabolism, defining PARK20 as a distinct early-onset parkinsonism with diagnostic and therapeutic implications.

References

• Human Mutation • 2013 • The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. PMID:23804563
• Neurogenetics • 2014 • PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family. PMID:24816432
• 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
• Frontiers in Molecular Neuroscience • 2020 • Temporal Vestibular Deficits in synaptojanin 1 (synj1) Mutants. PMID:33584199

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