This study aimed to elucidate the genetic causes underlying early-onset Parkinsonism (EOP) in a consanguineous Iranian family. To attain this, homozygosity mapping and whole-exome sequencing were performed. As a result, a homozygous mutation (c.773G>A; p.Arg258Gln) lying within the NH2-terminal Sac1-like inositol phosphatase domain of polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1), which has been implicated in the regulation of endocytic traffic at synapses, was identified as the disease-segregating mutation. This mutation impaired the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro. We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. Our finding not only opens new avenues of investigation in the synaptic dysfunction mechanisms associated with Parkinsonism, but also suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.
In this study we identified a mutation in synaptojanin 1 as a cause of early-onset progressive Parkinsonism and generalized seizures. This mutation impaired the phosphatase activity of synaptojanin 1 against its Sac1 domain substrates in vitro, suggesting that defects in phosphoinositide metabolism at synapse may play an important role in the development of Parkinsonism. This finding opens new avenues of investigation in the field of Parkinson research and suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.