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The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures.

Human mutation | Sep 15, 2013

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.

Pubmed ID: 23804563 RIS Download

Mesh terms: Adult | Age of Onset | Brain | Consanguinity | Epilepsy, Generalized | Exome | Female | Genes, Recessive | Genotype | HEK293 Cells | Humans | Male | Parkinsonian Disorders | Phosphoric Monoester Hydrolases | Phylogeny | Polymorphism, Single Nucleotide | Sequence Alignment | Sequence Analysis, DNA

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Associated grants

  • Agency: NIMH NIH HHS, Id: R01MH095797
  • Agency: NINDS NIH HHS, Id: R01 NS072359
  • Agency: NIDA NIH HHS, Id: P30 DA018343
  • Agency: NINDS NIH HHS, Id: R01 NS060809
  • Agency: NINDS NIH HHS, Id: R01NS079388
  • Agency: NINDS NIH HHS, Id: R01 NS079388
  • Agency: NINDS NIH HHS, Id: R01NS060809
  • Agency: NINDS NIH HHS, Id: R37NS036251
  • Agency: NIMH NIH HHS, Id: R01 MH095797
  • Agency: NINDS NIH HHS, Id: R37 NS036251
  • Agency: NINDS NIH HHS, Id: R01 NS056049
  • Agency: NINDS NIH HHS, Id: R01NS072359
  • Agency: NINDS NIH HHS, Id: R01 NS060123

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