The Sac1 Domain of SYNJ 1 Identified Mutated in a Family with Early‐Onset Progressive P arkinsonism with Generalized Seizures
| Autor: | Catharine E. Krebs, Pietro De Camilli, Gholam Ali Shahidi, Gilbert Di Paolo, Hossein Darvish, Joseph D. Buxbaum, Zhenyu Yue, Ruth H. Walker, Vladimir Makarov, Siamak Karkheiran, Mian Cao, James C. Powell, Coro Paisán-Ruiz |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Genotype Phosphatase Genes Recessive Consanguinity Biology medicine.disease_cause Polymorphism Single Nucleotide Article Parkinsonian Disorders Polyphosphoinositide Phosphatase Genetics medicine Humans Exome Age of Onset Phylogeny Genetics (clinical) Exome sequencing Mutation Parkinsonism Brain Sequence Analysis DNA medicine.disease Disease gene identification Phenotype Phosphoric Monoester Hydrolases HEK293 Cells Epilepsy Generalized Female Sequence Alignment |
| Zdroj: | Human Mutation. 34:1200-1207 |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.22372 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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