These authors contributed equally to this work.
The Sac1 Domain of SYNJ1 Identified Mutated in a Family with Early-Onset Progressive Parkinsonism with Generalized Seizures
Article first published online: 19 JUL 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 9, pages 1200–1207, September 2013
How to Cite
Krebs, C. E., Karkheiran, S., Powell, J. C., Cao, M., Makarov, V., Darvish, H., Di Paolo, G., Walker, R. H., Shahidi, G. A., Buxbaum, J. D., De Camilli, P., Yue, Z. and Paisán-Ruiz, C. (2013), The Sac1 Domain of SYNJ1 Identified Mutated in a Family with Early-Onset Progressive Parkinsonism with Generalized Seizures. Hum. Mutat., 34: 1200–1207. doi: 10.1002/humu.22372
Communicated by Christine Van Broeckhoven
Contract grant sponsors: The Parkinson's Disease Foundation; Ellison Foundation; Michael J. Fox Foundation; NIH/NINDS (R01NS060809, R01NS072359, R37NS036251, R01NS079388); NIMH (R01MH095797).
- Issue published online: 14 AUG 2013
- Article first published online: 19 JUL 2013
- Accepted manuscript online: 26 JUN 2013 01:06PM EST
- Manuscript Accepted: 18 JUN 2013
- Manuscript Received: 17 APR 2013
- The Parkinson's Disease Foundation
- Ellison Foundation
- Michael J. Fox Foundation
- NIH/NINDS. Grant Numbers: R01NS060809, R01NS072359, R37NS036251, R01NS079388
- NIMH. Grant Number: R01MH095797
- homozygosity mapping;
- whole-exome sequencing;
- autosomal recessive Parkinsonism
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.