A Novel SYNJ1 Mutation in a Tunisian Family with Juvenile Parkinson’s Disease Associated with Epilepsy

Abstract

Mutations in SYNJ1 gene have been described in few families with juvenile atypical Parkinson disease (PD). This gene encodes for "Synaptojanin 1," an enzyme playing a major role in the phosphorylation and the recycling of synaptic vesicles. In this study, we report two siblings, from a consanguineous Tunisian family, presenting juvenile PD. Both siblings developed mild Parkinsonism at 16 and 21 years old respectively. One patient had generalized tonic-clonic seizures since the age of 7 years. There was no evidence of sleep or autonomic dysfunctions and psychiatric disorders in both cases, but they developed a moderate cognitive impairment. They kept a good respond to low doses of levodopa treatment with no dyskinesia or motor fluctuations. We designed an NGS-based screening of 22 currently most prevalent parkinsonism-associated genes. Genetic study revealed a novel compound heterozygous mutation (p.Leu1406Phefs*42 and p.Lys1321Glu) in SYNJ1 gene. The p.Lys1321Glu mutation is located in the proline-rich domain and leads to a significant change in the 3D structure of the protein (RMS = 12.58 Å). The p.Leu1406Phefs*42 mutation disrupt the AP2 binding sites and subsequently disable synaptic and vesicle endocytic recycling in neurons. This is the first report of mutation in the C-terminal domain of Synaptojanin 1 protein causing mild juvenile PD with generalized seizures, cognitive impairment, and good respond to levodopa treatment.

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium

“…MAGMA analyses also identified SYNJ1 as significant in this association. Mutations in SYNJ1 are linked to Parkinson’s disease, but its association with platelet reactivity has not been previously described 41,42 . Regression models adjusted for CYP2C19*2 also demonstrated a suggestive association with SYNJ1 , and for NR3C2 , known to be associated with schizophrenia 37 …”

Hsc70 Ameliorates the Vesicle Recycling Defects Caused by Excess α-Synuclein at Synapses

“…Furthermore, GWAS studies have identified genetic variations and altered expression of GAK, the ubiquitously expressed version of neuronal-specific auxilin, among the top risk factors for familial PD across multiple populations worldwide (Pankratz et al, 2009;Tseng et al, 2013;Nagle et al, 2016). Several mutations in synaptojanin-1 have also been linked to early onset Parkinsonism (Krebs et al, 2013;Chen et al, 2015;Ben Romdhan et al, 2018). Transgenic mice carrying one of the synaptojanin-1 mutations (R258Q) in the Sac domain accumulated CCVs within their synapses and exhibited impaired synaptic vesicle recycling, as well as motor deficits and increased death (Cao et al, 2017).…”

Hsc70 Ameliorates the Vesicle Recycling Defects Caused by Excess α-Synuclein at Synapses

“…Furthermore, GWAS studies have identified genetic variations and increased expression of GAK, the ubiquitously expressed Hsc70 co-chaperone, amongst the top risk factors for familial PD across multiple populations worldwide (Pankratz et al, 2009;Tseng et al, 2013;Nagle et al, 2016). Several mutations in synaptojanin 1 have also been linked to early onset Parkinsonism (Krebs et al, 2013;Chen et al, 2015;Ben Romdhan et al, 2018). Transgenic mice carrying one of the synaptojanin I mutations (R258Q) in the Sac domain accumulated CCVs within their synapses and exhibited impaired synaptic vesicle recycling, as well as motor deficits and increased death (Cao et al, 2017).…”