This report describes Parkinson disease 20 (PARK20), which is an early-onset subtype of Parkinson disease; PARK20 exhibits autosomal recessive inheritance. The human gene implicated in this disease is SYNJ1 (Synaptojanin 1), a inositol 5-phosphatase that has a role in clathrin-mediated endocytosis and synaptic vesicle dynamics; SYNJ1 appears to affect synaptic transmission and membrane trafficking. There is a single orthologous gene in Drosophila, Dmel\Synj for which classical loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Synj is also orthologous to a second human gene, SYNJ2. SYNJ1 is also implicated in a form of early infantile epileptic encephalopathy (MIM:617389).
The human SYNJ1 gene has not been introduced in flies.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R228Q in the fly Synj gene (corresponds to R258Q in the human SYNJ1 gene; designated SynjRQ). This variant is in the SAC1 domain of the enzyme; based on work in Drosophila, it does not appear to affect the presynaptic vesicle recycling function of SYNJ1. Rather, it is concluded that the Synj1-SAC1 domain drives autophagosome biogenesis within synapses, independent from and in parallel to the role of Synaptojanin in endocytosis.
Animals homozygous or hemizygous for loss-of-function alleles of Dmel\Synj typically die in the larval stage; mutant larvae exhibit defects in active synaptic vesicle endocytosis, neurophysiology defects, and locomotor defects. Genetic and physical interactions of Dmel\Synj have been described; see below and in the Synj gene report.
[updated Sep. 2017 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
[PARKINSON DISEASE 20, EARLY-ONSET; PARK20](https://omim.org/entry/615530)
[SYNAPTOJANIN 1; SYNJ1](https://omim.org/entry/604297)
Parkinson disease 20 is characterized by young adult-onset of parkinsonism. Additional features may include seizures, cognitive decline, abnormal eye movements, and dystonia (summary by Krebs et al., 2013, pubmed:23804563; and Quadri et al., 2013, pubmed:23804577) [from MIM:615530; 2017.09.22]
Parkinson disease-20 (PARK20) is caused by homozygous mutation in the SYNJ1 gene [from MIM:615530; 2017.09.22]
SYNJ1 is a inositol 5-phosphatase which has a role in clathrin-mediated endocytosis; it may affect synaptic transmission and membrane trafficking. [Gene Cards, SYNJ1; 2017.09.22]
The endocytic membrane-trafficking pathway and disruption of synaptic vesicle endocytosis appear to play major roles in the risk of Parkinson disease. A substantial amount of genetic variation in PD and parkinsonism has been associated with vesicle trafficking via endosomal gene alterations. (Bandres-Ciga et al., 2019, pubmed:30675927; Nguyen et al., 2019, pubmed:30509690). Relevant genes include DNAJC6 (see FBhh0000594, FBhh0000593), SYNJ1 (see FBhh0000626), GAK (see FBhh0000593) and SH3GL2, which are linked to clathrin-coated vesicles, and VPS35 (see FBhh0000030) and DNAJC13 (see FBhh0001155), which participate in recycling components from the endosomes to the Golgi. In addition, LRRK2 (see FBhh0000011) and PLA2G6 (see FBhh0000243, FBhh0000232) have been shown to interact with genes involved in endocytic membrane trafficking.
Synaptojanin-1 is a polyphosphoinositide phosphatase that has a role in clathrin-coated pit and synaptic vesicle dynamics (Perera et al., 2006, pubmed:17158794; summary by Hardies et al., 2016, pubmed:27435091). [from MIM:604297; 2017.09.22]
Many to one: 2 human to 1 Drosophila. The second human gene is SYNJ2.
High-scoring ortholog of human SYNJ1; moderate-scoring ortholog of SYNJ2 (1 Drosophila to 2 human). Dmel\Synj shares 39-46% identity and 55-62% similarity with the human genes.
