SYNJ1

Summary

SYNJ1 (synaptojanin 1, HGNC:11503) is a protein-coding gene on chromosome 21q22.11, encoding Synaptojanin-1 (O43426). Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate.

This gene encodes a phosphoinositide phosphatase that regulates levels of membrane phosphatidylinositol-4,5-bisphosphate. As such, expression of this enzyme may affect synaptic transmission and membrane trafficking. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8867 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 1,568 total — 42 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 122
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_203446

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11503
Approved symbol	SYNJ1
Name	synaptojanin 1
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Aliases	INPP5G, PARK20
Ensembl gene	ENSG00000159082
Ensembl biotype	protein_coding
OMIM	604297
Entrez	8867

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000357345, ENST00000382491, ENST00000418301, ENST00000429236, ENST00000438952, ENST00000456084, ENST00000464778, ENST00000467445, ENST00000630077, ENST00000674204, ENST00000674308, ENST00000674351, ENST00000902244, ENST00000902245, ENST00000963072

RefSeq mRNA: 4 — MANE Select: NM_203446 NM_001160302, NM_001160306, NM_003895, NM_203446

CCDS: CCDS33540, CCDS54483, CCDS54484

Canonical transcript exons

ENST00000674351 — 33 exons

Exon	Start	End
ENSE00001043068	32643410	32643457
ENSE00001594835	32699838	32700105
ENSE00001600415	32641896	32641966
ENSE00001604255	32653288	32653366
ENSE00001611870	32681496	32681648
ENSE00001615936	32685748	32685917
ENSE00001619493	32676332	32676355
ENSE00001628547	32645646	32645789
ENSE00001640014	32678645	32678801
ENSE00001659680	32634861	32634884
ENSE00001660563	32686978	32687074
ENSE00001661250	32666433	32666573
ENSE00001672736	32639671	32639779
ENSE00001677991	32673340	32673531
ENSE00001692306	32664913	32665071
ENSE00001692945	32701961	32702047
ENSE00001694887	32644968	32645006
ENSE00001695277	32670288	32670372
ENSE00001706423	32656687	32656902
ENSE00001709732	32628763	32631801
ENSE00001710675	32688306	32688367
ENSE00001711441	32694228	32694311
ENSE00001716834	32642095	32642133
ENSE00001719041	32684038	32684119
ENSE00001723440	32695057	32695282
ENSE00001768777	32638908	32639125
ENSE00001798903	32727946	32728013
ENSE00001800575	32646393	32646602
ENSE00002276949	32665943	32666135
ENSE00003510649	32657716	32657872
ENSE00003560819	32657003	32657120
ENSE00003584985	32650184	32650346
ENSE00003633787	32726772	32726917

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.2099 / max 516.7301, expressed in 1599 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190202	4.9787	1380
190204	1.9083	659
190203	0.7989	333
190201	0.2526	96
190205	0.1354	64
190198	0.0836	37
190200	0.0524	1

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	98.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.52	gold quality
pons	UBERON:0000988	98.24	gold quality
substantia nigra pars compacta	UBERON:0001965	98.18	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.60	gold quality
middle temporal gyrus	UBERON:0002771	97.52	gold quality
superior frontal gyrus	UBERON:0002661	96.50	gold quality
endothelial cell	CL:0000115	96.34	gold quality
postcentral gyrus	UBERON:0002581	96.29	gold quality
superior vestibular nucleus	UBERON:0007227	96.23	gold quality
parietal lobe	UBERON:0001872	96.20	gold quality
orbitofrontal cortex	UBERON:0004167	96.11	gold quality
primary visual cortex	UBERON:0002436	95.76	gold quality
CA1 field of hippocampus	UBERON:0003881	95.69	gold quality
entorhinal cortex	UBERON:0002728	95.60	gold quality
occipital lobe	UBERON:0002021	95.33	gold quality
lateral globus pallidus	UBERON:0002476	94.78	gold quality
prefrontal cortex	UBERON:0000451	94.65	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.44	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.28	gold quality
secondary oocyte	CL:0000655	93.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.81	gold quality
frontal cortex	UBERON:0001870	93.47	gold quality
pigmented layer of retina	UBERON:0001782	93.24	gold quality
cerebral cortex	UBERON:0000956	93.05	gold quality
medulla oblongata	UBERON:0001896	92.97	gold quality
oocyte	CL:0000023	92.94	gold quality
neocortex	UBERON:0001950	92.82	gold quality
cerebellar vermis	UBERON:0004720	92.58	gold quality
ventral tegmental area	UBERON:0002691	91.97	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-110499	no	1305.57
E-ANND-3	no	4.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ZNF699

miRNA regulators (miRDB)

208 targeting SYNJ1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595

Literature-anchored findings (GeneRIF, showing 28)

• SYNJ1 gene is linked to bipolar disorder (PMID:15261714)
• Data show that in the presence of SNX9, synaptojanin-1 is able to colocalize with distinct ACK1 containing vesicles. (PMID:16137687)
• Trisomy for SYNJ1 in Down syndrome is functionally linked to the enlargement of early endosomes. (PMID:22511594)
• Synj1 reduction ameliorates AD-associated behavioral and synaptic deficits, providing evidence that Synj1 and, more generally, phosphoinositide metabolism may be promising therapeutic targets (PMID:23115165)
• Findings suggest that SYNJ1 mutation is responsible for the early-onset Parkinsonism phenotype probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. (PMID:23804563)
• Results indicate that SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. (PMID:23804577)
• a novel mechanism by which reduction of a PI(4,5)P2-degrading enzyme, synj1, improves amyloid-induced neuropathology and behavior deficits through accelerating cellular Abeta clearance. (PMID:24052255)
• This review presented that SYNJ1 in recessive forms of juvenile parkinsonism. (PMID:24262182)
• the clinical progression of the Italian siblings with SYNJ1-related early-onset atypical parkinsonism seems to present a more severe progression in the early stages (PMID:24532203)
• Our data suggest that the previously reported Arg258Gln mutation in SYNJ1 is not a frequent cause of Parkinson disease (PMID:24609975)
• This is the third reported family with autosomal recessive, early-onset parkinsonism associated with the SYNJ1 p.Arg258Gln mutation. This work contributes to the definition of the genetic and clinical aspects of PARK20. (PMID:24816432)
• This study demonstrated that SYNJ1 was significantly higher in Down syndrome and correlated with several measures of Abeta. SYNJ1 was higher in down syndrome with Alzheimer disease and significantly higher than SYNJ1 in sporadic Alzheimer disease. (PMID:24927707)
• Studying PD genes as a network regulating synaptic activity could bring insight into understanding the neuropathological processes of PD and help identify new genes at fault in this devastating disorder. (PMID:25302295)
• Mutations in SYNJ1 gene do not play a major role in early-onset or familial PD in our population. (PMID:26149920)
• SYNJ1 deficiency leads to early onset refractory seizures and progressive neurological decline. (PMID:27435091)
• This study identified a novel homozygous missense mutation (c.1376C > G, p.Arg459Pro) in SYNJ1 in an ARJP family from eastern India. (PMID:27496670)
• Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses (PMID:28231468)
• Thus, synaptojanin is essential for macroautophagy within presynaptic terminals, coupling protein turnover with synaptic vesicle cycling and linking presynaptic-specific autophagy defects to Parkinson’s disease. (PMID:28331029)
• Excess of rare putative functional variants at SYNJ1 in schizophrenia. (PMID:28421333)
• Data indicate that Synj1 plays a crucial role in regulating the homeostasis and functions of early endosomal compartments in different cell types, and highlight defective cellular pathways in PARK20. In addition, they strengthen the link between endosomal trafficking and Parkinson’s disease. (PMID:29515184)
• SYNJ1 contributes to memory deficits in the aging hippocampus in all forms of Alzheimer’s disease. (PMID:29874583)
• A novel mutation in the C-terminal domain identified in family members with juvenile PD and epilepsy. (PMID:30187305)
• A novel homozygous SYNJ1 mutation in two siblings with typical Parkinson’s disease. (PMID:31751865)
• TGFbeta receptor endocytosis and Smad signaling require synaptojanin1, PI3K-C2alpha-, and INPP4B-mediated phosphoinositide conversions. (PMID:31913757)
• The lipid phosphatase Synaptojanin 1 undergoes a significant alteration in expression and solubility and is associated with brain lesions in Alzheimer’s disease. (PMID:32493451)
• A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations. (PMID:33349335)
• Asparagine endopeptidase cleaves synaptojanin 1 and triggers synaptic dysfunction in Parkinson’s disease. (PMID:33677035)
• alpha-Synuclein induces deficiency in clathrin-mediated endocytosis through inhibiting synaptojanin1 expression. (PMID:37788328)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	synj1	ENSDARG00000025011
mus_musculus	Synj1	ENSMUSG00000022973
rattus_norvegicus	Synj1	ENSRNOG00000002051
drosophila_melanogaster	CG9784	FBGN0030761
drosophila_melanogaster	CG6805	FBGN0034179
drosophila_melanogaster	Synj	FBGN0034691
drosophila_melanogaster	sp3	FBGN0038890
caenorhabditis_elegans		WBGENE00006763
caenorhabditis_elegans	sac-2	WBGENE00012353

Paralogs (13): SYNJ2 (ENSG00000078269), FIG4 (ENSG00000112367), OCRL (ENSG00000122126), INPP5K (ENSG00000132376), INPP5E (ENSG00000148384), INPPL1 (ENSG00000165458), INPP5D (ENSG00000168918), SH2D1A (ENSG00000183918), INPP5J (ENSG00000185133), SH2D1B (ENSG00000198574), INPP5F (ENSG00000198825), INPP5B (ENSG00000204084), SACM1L (ENSG00000211456)

Protein

Protein identifiers

Synaptojanin-1 — O43426 (reviewed: O43426)

Alternative names: Synaptic inositol 1,4,5-trisphosphate 5-phosphatase 1

All UniProt accessions (7): O43426, A0A0D9SGJ6, C9J1Z6, C9JW66, H7BZ56, H7BZC2, J3KPK1

UniProt curated annotations — full annotation on UniProt →

Function. Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. Has a role in clathrin-mediated endocytosis. Hydrolyzes PIP2 bound to actin regulatory proteins resulting in the rearrangement of actin filaments downstream of tyrosine kinase and ASH/GRB2.

Subunit / interactions. Interacts with ASH/GRB2. Interacts with PACSIN1, PACSIN2 and PACSIN3. Interacts with AMPH, SH3GL1, SH3GL2 and SH3GL3. Interacts with MYO1E (via SH3 domain). Interacts with BIN1 and DNM1. Interacts with EPS15.

Subcellular location. Cytoplasm. Perinuclear region.

Disease relevance. Parkinson disease 20, early-onset (PARK20) [MIM:615530] An early-onset form of Parkinson disease, a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. PARK20 is characterized by young adult-onset of parkinsonism. Additional features may include seizures, cognitive decline, abnormal eye movements, and dystonia. The disease is caused by variants affecting the gene represented in this entry. Developmental and epileptic encephalopathy 53 (DEE53) [MIM:617389] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE53 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Interacts with EPS15 (a clathrin coat-associated protein) via a C-terminal domain containing three Asn-Pro-Phe (NPF) repeats. The C-terminal proline-rich region mediates binding to a variety of SH3 domain-containing proteins including AMPH, SH3GL1, SH3GL2 and SH3GL3.

Similarity. Belongs to the synaptojanin family. In the central section; belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.

Isoforms (4)

UniProt ID	Names	Canonical?
O43426-1	1, Synaptojanin-170	yes
O43426-2	2, Synaptojanin-145
O43426-4	3
O43426-5	4

RefSeq proteins (4): NP_001153774, NP_001153778, NP_003886, NP_982271* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000300	IPPc	Domain
IPR000504	RRM_dom	Domain
IPR002013	SAC_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR015047	SYNJ1/2_RRM	Domain
IPR034971	SYNJ1_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR046985	IP5	Family

Pfam: PF02383, PF08952, PF22669

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + phosphate (RHEA:22764)

UniProt features (87 total): strand 19, helix 15, modified residue 13, sequence variant 9, compositionally biased region 7, region of interest 6, splice variant 6, turn 4, repeat 3, domain 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2VJ0	X-RAY DIFFRACTION	1.6
1W80	X-RAY DIFFRACTION	1.9
7A0V	X-RAY DIFFRACTION	2.3
7A17	X-RAY DIFFRACTION	2.73
2DNR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43426-F1	68.09	0.34

Antibody-complex structures (SAbDab): 2 — 7A0V, 7A17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13): 820, 830, 1053, 1150, 1178, 1201, 1220, 1292, 1318, 1345, 1349, 1551, 1565

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-1855183	Synthesis of IP2, IP, and Ins in the cytosol
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-1430728	Metabolism
R-HSA-1483249	Inositol phosphate metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-199991	Membrane Trafficking
R-HSA-556833	Metabolism of lipids
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 534 (showing top): RNGTGGGC_UNKNOWN, GOBP_LIPID_MODIFICATION, GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_COGNITION, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_BEHAVIOR, GOBP_ENDOSOME_ORGANIZATION, GOBP_VESICLE_LOCALIZATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_VESICLE_ORGANIZATION, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, MODULE_563, GOBP_POLYOL_METABOLIC_PROCESS

GO Biological Process (15): phosphatidylinositol biosynthetic process (GO:0006661), neurotransmitter transport (GO:0006836), learning (GO:0007612), synaptic vesicle priming (GO:0016082), synaptic vesicle uncoating (GO:0016191), inositol phosphate metabolic process (GO:0043647), phosphatidylinositol metabolic process (GO:0046488), phosphatidylinositol dephosphorylation (GO:0046856), synaptic vesicle endocytosis (GO:0048488), synaptic vesicle transport (GO:0048489), membrane organization (GO:0061024), positive regulation of endosome organization (GO:1904980), lipid metabolic process (GO:0006629), endocytosis (GO:0006897), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092)

GO Molecular Function (13): RNA binding (GO:0003723), phosphatidylinositol-3-phosphate phosphatase activity (GO:0004438), phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity (GO:0004439), phosphatidylinositol phosphate 5-phosphatase activity (GO:0034595), phosphatidylinositol phosphate 4-phosphatase activity (GO:0034596), phosphatidylinositol-4-phosphate phosphatase activity (GO:0043812), phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity (GO:0043813), phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity (GO:0052629), inositol-1,4,5-trisphosphate 5-phosphatase activity (GO:0052658), nucleic acid binding (GO:0003676), protein binding (GO:0005515), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791)

GO Cellular Component (11): cytoplasm (GO:0005737), cytosol (GO:0005829), vesicle membrane (GO:0012506), membrane (GO:0016020), membrane coat (GO:0030117), clathrin coat of coated pit (GO:0030132), terminal bouton (GO:0043195), perinuclear region of cytoplasm (GO:0048471), synaptic membrane (GO:0097060), presynapse (GO:0098793), microtubule (GO:0005874)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Inositol phosphate metabolism	2
Metabolism	2
PI Metabolism	1
Membrane Trafficking	1
Phospholipid metabolism	1
Metabolism of lipids	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
phosphatidylinositol metabolic process	2
transport	2
phosphatidylinositol monophosphate phosphatase activity	2
phosphatidylinositol phosphate 5-phosphatase activity	2
phosphatidylinositol phosphate phosphatase activity	2
phosphatidylinositol-3,5-bisphosphate phosphatase activity	2
binding	2
synapse	2
biosynthetic process	1
learning or memory	1
synaptic vesicle exocytosis	1
protein-containing complex assembly	1
exocytic process	1
synaptic vesicle endocytosis	1
clathrin coat disassembly	1
organophosphate metabolic process	1
polyol metabolic process	1
phosphorus metabolic process	1
phospholipid dephosphorylation	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
cellular process	1
establishment of vesicle localization	1
synaptic vesicle localization	1
cellular component organization	1
endosome organization	1
positive regulation of organelle organization	1
regulation of endosome organization	1
primary metabolic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
phosphatidylinositol phosphate biosynthetic process	1
nucleic acid binding	1
phosphatidylinositol-4,5-bisphosphate phosphatase activity	1
phosphatidylinositol phosphate 4-phosphatase activity	1
phosphatidylinositol-3-phosphate biosynthetic process	1

Protein interactions and networks

STRING

1988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SYNJ1	AMPH	P49418	995
SYNJ1	BIN1	O00499	994
SYNJ1	SH3GL2	Q99962	993
SYNJ1	SH3GL1	Q99961	950
SYNJ1	SH3GL3	Q99963	929
SYNJ1	ITSN1	Q15811	929
SYNJ1	DNAJC6	O75061	907
SYNJ1	GRB2	P29354	906
SYNJ1	DNM1	Q05193	867
SYNJ1	EPS15	P42566	863
SYNJ1	ITSN2	Q9NZM3	861
SYNJ1	WASL	O00401	839
SYNJ1	PACSIN1	Q9BY11	833
SYNJ1	SNAP91	O60641	825
SYNJ1	SNX9	Q9Y5X1	801

IntAct

78 interactions, top by confidence:

A	B	Type	Score
SNX9	SYNJ1	psi-mi:“MI:0914”(association)	0.790
SNX9	SYNJ1	psi-mi:“MI:0407”(direct interaction)	0.790
SYNJ1	SNX9	psi-mi:“MI:0915”(physical association)	0.790
AMPH	BIN1	psi-mi:“MI:0914”(association)	0.740
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
SYNJ1	AMPH	psi-mi:“MI:0407”(direct interaction)	0.670
AMPH	SYNJ1	psi-mi:“MI:0407”(direct interaction)	0.670
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
SNX9	WASL	psi-mi:“MI:0914”(association)	0.640
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
SYNJ1	ITSN1	psi-mi:“MI:0915”(physical association)	0.570
SYNJ1	Fnbp4	psi-mi:“MI:0407”(direct interaction)	0.560
SORBS2	SYNJ1	psi-mi:“MI:0407”(direct interaction)	0.560
	SYNJ1	psi-mi:“MI:0407”(direct interaction)	0.560
SYNJ1	Pacsin1	psi-mi:“MI:0407”(direct interaction)	0.560
Grb2	SYNJ1	psi-mi:“MI:0407”(direct interaction)	0.560
SYNJ1	SH3GL2	psi-mi:“MI:0407”(direct interaction)	0.560
SYNJ1		psi-mi:“MI:0407”(direct interaction)	0.560
Pacsin1	SYNJ1	psi-mi:“MI:0407”(direct interaction)	0.560
ALKBH2	ODAD3	psi-mi:“MI:0914”(association)	0.530

BioGRID (111): SYNJ1 (Affinity Capture-MS), SYNJ1 (Affinity Capture-MS), SYNJ1 (Proximity Label-MS), SYNJ1 (Affinity Capture-MS), SYNJ1 (Affinity Capture-MS), SYNJ1 (Affinity Capture-MS), SYNJ1 (Affinity Capture-MS), SYNJ1 (Proximity Label-MS), SYNJ1 (Affinity Capture-MS), SYNJ1 (Proximity Label-MS), SYNJ1 (Affinity Capture-Western), SYNJ1 (Far Western), SYNJ1 (Proximity Label-MS), SYNJ1 (Proximity Label-MS), SYNJ1 (Proximity Label-MS)

ESM2 similar proteins: A1L244, A4VCH0, A6QL88, F4JIN3, G5ECL2, I1R9A6, I1S489, O13943, O14127, O15056, O18964, O43001, O43426, O55207, O60162, P0C9C0, P0C9C1, P0C9C2, P32368, P34203, P34260, P40559, P46580, P50942, P91133, Q00942, Q09600, Q12271, Q18891, Q55AW9, Q5R921, Q60V75, Q62910, Q6GM29, Q7X911, Q7XVN7, Q8CHC4, Q8RW97, Q8TGA2, Q94A27

Diamond homologs: A1L244, A4VCH0, A6QL88, A8E7C5, O14127, O15056, O18964, O43001, O43426, O55207, O60162, P32368, P42837, P50942, Q12271, Q55AW9, Q5R921, Q62910, Q6GM29, Q7X911, Q7Z9H9, Q8CDA1, Q8CHC4, Q96328, Q9C5G5, Q9D2G5, Q9EP69, Q9ES21, Q9NTJ5, Q9W0I6, Q9Y2H2, A0FI79, A8MR21, D3ZGS3, G5ECL2, O14306, O76745, O80560, P32019, P34370

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
EPHB2	down-regulates	SYNJ1	phosphorylation
CDK5	“down-regulates activity”	SYNJ1	phosphorylation
“AP-2 complex”	“up-regulates activity”	SYNJ1	binding
SYNJ1	“up-regulates activity”	MYO1E	binding
PAK6	“up-regulates activity”	SYNJ1	phosphorylation
PAK4	“up-regulates activity”	SYNJ1	phosphorylation
PAK5	“up-regulates activity”	SYNJ1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
trans-Golgi Network Vesicle Budding	5	25.9×	6e-05
Clathrin-mediated endocytosis	14	24.4×	1e-13
Recycling pathway of L1	5	22.9×	9e-05
Golgi Associated Vesicle Biogenesis	5	20.4×	1e-04
Cargo recognition for clathrin-mediated endocytosis	9	19.2×	8e-08
L1CAM interactions	6	14.7×	1e-04
Membrane Trafficking	16	12.1×	2e-11
Potential therapeutics for SARS	5	11.7×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle endocytosis	6	43.9×	1e-06
endocytosis	10	16.1×	3e-07
neuron projection development	5	10.3×	6e-03
actin filament organization	5	10.1×	7e-03
intracellular protein transport	7	7.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1568 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	14
Uncertain significance	734
Likely benign	677
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069960	NM_003895.4(SYNJ1):c.12_13dup (p.Trp5fs)	Pathogenic
1070684	NM_203446.3(SYNJ1):c.3438dup (p.Ala1147fs)	Pathogenic
1074545	NM_203446.3(SYNJ1):c.1093dup (p.Tyr365fs)	Pathogenic
1075587	NM_203446.3(SYNJ1):c.1279_1280dup (p.Met428fs)	Pathogenic
1076901	NM_203446.3(SYNJ1):c.3865C>T (p.Arg1289Ter)	Pathogenic
1206765	NM_203446.3(SYNJ1):c.289C>T (p.Arg97Ter)	Pathogenic
1323673	NM_203446.3(SYNJ1):c.631C>T (p.Arg211Ter)	Pathogenic
1361698	NM_203446.3(SYNJ1):c.295del (p.Thr99fs)	Pathogenic
1422351	NM_203446.3(SYNJ1):c.345del (p.Ile116fs)	Pathogenic
1456091	NM_203446.3(SYNJ1):c.748C>T (p.Arg250Ter)	Pathogenic
1457606	NM_203446.3(SYNJ1):c.-12G>T	Pathogenic
1457746	NM_203446.3(SYNJ1):c.1696_1699del (p.Pro566fs)	Pathogenic
1458746	NC_000021.8:g.(?34072128)(34074377_?)del	Pathogenic
1954917	NM_203446.3(SYNJ1):c.2125C>T (p.Arg709Ter)	Pathogenic
2030810	NM_203446.3(SYNJ1):c.2619dup (p.Glu874Ter)	Pathogenic
2062038	NM_203446.3(SYNJ1):c.1066C>T (p.Gln356Ter)	Pathogenic
2095036	NM_203446.3(SYNJ1):c.3656dup (p.Thr1220fs)	Pathogenic
2122161	NM_203446.3(SYNJ1):c.2896_2897del (p.Ile966fs)	Pathogenic
2424784	NC_000021.8:g.(?34011198)(34100351_?)del	Pathogenic
265687	NM_203446.3(SYNJ1):c.741_745del (p.Gln248fs)	Pathogenic
2936446	NM_203446.3(SYNJ1):c.1480C>T (p.Arg494Ter)	Pathogenic
2945224	NM_003895.4(SYNJ1):c.8del (p.Lys3fs)	Pathogenic
2946094	NM_203446.3(SYNJ1):c.1213C>T (p.Gln405Ter)	Pathogenic
3248177	NC_000021.9:g.(?32727926)(32728060_?)del	Pathogenic
3451988	NM_203446.3(SYNJ1):c.3296_3297dup (p.Ala1100fs)	Pathogenic
3750614	NM_203446.3(SYNJ1):c.2242_2243del (p.Gln748fs)	Pathogenic
3752740	NM_203446.3(SYNJ1):c.3526C>T (p.Gln1176Ter)	Pathogenic
3755311	NM_203446.3(SYNJ1):c.2665_2666del (p.Gln889fs)	Pathogenic
393356	NM_203446.3(SYNJ1):c.1259G>C (p.Arg420Pro)	Pathogenic
393358	NM_203446.3(SYNJ1):c.2411G>A (p.Trp804Ter)	Pathogenic

SpliceAI

5839 predictions. Top by Δscore:

Variant	Effect	Δscore
21:32631797:TTTAC:T	acceptor_gain	1.0000
21:32631798:TTAC:T	acceptor_gain	1.0000
21:32631799:TAC:T	acceptor_gain	1.0000
21:32631799:TACC:T	acceptor_loss	1.0000
21:32631800:AC:A	acceptor_gain	1.0000
21:32631801:CC:C	acceptor_gain	1.0000
21:32631802:C:CC	acceptor_gain	1.0000
21:32631802:CT:C	acceptor_loss	1.0000
21:32639666:CCTA:C	donor_loss	1.0000
21:32639667:CTA:C	donor_loss	1.0000
21:32639668:TACC:T	donor_loss	1.0000
21:32639669:ACCTT:A	donor_loss	1.0000
21:32639775:ATCGT:A	acceptor_gain	1.0000
21:32639776:TCGT:T	acceptor_gain	1.0000
21:32639777:CGT:C	acceptor_gain	1.0000
21:32639777:CGTC:C	acceptor_gain	1.0000
21:32641892:CTA:C	donor_loss	1.0000
21:32641894:A:AC	donor_gain	1.0000
21:32641895:C:CC	donor_gain	1.0000
21:32641895:CCGGT:C	donor_gain	1.0000
21:32641963:CGTC:C	acceptor_gain	1.0000
21:32641964:GTC:G	acceptor_gain	1.0000
21:32641965:TC:T	acceptor_gain	1.0000
21:32641966:CC:C	acceptor_gain	1.0000
21:32641966:CCTG:C	acceptor_loss	1.0000
21:32641967:C:CC	acceptor_gain	1.0000
21:32641967:C:CG	acceptor_loss	1.0000
21:32641968:T:C	acceptor_loss	1.0000
21:32641973:C:CT	acceptor_gain	1.0000
21:32641974:A:T	acceptor_gain	1.0000

AlphaMissense

8568 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000097716 (21:32712467 T>C), RS1000113626 (21:32727935 G>A,T), RS1000132731 (21:32638714 C>T), RS1000135228 (21:32683036 T>C), RS1000138931 (21:32635654 C>T), RS1000145024 (21:32709151 C>T), RS1000180237 (21:32675635 C>T), RS1000235517 (21:32675349 C>A,T), RS1000238158 (21:32684688 T>C), RS1000297141 (21:32721748 T>C,G), RS1000301546 (21:32715025 T>C), RS1000335285 (21:32722414 T>C), RS1000348151 (21:32640735 T>C), RS1000404884 (21:32722054 G>A), RS1000406550 (21:32667698 T>A)

Disease associations

OMIM: gene MIM:604297 | disease phenotypes: MIM:615530, MIM:617389, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
early-onset Parkinson disease 20	Strong	Autosomal recessive
developmental and epileptic encephalopathy, 53	Strong	Autosomal recessive
young-onset Parkinson disease	Supportive	Autosomal recessive
atypical juvenile parkinsonism	Supportive	Autosomal recessive
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AR

Mondo (6): early-onset Parkinson disease 20 (MONDO:0014233), developmental and epileptic encephalopathy, 53 (MONDO:0033362), developmental and epileptic encephalopathy, 1 (MONDO:0010632), young-onset Parkinson disease (MONDO:0017279), atypical juvenile parkinsonism (MONDO:0018321), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (2): Atypical juvenile parkinsonism (Orphanet:391411), Young-onset Parkinson disease (Orphanet:2828)

HPO phenotypes

122 total (30 of 122 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000338	Hypomimic face
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000605	Supranuclear gaze palsy
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000651	Diplopia
HP:0000658	Eyelid apraxia
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000713	Agitation
HP:0000716	Depression
HP:0000717	Autism
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010485_18	Platelet reactivity in response to clopidogrel treatment	4.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523136 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,797 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1201303	PYRVINIUM	4	1,797

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Inositol polyphosphate phosphatases

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	IC50	1000	nM	PYRVINIUM

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
sodium arsenite	increases abundance, increases expression	2
Formaldehyde	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases expression	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4420452	Binding	Inhibition of C-Myc/DDK-tagged human recombinant SYNJ1 expressed in HEK293T cells assessed as reduction in 5’-phosphatase activity incubated for 8 mins using fluorescently-labeled PI(3,4)P2 probe and Tapp1 PH-domain as detector protein by f	Synaptojanin-2 inhibitors for use in the treatment of cancer

Cellosaurus cell lines

9 cell lines: 4 induced pluripotent stem cell, 3 cancer cell line, 2 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2HZ	Abcam HeLa SYNJ1 KO	Cancer cell line	Female
CVCL_D3YD	WIBRe001-A-48	Embryonic stem cell	Female
CVCL_D3YE	WIBRe001-A-47	Embryonic stem cell	Female
CVCL_E1HU	WTC11 AAVS1-NEUROG2 SYNJ1-KO	Induced pluripotent stem cell	Male
CVCL_E4UZ	KOLF2.1J SYNJ1 71.0kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E7MP	KOLF2.1J SYNJ1 R219Q SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7MQ	KOLF2.1J SYNJ1 R219Q SNV/WT	Induced pluripotent stem cell	Male
CVCL_TR33	HAP1 SYNJ1 (-) 1	Cancer cell line	Male
CVCL_TR34	HAP1 SYNJ1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07267065	PHASE1	NOT_YET_RECRUITING	AAV2-hAADC for Parkinson’s Disease (PDCS-01)
NCT04033393	Not specified	UNKNOWN	Dual-task Performance in Young-onset PD
NCT04722198	Not specified	UNKNOWN	Effects of Lactobacillus Plantarum PS128 on Symptoms of Early-onset Parkinson’s Disease: a Pilot Study