VPS35 Gene - VPS35 Retromer Complex Component
Genetic and Functional Insights into VPS35: Role in Parkinson's Disease and Retromer-Mediated Protein Sorting
Gene Information Card
| Symbol | VPS35 |
|---|---|
| Full Name | VPS35 retromer complex component |
| Gene Type | protein coding |
| Chromosomal Location | 16q11.2 |
| NCBI Gene ID | 55737 ncbi.nlm.nih.gov/gene/55737 |
| Ensembl ID | ENSG00000083312 |
| UniProt ID | Q96QK1 |
| OMIM ID | 601501 |
| HGNC ID | 13487 |
| Aliases | FLJ11856, MEM3, PARK17 |
Description
The VPS35 gene encodes a core component of the retromer complex, which is essential for endosomal protein sorting and recycling of transmembrane receptors. VPS35 is ubiquitously expressed and plays a critical role in neuronal function. Mutations in VPS35, particularly the p.Asp620Asn variant, are associated with autosomal dominant Parkinson's disease (PARK17). The protein is involved in multiple cellular processes including autophagy, synaptic plasticity, and mitochondrial homeostasis.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Parkinson's disease 17 (PARK17) | Dominant-negative effect of p.Asp620Asn mutation leading to impaired retromer function and altered trafficking of dopamine receptors and other cargo | OMIM: 614203; ClinVar: pathogenic |
| Alzheimer's disease (potential modifier) | Reduced VPS35 expression may impair amyloid precursor protein (APP) trafficking, contributing to amyloid-beta accumulation | PubMed studies; not clinically validated |
| Neurodegeneration with brain iron accumulation (NBIA) (rare) | Loss-of-function mutations in VPS35 have been reported in atypical cases, but evidence is limited | Case reports; not widely confirmed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebral cortex) | ~30 nTPM | High |
| Testis | ~25 nTPM | High |
| Liver | ~20 nTPM | Medium |
| Kidney | ~18 nTPM | Medium |
| Heart | ~15 nTPM | Medium |
| Lung | ~12 nTPM | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | ~35 nTPM | Neuronal model; high expression |
| HeLa (cervical carcinoma) | ~28 nTPM | Common cell line; moderate-high |
| HEK293 (embryonic kidney) | ~25 nTPM | Used for functional studies |
| HepG2 (hepatocellular carcinoma) | ~20 nTPM | Liver-derived; moderate |
| A549 (lung carcinoma) | ~15 nTPM | Low-moderate |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Asp620Asn (c.1858G>A) | Missense | Rare (found in <0.1% of population) | Dominant-negative; impairs retromer function, leading to Parkinson's disease |
| p.Leu774Met (c.2320C>A) | Missense | Very rare | Uncertain significance; possibly benign |
| p.Arg524Trp (c.1570C>T) | Missense | Very rare | Uncertain significance; not clearly pathogenic |
| p.Pro316Ser (c.946C>T) | Missense | Very rare | Uncertain significance; reported in one PD case |
Mutation functional classification
Loss of Function (LOF)
Complete loss of VPS35 function is likely embryonic lethal in animal models; partial loss may contribute to neurodegeneration but is not the primary mechanism for PD.
Gain of Function (GOF)
No clear gain-of-function mechanism reported for VPS35 mutations.
Dominant Negative (DN)
The p.Asp620Asn mutation acts as a dominant-negative, disrupting retromer complex assembly and function, leading to impaired endosomal trafficking.
View complete mutation data：
Gene Ontology (GO)
| • protein binding | • retromer complex |
| • endosome to Golgi transport | • protein homodimerization activity |
| • intracellular protein transport | • regulation of autophagy |
| • synaptic vesicle recycling |
Pathways
• Retromer-mediated endosomal sorting
• Parkinson's disease pathway
• Endocytosis
• Autophagy
• Neurotrophin signaling
Protein Summary
VPS35 is a 796-amino acid protein that forms the core of the retromer complex along with VPS26 and VPS29. It functions as a scaffold for cargo recognition and recruitment of accessory proteins. The protein is highly conserved across species and is essential for endosome-to-Golgi retrieval of transmembrane receptors such as sortilin and cation-independent mannose-6-phosphate receptor. In neurons, VPS35 regulates AMPA receptor trafficking and mitochondrial dynamics. The pathogenic p.Asp620Asn mutation disrupts retromer function, leading to dopaminergic neuron degeneration.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| VPS35 Knockout HEK293 Cell Line | EDJ-KQ16107 | Human | 55737 | Details Get a Quote |
| VPS35L Knockout HEK293 Cell Line | EDJ-KQ16108 | Human | 57020 | Details Get a Quote |
| VPS35L Knockout HeLa Cell Line | EDJ-KQ46044 | Human | 57020 | Details Get a Quote |
| VPS35 Knockout A-549 Cell Line | EDJ-KQ47269 | Human | 55737 | Details Get a Quote |
| VPS35 Knockout HCT 116 Cell Line | EDJ-KQ47270 | Human | 55737 | Details Get a Quote |
| VPS35 Knockout HeLa Cell Line | EDJ-KQ47271 | Human | 55737 | Details Get a Quote |
| VPS35L Knockout A-549 Cell Line | EDJ-KQ47272 | Human | 57020 | Details Get a Quote |
| VPS35L Knockout HCT 116 Cell Line | EDJ-KQ47273 | Human | 57020 | Details Get a Quote |
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