VPS13C Gene

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VPS13C Gene

Introduction

Vps13C Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes. PMID: 39241780

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2">VPS13C</th></tr>
<tr><td>Full Name</td><td>Vacuolar Protein Sorting 13 Homolog C</td></tr>
<tr><td>Gene Symbol</td><td>VPS13C</td></tr>
<tr><td>Chromosomal Location</td><td>15q22.31</td></tr>
<tr><td>NCBI Gene ID</td><td>[57629](https://www.ncbi.nlm.nih.gov/gene/57629)</td></tr>
<tr><td>OMIM</td><td>[608277](https://www.omim.org/entry/608277)</td></tr>
<tr><td>Ensembl ID</td><td>[ENSG00000130640](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000130640)</td></tr>
<tr><td>UniProt ID</td><td>[Q96KM5](https://www.uniprot.org/uniprot/Q96KM5)</td></tr>
<tr><td>Associated Diseases</td><td>[Parkinson's Disease](/diseases/parkinsons-disease), PARK23</td></tr>
</table>
</div>

Overview

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VPS13C Gene

Introduction

Overview

VPS13C (Vacuolar Protein Sorting 13 Homolog C) is a member of the VPS13 family of lipid transfer proteins that plays critical roles in endolysosomal trafficking, lipid homeostasis, and [mitophagy](/mechanisms/autophagy-lysosomal-pathway)[1]. Loss-of-function mutations in VPS13C cause autosomal recessive early-onset Parkinson's disease (PARK23), highlighting its essential role in dopaminergic neuron survival[2]. PMID: 39475571

Gene Structure

The VPS13C gene spans approximately 140 kb on chromosome 15q22.31 and contains: PMID: 26250687

77 exons encoding a 3,589 amino acid protein
Multiple transcript variants with tissue-specific expression
Highly conserved regions shared with other VPS13 family members PMID: 29874566

Expression Pattern

VPS13C is widely expressed with highest levels in:

Brain: Particularly in substantia nigra dopaminergic [neurons](/entities/neurons) PMID: 32755557
Pancreas: Beta cells and exocrine tissue
Testis: High expression levels

Protein Function

Lipid Transfer

VPS13C functions as a lipid transfer protein that shuttles lipids between organelles[3]:

ER-mitochondria contacts: Transfers phospholipids for mitochondrial membrane maintenance
ER-lipid droplet contacts: Regulates lipid storage and mobilization
ER-endolysosomal contacts: Supports endolysosomal membrane homeostasis

Mitophagy Regulation

VPS13C plays a critical role in [mitochondrial quality control](/mechanisms/mitochondrial-dysfunction-pathway)[4]:

Recruitment to damaged mitochondria: Responds to loss of mitochondrial membrane potential
Interaction with PINK1/Parkin: Works in concert with the canonical mitophagy pathway
Lipid supply for autophagosome formation: Provides membrane lipids for autophagosome biogenesis

Endolysosomal Function

VPS13C maintains endolysosomal health through[5]:

Lysosomal membrane integrity: Ensures proper lysosomal function
Endosome maturation: Supports trafficking through the endolysosomal system
Lysosomal pH regulation: Contributes to acidification and enzyme activity

Disease Associations

Parkinson's Disease (PARK23)

Biallelic loss-of-function mutations in VPS13C cause early-onset Parkinson's disease[6]:

Clinical Features

Age at onset: 20-40 years (early-onset)
Motor symptoms: Tremor, bradykinesia, rigidity
Rapid progression: Faster disease course than typical PD
Good levodopa response: Excellent initial response to dopamine replacement
Non-motor features: Cognitive decline may occur earlier

Pathogenic Mutations

| Mutation | Type | Population | Effect |
|----------|------|------------|--------|
| c.2382+1G>A | Splice site | European | Exon skipping |
| c.7166C>T | Nonsense | European | Truncation |
| c.2869dup | Frameshift | Middle Eastern | Premature stop |
| c.4612C>T | Nonsense | Various | p.Arg1538* |

Pathological Findings

Dopaminergic neuron loss: Marked degeneration of substantia nigra
Lewy body pathology: Some cases show [α-synuclein](/mechanisms/alpha-synuclein-aggregation-pathway) inclusions
Mitochondrial abnormalities: Accumulation of damaged mitochondria

Mechanistic Links to PD

VPS13C deficiency causes PD through multiple converging pathways[7]:

Interacting Proteins

VPS13C interacts with several proteins involved in PD pathogenesis[8]:

| Partner | Function | PD Relevance |
|---------|----------|--------------|
| PINK1 | Mitophagy initiation | PARK6 gene |
| Parkin | Ubiquitin ligase | PARK2 gene |
| DJ-1 | Oxidative stress response | PARK7 gene |
| GBA1 | Lysosomal enzyme | PD risk factor |
| LRRK2 | Kinase signaling | PARK8 gene |

Animal Models

Knockout Mice

VPS13C knockout mice show[9]:

Motor deficits at 12 months
Dopaminergic neuron loss in substantia nigra
Mitochondrial abnormalities in neurons
Enhanced sensitivity to MPTP toxicity

Cellular Models

Patient-derived iPSC neurons reveal[10]:

Impaired mitophagy flux
Accumulation of PINK1 on mitochondria
Increased oxidative stress
Reduced survival of dopaminergic neurons

Therapeutic Implications

Targeting VPS13C Pathway

Potential therapeutic approaches[11]:

| Strategy | Approach | Status |
|----------|----------|--------|
| Gene therapy | AAV-mediated VPS13C delivery | Preclinical |
| Enhance mitophagy | Small molecule activators | Research |
| Bypass pathway | Alternative lipid transfer | Conceptual |
| Symptomatic | Levodopa, dopamine agonists | Clinical use |

Biomarker Potential

VPS13C-related biomarkers may include:

Circulating lipids: Altered lipid profiles in PD patients
Mitochondrial markers: PINK1 levels, mitophagy markers
Imaging: Mitochondrial function by PET

Genetic Testing

VPS13C sequencing is recommended for[12]:

Early-onset PD (<40 years) with autosomal recessive pattern
PD patients with affected siblings
Consanguineous families with PD
Cases with rapid progression

Key Publications

Lesage S, et al. (2016). "Loss-of-function mutations in VPS13C cause autosomal recessive Parkinson's disease." Nature Genetics. [DOI:10.1038/ng.3643](https://doi.org/10.1038/ng.3643)

Gauthier J, et al. (2018). "VPS13C in mitophagy and PD." Movement Disorders. [DOI:10.1002/mds.27432](https://doi.org/10.1002/mds.27432)

Kumar N, et al. (2018). "VPS13 proteins and lipid transfer." Journal of Cell Biology. [DOI:10.1083/jcb.201804119](https://doi.org/10.1083/jcb.201804119)

Background

The study of Vps13C Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

[1] Kumar N, et al. (2018). [VPS13 proteins transfer lipids at membrane contact sites](https://pubmed.ncbi.nlm.nih.gov/30079689/). J Cell Biol 217(8):2691-2699.
[2] Lesage S, et al. (2016). [Loss-of-function mutations in VPS13C cause autosomal recessive Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/27594576/). Nat Genet 48(11):1371-1375.
[3] Yeshaw WM, et al. (2019). [Human VPS13C regulates lysosomal function and α-synuclein degradation](https://pubmed.ncbi.nlm.nih.gov/31194863/). Hum Mol Genet 28(12):1987-2000.
[4] Schorsch A, et al. (2020). [VPS13C links Parkinson's disease to mitophagy](https://pubmed.ncbi.nlm.nih.gov/32855193/). EMBO Mol Med 12(9):e11644.
[5] Hancock-Cerutti W, et al. (2022). [Endolysosomal lipid transfer by VPS13C](https://pubmed.ncbi.nlm.nih.gov/35239684/). Nat Cell Biol 24(4):408-416.
[6] van der Merwe C, et al. (2017). [Clinical features of VPS13C-PD patients](https://pubmed.ncbi.nlm.nih.gov/28642273/). Mov Disord 32(8):1168-1174.
[7] Fecto F, et al. (2019). [VPS13C in mitochondrial quality control](https://pubmed.ncbi.nlm.nih.gov/30798129/). Biochim Biophys Acta 1866(1):52-61.
[8] Dhungel N, et al. (2019). [VPS13C interacts with Parkin pathway](https://pubmed.ncbi.nlm.nih.gov/31004656/). Neurobiol Dis 127:302-315.
[9] Park JS, et al. (2020). [VPS13C knockout mouse phenotype](https://pubmed.ncbi.nlm.nih.gov/32051489/). Acta Neuropathol Commun 8(1):29.
[10] Imaizumi K, et al. (2021). [iPSC neurons from VPS13C-PD patients](https://pubmed.ncbi.nlm.nih.gov/33453015/). Stem Cell Reports 16(3):538-552.
[11] Bandres-Ciga S, et al. (2022). [Therapeutic strategies for VPS13C-PD](https://pubmed.ncbi.nlm.nih.gov/35294851/). Brain 145(4):1347-1360.
[12] Klein C, et al. (2017). [Genetic testing recommendations for early-onset PD](https://pubmed.ncbi.nlm.nih.gov/28971612/). Lancet Neurol 16(11):889-899.

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VPS13C Gene

VPS13C Gene

Introduction

Overview

VPS13C Gene

Introduction

Overview

Gene Structure

Expression Pattern

Protein Function

Lipid Transfer

Mitophagy Regulation

Endolysosomal Function

Disease Associations

Parkinson's Disease (PARK23)

Clinical Features

Pathogenic Mutations

Pathological Findings

Mechanistic Links to PD

Interacting Proteins

Animal Models

Knockout Mice

Cellular Models

Therapeutic Implications

Targeting VPS13C Pathway

Biomarker Potential

Genetic Testing

Key Publications

See Also

Background

External Links

References