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From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences
Damla Aygun1, Didem Yücel Yılmaz1
1Department of Pediatric Metabolism, Institute of Child Health, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
International Journal of Molecular Sciences
|June 26, 2025
Summary
A novel VPS51 gene variant causes severe neurometabolic disease by disrupting vesicular trafficking and autophagy. This leads to impaired cellular homeostasis and altered mitochondrial metabolism in affected individuals.
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Neuroscience
Background:
- Vesicular trafficking and autophagy are crucial for cellular homeostasis and implicated in metabolic and neurometabolic diseases.
- Genetic defects in these pathways can lead to severe developmental and neurological impairments.
- The GARP/EARP complex, involving VPS51, regulates Golgi-associated retrograde protein transport.
Purpose of the Study:
- To investigate the molecular and cellular effects of a novel VPS51 gene variant in two siblings with a severe neurometabolic disorder.
- To elucidate the impact of VPS51 dysfunction on vesicular trafficking, autophagy, and mitochondrial function.
- To characterize the proteomic changes associated with this novel genetic variation.
Main Methods:
- Genetic analysis to identify the VPS51 variant (c.1511C>T; p.Thr504Met).
- RNA and protein analysis in patient-derived fibroblasts, including mRNA expression, Western blotting, and comparative proteomics.
- Live-cell confocal microscopy to assess organelle interactions, specifically mitochondria-lysosome contact sites.
Main Results:
- The novel VPS51 variant led to decreased VPS51 mRNA and protein levels, alongside altered expression of autophagy-related genes (LC3B, p62, RAB7A, TBC1D15).
- Proteomic analysis identified 585 differentially expressed proteins, revealing disruptions in vesicular trafficking, lysosomal function, and mitochondrial metabolism (downregulated β-oxidation/oxidative phosphorylation, upregulated glycolysis/lipid synthesis).
- Increased mitochondria-lysosome contact sites were observed in patient fibroblasts, indicating impaired organelle communication due to VPS51 dysfunction.
Conclusions:
- The novel VPS51 variant significantly impacts intracellular transport, autophagy, and cellular metabolism, contributing to the observed neurometabolic disorder.
- VPS51 dysfunction disrupts the balance between catabolic and anabolic pathways, affecting mitochondrial function.
- This study provides novel insights into the pathophysiology of VPS51-related disorders and highlights the importance of organelle communication in maintaining cellular health.
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