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EPG5
ectopic P-granules 5 autophagy tethering factor
The EPG5 gene provides instructions for a protein that plays a key role in autophagy, a cellular recycling process, and in the immune system's response to infections. EPG5 encodes a protein essential for the interaction between autophagosomes and lysosomes, enabling the breakdown and recycling of cellular components.
EPG5 is located on the long (q) arm of chromosome 18, at band 18q12.3-q21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The EPG5 gene, or ectopic P-granules 5 autophagy tethering factor, is crucial for normal cellular function. It provides the genetic blueprint for a protein involved in autophagy, a fundamental cellular process for waste removal and recycling. Additionally, the EPG5 protein contributes to the body's defence mechanisms against infections.
Understanding the EPG5 gene's role helps in comprehending conditions linked to its dysfunction, particularly those affecting cellular waste management and immune responses.
What the gene does
The protein produced from the EPG5 gene is critical for a process called autophagy. Autophagy is the cell's mechanism for breaking down and recycling old or unneeded cellular components, including damaged organelles and certain proteins. This process is particularly important when cells need to conserve energy or clear out waste materials.
Specifically, the EPG5 protein facilitates the interaction between autophagosomes, which are compartments that collect material to be recycled, and lysosomes, which are cellular structures containing enzymes that break down these materials. This interaction is vital for the efficient transfer and degradation of cellular waste. Beyond its role in recycling, the EPG5 protein also assists the cell in recognising and responding to pathogens like bacteria and viruses. It helps transport microbial components within cells, allowing them to engage with immune proteins and trigger an immune response to fight infection.
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Chromosome location
The EPG5 gene is situated on chromosome 18, one of the 23 pairs of chromosomes in humans. Its specific location is within the 18q12.3-q21.1 region. This designation indicates its position on the long (q) arm of chromosome 18, between bands 12.3 and 21.1.
Protein structure
The EPG5 protein is a large protein composed of 2579 amino acids. Its structure includes several distinct regions, such as various disordered regions. Specifically, there are disordered regions found at amino acids 1-46, 92-132, and 535-564. Additionally, a coiled coil domain is present between amino acids 1607 and 1633. These structural features are integral to the protein's function in cellular processes.
Key variants
Genetic variations, or variants, in the EPG5 gene can affect the function of the EPG5 protein. These variants can range from single nucleotide changes to larger deletions or insertions within the gene sequence. Depending on their nature and location, EPG5 variants can lead to a protein that is non-functional, partially functional, or produced in insufficient amounts.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.102del | p.Ser35fs | Pathogenic | ★★☆☆ | Vici syndrome |
c.1576C>T | p.Arg526Ter | Pathogenic | ★★☆☆ | Vici syndrome |
c.2449del | p.Ser817fs | Pathogenic/Likely pathogenic | ★★☆☆ | Vici syndrome |
c.3148C>T | p.Gln1050Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Vici syndrome |
c.3200del | p.Leu1067fs | Pathogenic/Likely pathogenic | ★★☆☆ | Vici syndrome |
c.3881G>A | p.Trp1294Ter | Pathogenic/Likely pathogenic | ★★☆☆ | EPG5-related disorders |
c.6541G>T | p.Glu2181Ter | Pathogenic | ★★☆☆ | Vici syndrome |
c.6724del | p.Met2242fs | Pathogenic | ★★☆☆ | Vici syndrome |
c.1187dup | p.Tyr396Ter | Pathogenic | ★☆☆☆ | Vici syndrome |
c.3132_3133dup | p.Leu1045fs | Pathogenic | ★☆☆☆ | Vici syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the EPG5 gene are primarily associated with Vici syndrome. Vici syndrome is a rare, severe multisystem disorder that affects various parts of the body, including the brain, immune system, heart, skin, and eyes. This condition often results from EPG5 gene mutations that lead to a shortened or non-functional protein, impairing autophagy and immune responses.
No disease links recorded for this gene in our reference set.
UK clinical status
The EPG5 gene is part of several gene panels used within the NHS Genomic Medicine Service. It is included in panels related to Clefting, Congenital myopathy, COVID-19 research, DDG2P, Dilated Cardiomyopathy and conduction defects, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), Paediatric or syndromic cardiomyopathy (R135), Primary immunodeficiency or monogenic inflammatory bowel disease (R15), Undiagnosed metabolic disorders, and Vici Syndrome and other autophagy disorders. Its presence on these panels indicates its recognised clinical relevance in the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the EPG5 gene?
The EPG5 gene provides instructions for a protein crucial for autophagy, a cellular recycling process. It helps combine waste-collecting autophagosomes with lysosomes for breakdown and also assists the immune system in detecting and responding to infections.
What condition is most commonly associated with EPG5 gene variants?
Variants in the EPG5 gene are most commonly associated with Vici syndrome. This is a severe, rare condition affecting multiple organ systems due to impaired cellular waste management and immune function.
How does EPG5 contribute to the immune system?
The EPG5 protein helps the immune system by transporting molecules from foreign invaders, such as bacteria and viruses, within cells. This allows these molecules to interact with specific immune system proteins, triggering a response to fight the infection.
References
- Piano Mortari E, Folgiero V, Marcellini V. The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity. Autophagy. 2018. PMID: 29130391
- Hori I, Otomo T, Nakashima M. Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. Scientific reports. 2017. PMID: 28615637
- Baron O, Boudi A, Dias C. Stall in Canonical Autophagy-Lysosome Pathways Prompts Nucleophagy-Based Nuclear Breakdown in Neurodegeneration. Current biology : CB. 2017. PMID: 29174892
- Wang Z, Miao G, Xue X. The Vici Syndrome Protein EPG5 Is a Rab7 Effector that Determines the Fusion Specificity of Autophagosomes with Late Endosomes/Lysosomes. Molecular cell. 2016. PMID: 27588602
- Cullup T, Kho AL, Dionisi-Vici C. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature genetics. 2013. PMID: 23222957